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Ahmed J, Stephen B, Khawaja MR, Yang Y, Salih I, Barrientos-Toro E, Raso MG, Karp DD, Piha-Paul SA, Sood AK, Ng CS, Johnson A, Soliman PT, Meric-Bernstam F, Lu KH, Naing A. A phase I study of temsirolimus in combination with metformin in patients with advanced or recurrent endometrial cancer. Gynecol Oncol 2025; 193:73-80. [PMID: 39787747 DOI: 10.1016/j.ygyno.2024.12.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 12/23/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025]
Abstract
INTRODUCTION Molecular alterations in the PI3K/AKT and Ras/Raf/MEK/ERK pathways are frequently observed in patients with endometrial cancers. However, mTOR inhibitors, such as temsirolimus, have modest clinical benefits. In addition to inducing metabolic changes in cells, metformin activates AMPK, which in turn inhibits the mTOR pathway. In this phase 1 clinical trial we hypothesized that combining metformin with temsirolimus would potentiate the antitumor activity against advanced or recurrent endometrial cancer. METHODS The dose-expansion cohort used a Simon Minimax two-stage design. The objectives of the endometrial cancer expansion cohort were to evaluate the clinical tumor response, as indicated by the objective response and clinical benefit rates, as well as an ongoing safety assessment of the combination treatment. RESULTS Forty patients were enrolled in this study. The most common treatment-related adverse events (reported in 32 patients) were hypertriglyceridemia (n = 14), diarrhea (n = 13), mucositis (n = 13), anorexia (n = 12), and anemia (n = 10). The grade 3 adverse events were 2 instances each of anemia and thrombocytopenia and 1 instance each of mucositis, fatigue, weight loss, hypokalemia, hypophosphatemia, and increased aspartate aminotransferase and alanine transaminase levels. Among the 33 patients evaluable for response, objective response was seen in two (6 %; both partial responses), and 13 (39 %) patients had stable disease, including 11 for ≥4 months, representing a clinical benefit rate of 39 %. CONCLUSIONS The results of this single-center clinical trial showed that, in patients with advanced or recurrent endometrial cancer, metformin can be safely added to temsirolimus providing limited response without added safety concerns. CLINICAL TRIAL REGISTRATION NUMBER NCT01529593.
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Affiliation(s)
- Jibran Ahmed
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
| | - Bettzy Stephen
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Muhammad R Khawaja
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Yali Yang
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Israa Salih
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elizve Barrientos-Toro
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Maria Gabriela Raso
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Daniel D Karp
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sarina A Piha-Paul
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Chaan S Ng
- Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Amber Johnson
- Precision Oncology Decision Support, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Pamela T Soliman
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Karen H Lu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Aung Naing
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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Wang B, Cao X, Garcia-Mansfield K, Zhou J, Manousopoulou A, Pirrotte P, Wang Y, Wang LD, Feng M. Phosphoproteomic Profiling Reveals mTOR Signaling in Sustaining Macrophage Phagocytosis of Cancer Cells. Cancers (Basel) 2024; 16:4238. [PMID: 39766137 PMCID: PMC11674635 DOI: 10.3390/cancers16244238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 12/13/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Macrophage-mediated cancer cell phagocytosis has demonstrated considerable therapeutic potential. While the initiation of phagocytosis, facilitated by interactions between cancer cell surface signals and macrophage receptors, has been characterized, the mechanisms underlying its sustentation and attenuation post-initiation remain poorly understood. Methods: Through comprehensive phosphoproteomic profiling, we interrogated the temporal evolution of the phosphorylation profiles within macrophages during cancer cell phagocytosis. Results: Our findings reveal that activation of the mTOR pathway occurs following the initiation of phagocytosis and is crucial in sustaining phagocytosis of cancer cells. mTOR inhibition impaired the phagocytic capacity, but not affinity, of the macrophages toward the cancer cells by delaying phagosome maturation and impeding the transition between non-phagocytic and phagocytic states of macrophages. Conclusions: Our findings delineate the intricate landscape of macrophage phagocytosis and highlight the pivotal role of the mTOR pathway in mediating this process, offering valuable mechanistic insights for therapeutic interventions.
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Affiliation(s)
- Bixin Wang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Xu Cao
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Krystine Garcia-Mansfield
- Cancer and Cell Biology Division, Translational Genomics Institute, Phoenix, AZ 85004, USA
- Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Jingkai Zhou
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Antigoni Manousopoulou
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Patrick Pirrotte
- Cancer and Cell Biology Division, Translational Genomics Institute, Phoenix, AZ 85004, USA
- Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Yingyu Wang
- Center for Informatics, City of Hope, Duarte, CA 91010, USA
| | - Leo D. Wang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
- Department of Pediatrics, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Mingye Feng
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
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Trapani D, Scalia R, Giordano E, Castellano G, Doi G, Gaeta A, Pellizzari G, Carnevale Schianca A, Katrini J, D'Ambrosio S, Santoro C, Guidi L, Valenza C, Belli C, Gandini S, Russo A, Curigliano G. Interstitial lung disease in patients enrolled in early-phase clinical trials: the ILDE study. ESMO Open 2024; 9:103658. [PMID: 39096894 PMCID: PMC11345526 DOI: 10.1016/j.esmoop.2024.103658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 06/29/2024] [Accepted: 07/01/2024] [Indexed: 08/05/2024] Open
Abstract
BACKGROUND Interstitial lung disease (ILD) encompasses a heterogeneous group of disorders sharing pathophysiological inflammatory mechanisms, leading to parenchymal distortions. The prevalence of ILD with new cancer drugs is underreported: the identification of potential determinants is priority. MATERIALS AND METHODS ILDE is a retrospective study aimed at describing the clinical course and potential determinants of ILD in patients receiving experimental treatments. RESULTS We identified 226 eligible patients, of whom 5.3% (n = 12) had ILD. In five patients, the diagnosis was radiological, while seven patients had initial cough, dyspnea, fatigue or fever. ILD was graded as grade 1 (G1) in four, G2 in five and G3 in three patients. The first occurrence of ILD resolved completely in 50% of patients (n = 6/12). No patient had fatal ILD. Eight patients (66.7%) resumed the treatment after the first episode of ILD, while four patients (33.3%) had to discontinue the therapy. Five out of six patients had resolved the first ILD episode and then resumed treatment, experiencing a second ILD episode (n = 5/6; 83.3%). The second ILD event was G1 in three patients and G2 in two patients, resulting in three patients who eventually discontinued the treatment (n = 3/5; 60%). Correlation analysis showed a higher risk of ILD in older patients (P = 0.051), those who had received previous chest radiation therapy (P = 0.047) or those receiving antibody-drug conjugates (P = 0.006). In a survival analysis adjusted for immortal time bias, ILD was not independently prognostic (hazard ratio 0.50, 95% confidence interval 0.23-1.09, P = 0.082). CONCLUSIONS In ILDE, patients experiencing ILD had generally good outcomes, and many could resume the cancer treatments. Implementing best practices to prompt diagnosis and management of ILD is critical to treat a potentially severe adverse effect of new drugs, while not affecting patients' outcomes. Research efforts to identify risk factors is warranted, to implement risk-based monitoring schedules and develop ad hoc strategies to improve the cure rates of ILD.
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Affiliation(s)
- D Trapani
- Department of Oncology & Hemato-Oncology, University of Milan, Milan; Division of New Drugs & Early Drug Development, European Institute of Oncology, IRCCS, Milan
| | - R Scalia
- Department of Oncology & Hemato-Oncology, University of Milan, Milan; Division of New Drugs & Early Drug Development, European Institute of Oncology, IRCCS, Milan; Department of Surgical and Oncological Sciences, University of Palermo, Palermo
| | - E Giordano
- Department of Oncology & Hemato-Oncology, University of Milan, Milan; Division of New Drugs & Early Drug Development, European Institute of Oncology, IRCCS, Milan
| | - G Castellano
- Division of New Drugs & Early Drug Development, European Institute of Oncology, IRCCS, Milan
| | - G Doi
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - A Gaeta
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - G Pellizzari
- Department of Oncology & Hemato-Oncology, University of Milan, Milan; Division of New Drugs & Early Drug Development, European Institute of Oncology, IRCCS, Milan
| | - A Carnevale Schianca
- Department of Oncology & Hemato-Oncology, University of Milan, Milan; Division of New Drugs & Early Drug Development, European Institute of Oncology, IRCCS, Milan
| | - J Katrini
- Department of Oncology & Hemato-Oncology, University of Milan, Milan; Division of New Drugs & Early Drug Development, European Institute of Oncology, IRCCS, Milan
| | - S D'Ambrosio
- Department of Oncology & Hemato-Oncology, University of Milan, Milan; Division of New Drugs & Early Drug Development, European Institute of Oncology, IRCCS, Milan
| | - C Santoro
- Department of Oncology & Hemato-Oncology, University of Milan, Milan; Division of New Drugs & Early Drug Development, European Institute of Oncology, IRCCS, Milan
| | - L Guidi
- Department of Oncology & Hemato-Oncology, University of Milan, Milan; Division of New Drugs & Early Drug Development, European Institute of Oncology, IRCCS, Milan
| | - C Valenza
- Department of Oncology & Hemato-Oncology, University of Milan, Milan; Division of New Drugs & Early Drug Development, European Institute of Oncology, IRCCS, Milan
| | - C Belli
- Division of New Drugs & Early Drug Development, European Institute of Oncology, IRCCS, Milan
| | - S Gandini
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - A Russo
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - G Curigliano
- Department of Oncology & Hemato-Oncology, University of Milan, Milan; Division of New Drugs & Early Drug Development, European Institute of Oncology, IRCCS, Milan.
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Yang J, Butti R, Cohn S, Toffessi-Tcheuyap V, Mal A, Nguyen M, Stevens C, Christie A, Mishra A, Ma Y, Kim J, Abraham R, Kapur P, Hammer RE, Brugarolas J. Unconventional mechanism of action and resistance to rapalogs in renal cancer. Proc Natl Acad Sci U S A 2024; 121:e2310793121. [PMID: 38861592 PMCID: PMC11194491 DOI: 10.1073/pnas.2310793121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 04/25/2024] [Indexed: 06/13/2024] Open
Abstract
mTORC1 is aberrantly activated in renal cell carcinoma (RCC) and is targeted by rapalogs. As for other targeted therapies, rapalogs clinical utility is limited by the development of resistance. Resistance often results from target mutation, but mTOR mutations are rarely found in RCC. As in humans, prolonged rapalog treatment of RCC tumorgrafts (TGs) led to resistance. Unexpectedly, explants from resistant tumors became sensitive both in culture and in subsequent transplants in mice. Notably, resistance developed despite persistent mTORC1 inhibition in tumor cells. In contrast, mTORC1 became reactivated in the tumor microenvironment (TME). To test the role of the TME, we engineered immunocompromised recipient mice with a resistance mTOR mutation (S2035T). Interestingly, TGs became resistant to rapalogs in mTORS2035T mice. Resistance occurred despite mTORC1 inhibition in tumor cells and could be induced by coculturing tumor cells with mutant fibroblasts. Thus, enforced mTORC1 activation in the TME is sufficient to confer resistance to rapalogs. These studies highlight the importance of mTORC1 inhibition in nontumor cells for rapalog antitumor activity and provide an explanation for the lack of mTOR resistance mutations in RCC patients.
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Affiliation(s)
- Juan Yang
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
| | - Ramesh Butti
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
| | - Shannon Cohn
- Department of Pediatrics, Dell Medical School, University of Texas at Austin, Austin, TX78723
| | - Vanina Toffessi-Tcheuyap
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
| | - Arijit Mal
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
| | - Mylinh Nguyen
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX75390-8816
| | - Christina Stevens
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
| | - Alana Christie
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
| | - Akhilesh Mishra
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
| | - Yuanqing Ma
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
| | - Jiwoong Kim
- Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX75390-8821
| | - Robert Abraham
- Oncology R&D Group, Pfizer Worldwide Research and Development, San Diego, CA92121
| | - Payal Kapur
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX75390-9234
| | - Robert E. Hammer
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX75390-8816
| | - James Brugarolas
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
- Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX75390-8852
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Naseri B, Mardi A, Khosrojerdi A, Baghbani E, Aghebati-Maleki L, Hatami-Sadr A, Heris JA, Eskandarzadeh S, Kafshdouz M, Alizadeh N, Baradaran B. Everolimus treatment enhances inhibitory immune checkpoint molecules' expression in monocyte-derived dendritic cells. Hum Immunol 2024; 85:110798. [PMID: 38569354 DOI: 10.1016/j.humimm.2024.110798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/05/2024]
Abstract
BACKGROUND Antigen-specific T-cell immunity is provided by dendritic cells (DCs), which are specialized antigen-presenting cells. Furthermore, they establish a link between innate and adaptive immune responses. Currently, DC modification is a new approach for the therapy of several disorders. During solid organ transplantation, Everolimus, which is a mammalian target of rapamycin (mTOR) inhibitor, was initially utilized to suppress the immune system's functionality. Due to the intervention of Everolimus in various signaling pathways in cells and its modulatory properties on the immune system, this study aims to investigate the effect of treatment with Everolimus on the maturation and expression of immune checkpoint genes in monocyte-derived DCs. METHODS To isolate monocytes from PBMCs, the CD14 marker was used via the MACS method. Monocytes were cultured and induced to differentiate into monocyte-derived DCs by utilizing GM-CSF and IL-4 cytokines. On the fifth day, immature DCs were treated with Everolimus and incubated for 24 h. On the sixth day, the flow cytometry technique was used to investigate the effect of Everolimus on the phenotypic characteristics of DCs. In the end, the expression of immune checkpoint genes in both the Everolimus-treated and untreated DCs groups was assessed using the real-time PCR method. RESULTS The findings of this research demonstrated that the administration of Everolimus to DCs led to a notable rise in human leukocyte antigen (HLA)-DR expression and a decrease in CD11c expression. Furthermore, there was a significant increase in the expression of immune checkpoint molecules, namely CTLA-4, VISTA, PD-L1, and BTLA, in DCs treated with Everolimus. CONCLUSION The findings of this study show that Everolimus can target DCs and affect their phenotype and function in order to shift them toward a partially tolerogenic state. However, additional research is required to gain a comprehensive understanding of the precise impact of Everolimus on the activation status of DCs.
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Affiliation(s)
- Bahar Naseri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirhossein Mardi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arezou Khosrojerdi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Elham Baghbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | | | | | - Mahshid Kafshdouz
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nazila Alizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Nelson BE, Tsimberidou AM, Fu X, Fu S, Subbiah V, Sood AK, Rodon J, Karp DD, Blumenschein G, Kopetz S, Pant S, Piha-Paul SA. A Phase I Trial of Bevacizumab and Temsirolimus in Combination With Valproic Acid in Advanced Solid Tumors. Oncologist 2023; 28:1100-e1292. [PMID: 37311055 PMCID: PMC10712705 DOI: 10.1093/oncolo/oyad158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 05/07/2023] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND Preclinical models suggest synergy between anti-angiogenesis therapy, mammalian target of rapamycin (mTOR), and histone deacetylase inhibitors to promote anticancer activity. METHODS This phase I study enrolled 47 patients between April 2012 and 2018 and determined safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) when combining bevacizumab, temsirolimus, and valproic acid in patients with advanced cancer. RESULTS Median age of enrolled patients was 56 years. Patients were heavily pretreated with a median of 4 lines of prior therapy. Forty-five patients (95.7%) experienced one or more treatment-related adverse events (TRAEs). Grade 3 TRAEs were lymphopenia (14.9%), thrombocytopenia (8.5%), and mucositis (6.4%). Grade 4 TRAEs included lymphopenia (2.1%) and CNS cerebrovascular ischemia (2.1%). Six patients developed DLTs across 10 dose levels with grade 3 infection, rash, mucositis, bowel perforation, elevated lipase, and grade 4 cerebrovascular ischemia. The MTD was dose level 9 (bevacizumab 5 mg/kg days 1 and 15 intravenously (IV) plus temsirolimus 25 mg days 1, 8, 15, and 22 IV and valproic acid 5 mg/kg on days 1-7 and 15-21 per orally (PO)). Objective response rate (ORR) was 7.9% with confirmed partial response (PRs) in 3 patients (one each in parotid gland, ovarian, and vaginal cancers). Stable disease (SD) ≥+6 months was seen in 5 patients (13.1%). Clinical benefit state (CBR: PR + SD ≥+6 months) was 21%. CONCLUSION Combination therapy with bevacizumab, temsirolimus, and valproic acid was feasible, but there were numerous toxicities, which will require careful management for future clinical development (ClinicalTrials.gov Identifier: NCT01552434).
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Affiliation(s)
- Blessie Elizabeth Nelson
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Apostolia M Tsimberidou
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xueyao Fu
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Siqing Fu
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vivek Subbiah
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jordi Rodon
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Daniel D Karp
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - George Blumenschein
- Department of Thoracic and Head and Neck Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shubham Pant
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sarina A Piha-Paul
- Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Panwar V, Singh A, Bhatt M, Tonk RK, Azizov S, Raza AS, Sengupta S, Kumar D, Garg M. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct Target Ther 2023; 8:375. [PMID: 37779156 PMCID: PMC10543444 DOI: 10.1038/s41392-023-01608-z] [Citation(s) in RCA: 291] [Impact Index Per Article: 145.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/25/2023] [Accepted: 08/14/2023] [Indexed: 10/03/2023] Open
Abstract
The mammalian target of rapamycin (mTOR) is a protein kinase that controls cellular metabolism, catabolism, immune responses, autophagy, survival, proliferation, and migration, to maintain cellular homeostasis. The mTOR signaling cascade consists of two distinct multi-subunit complexes named mTOR complex 1/2 (mTORC1/2). mTOR catalyzes the phosphorylation of several critical proteins like AKT, protein kinase C, insulin growth factor receptor (IGF-1R), 4E binding protein 1 (4E-BP1), ribosomal protein S6 kinase (S6K), transcription factor EB (TFEB), sterol-responsive element-binding proteins (SREBPs), Lipin-1, and Unc-51-like autophagy-activating kinases. mTOR signaling plays a central role in regulating translation, lipid synthesis, nucleotide synthesis, biogenesis of lysosomes, nutrient sensing, and growth factor signaling. The emerging pieces of evidence have revealed that the constitutive activation of the mTOR pathway due to mutations/amplification/deletion in either mTOR and its complexes (mTORC1 and mTORC2) or upstream targets is responsible for aging, neurological diseases, and human malignancies. Here, we provide the detailed structure of mTOR, its complexes, and the comprehensive role of upstream regulators, as well as downstream effectors of mTOR signaling cascades in the metabolism, biogenesis of biomolecules, immune responses, and autophagy. Additionally, we summarize the potential of long noncoding RNAs (lncRNAs) as an important modulator of mTOR signaling. Importantly, we have highlighted the potential of mTOR signaling in aging, neurological disorders, human cancers, cancer stem cells, and drug resistance. Here, we discuss the developments for the therapeutic targeting of mTOR signaling with improved anticancer efficacy for the benefit of cancer patients in clinics.
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Affiliation(s)
- Vivek Panwar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173229, India
| | - Aishwarya Singh
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida, Uttar Pradesh, 201313, India
| | - Manini Bhatt
- Department of Biomedical Engineering, Indian Institute of Technology, Ropar, Punjab, 140001, India
| | - Rajiv K Tonk
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, 110017, India
| | - Shavkatjon Azizov
- Laboratory of Biological Active Macromolecular Systems, Institute of Bioorganic Chemistry, Academy of Sciences Uzbekistan, Tashkent, 100125, Uzbekistan
- Faculty of Life Sciences, Pharmaceutical Technical University, 100084, Tashkent, Uzbekistan
| | - Agha Saquib Raza
- Rajive Gandhi Super Speciality Hospital, Tahirpur, New Delhi, 110093, India
| | - Shinjinee Sengupta
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida, Uttar Pradesh, 201313, India.
| | - Deepak Kumar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173229, India.
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida, Uttar Pradesh, 201313, India.
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Alchahin AM, Tsea I, Baryawno N. Recent Advances in Single-Cell RNA-Sequencing of Primary and Metastatic Clear Cell Renal Cell Carcinoma. Cancers (Basel) 2023; 15:4734. [PMID: 37835428 PMCID: PMC10571653 DOI: 10.3390/cancers15194734] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 09/22/2023] [Accepted: 09/22/2023] [Indexed: 10/15/2023] Open
Abstract
Over the past two decades, significant progress has been made in the treatment of clear cell renal cell carcinoma (ccRCC), with a shift towards adopting new treatment approaches ranging from monotherapy to triple-combination therapy. This progress has been spearheaded by fundamental technological advancements that have allowed a deeper understanding of the various biological components of this cancer. In particular, the rapid commercialization of transcriptomics technologies, such as single-cell RNA-sequencing (scRNA-seq) methodologies, has played a crucial role in accelerating this understanding. Through precise measurements facilitated by these technologies, the research community has successfully identified and characterized diverse tumor, immune, and stromal cell populations, uncovering their interactions and pathways involved in disease progression. In localized ccRCC, patients have shown impressive response rates to treatment. However, despite the emerging findings and new knowledge provided in the field, there are still patients that do not respond to treatment, especially in advanced disease stages. One of the key challenges lies in the limited study of ccRCC metastases compared to localized cases. This knowledge gap may contribute to the relatively low survival rates and response rates observed in patients with metastatic ccRCC. To bridge this gap, we here delve into recent research utilizing scRNA-seq technologies in both primary and metastatic ccRCC. The goal of this review is to shed light on the current state of knowledge in the field, present existing treatment options, and emphasize the crucial steps needed to improve survival rates, particularly in cases of metastatic ccRCC.
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Affiliation(s)
| | | | - Ninib Baryawno
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, 10000-19999 Stockholm, Sweden; (A.M.A.); (I.T.)
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9
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Ali ES, Mitra K, Akter S, Ramproshad S, Mondal B, Khan IN, Islam MT, Sharifi-Rad J, Calina D, Cho WC. Recent advances and limitations of mTOR inhibitors in the treatment of cancer. Cancer Cell Int 2022; 22:284. [PMID: 36109789 PMCID: PMC9476305 DOI: 10.1186/s12935-022-02706-8] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 09/06/2022] [Indexed: 11/17/2022] Open
Abstract
The PI3K-Akt-mechanistic (formerly mammalian) target of the rapamycin (mTOR) signaling pathway is important in a variety of biological activities, including cellular proliferation, survival, metabolism, autophagy, and immunity. Abnormal PI3K-Akt-mTOR signalling activation can promote transformation by creating a cellular environment conducive to it. Deregulation of such a system in terms of genetic mutations and amplification has been related to several human cancers. Consequently, mTOR has been recognized as a key target for the treatment of cancer, especially for treating cancers with elevated mTOR signaling due to genetic or metabolic disorders. In vitro and in vivo, rapamycin which is an immunosuppressant agent actively suppresses the activity of mTOR and reduces cancer cell growth. As a result, various sirolimus-derived compounds have now been established as therapies for cancer, and now these medications are being investigated in clinical studies. In this updated review, we discuss the usage of sirolimus-derived compounds and other drugs in several preclinical or clinical studies as well as explain some of the challenges involved in targeting mTOR for treating various human cancers.
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Affiliation(s)
- Eunus S. Ali
- College of Medicine and Public Health, Flinders University, Bedford Park, 5042 Australia
- Gaco Pharmaceuticals, Dhaka, 1000 Bangladesh
- Present Address: Department of Biochemistry and Molecular Genetics, and Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, 303 E Superior St, Chicago, IL 60611 USA
| | - Kangkana Mitra
- Faculty of Medicine and Pharmacy, Université Grenoble Alpes, Grenoble, France
| | - Shamima Akter
- Department of Bioinformatics and Computational Biology, George Mason University, Fairfax, VA 22030 USA
| | - Sarker Ramproshad
- Department of Pharmacy, Ranada Prasad Shaha University, Narayanganj, 1400 Bangladesh
| | - Banani Mondal
- Department of Pharmacy, Ranada Prasad Shaha University, Narayanganj, 1400 Bangladesh
| | - Ishaq N. Khan
- Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, 25100 Pakistan
| | - Muhammad Torequl Islam
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100 Bangladesh
| | | | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong China
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10
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Gendarme S, Pastré J, Billaud EM, Gibault L, Guillemain R, Oudard S, Medioni J, Lillo-Lelouet A, Israël-Biet D. Pulmonary toxicity of mTOR inhibitors. Comparisons of two populations: Solid organ recipients and cancer patients. Therapie 2022; 78:267-278. [DOI: 10.1016/j.therap.2022.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/14/2022] [Accepted: 05/24/2022] [Indexed: 10/18/2022]
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Swain SM, Nishino M, Lancaster LH, Li BT, Nicholson AG, Bartholmai BJ, Naidoo J, Schumacher-Wulf E, Shitara K, Tsurutani J, Conte P, Kato T, Andre F, Powell CA. Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)-related interstitial lung disease/pneumonitis-Focus on proactive monitoring, diagnosis, and management. Cancer Treat Rev 2022; 106:102378. [PMID: 35430509 DOI: 10.1016/j.ctrv.2022.102378] [Citation(s) in RCA: 95] [Impact Index Per Article: 31.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/07/2022] [Accepted: 03/08/2022] [Indexed: 01/19/2023]
Abstract
Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate targeting human epidermal growth factor receptor 2. Interstitial lung disease (ILD)/pneumonitis is an adverse event associated with T-DXd; in most cases, it is low grade (grade ≤ 2) and can be treated effectively but may develop to be fatal in some instances. It is important to increase patient and provider understanding of T-DXd-related ILD/pneumonitis to improve patient outcomes. Drug-related ILD/pneumonitis is a diagnosis of exclusion; other possible causes of lung injury/imaging findings must be ruled out for an accurate diagnosis. Symptoms can be nonspecific, and identifying early symptoms is challenging; therefore, diagnosis is often delayed. We reviewed characteristics of patients who developed T-DXd-related ILD/pneumonitis and its patterns, produced multidisciplinary guidelines on diagnosis and management, and described areas for future investigation. Ongoing studies are collecting data on T-DXd-related ILD/pneumonitis to further our understanding of its clinical patterns and mechanisms. SEARCH STRATEGY AND SELECTION CRITERIA: References were identified based on the guidelines used by the authors in treating interstitial lung disease and pneumonitis. Searches of the authors' own files were also completed. A search of PubMed with the search terms (trastuzumab deruxtecan) AND (interstitial lung disease) AND (guidelines) was conducted on November 1, 2021, with no restrictions based on publication date, and the two articles yielded by the search were included.
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Affiliation(s)
- Sandra M Swain
- Georgetown Lombardi Comprehensive Cancer Center and MedStar Health, 4000 Reservoir Road NW, 120 Building D, Washington DC 20057, United States.
| | - Mizuki Nishino
- Brigham and Women's Hospital and Dana Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, United States
| | - Lisa H Lancaster
- Vanderbilt University Medical Center, 1211 Medical Center Dr, Nashville, TN 37232, United States
| | - Bob T Li
- Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States
| | - Andrew G Nicholson
- Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, and National Heart and Lung Institute, Imperial College, London SW3 6NP, United Kingdom
| | | | - Jarushka Naidoo
- Johns Hopkins University, 1650 Orleans Street, Baltimore, MD 21231, United States; Beaumont Hospital and RCSI University of Health Sciences, 123, 2 St Stephen's Green, Dublin, D02 YN77, Ireland
| | | | - Kohei Shitara
- National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-shi, Chiba 277-8577, Japan
| | - Junji Tsurutani
- Advanced Cancer Translational Research Institute, Showa University, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8555, Japan
| | - Pierfranco Conte
- Istituto Oncologico Veneto, I.R.C.C.S and University of Padova, Via Gattamelata, 64, 35128, Padova PD, Italy
| | - Terufumi Kato
- Kanagawa Cancer Center, Nakao 2-3-2, Asahi-ku, Yokohama, 241-8515, Japan
| | - Fabrice Andre
- Gustave Roussy Institute, 114 Rue Edouard Vaillant, 94805 Villejuif, France
| | - Charles A Powell
- Pulmonary Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, 10 East 102nd Street, New York, NY 10029, United States
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12
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Belkacemi L, Sun Y, Darmani NA. Evidence for Bell-Shaped Dose-Response Emetic Effects of Temsirolimus and Analogs: The Broad-Spectrum Antiemetic Efficacy of a Large Dose of Temsirolimus Against Diverse Emetogens in the Least Shrew ( Cryptotis parva). Front Pharmacol 2022; 13:848673. [PMID: 35444553 PMCID: PMC9014009 DOI: 10.3389/fphar.2022.848673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/04/2022] [Indexed: 11/13/2022] Open
Abstract
Temsirolimus is a prodrug form of sirolimus (rapamycin). With its analogs (everolimus, ridaforolimus, and rapamycin), it forms a group of anticancer agents that block the activity of one of the two mammalian targets of rapamycin (mTOR) complexes, mTORC1. We investigated the emetic potential of varying doses (0, 0.5, 1, 2.5, 5, 10, 20, and 40 mg/kg, i.p.) of temsirolimus in the least shrew. Temsirolimus caused a bell-shaped and dose-dependent increase in both the mean vomit frequency and the number of shrews vomiting with maximal efficacy at 10 mg/kg (p < 0.05 and p < 0.02, respectively). Its larger doses (20 or 40 mg/kg) had no significant emetic effect. We also evaluated the emetic potential of its analogs (5, 10, and 20 mg/kg, i.p.), all of which exhibited a similar emetic profile. Our observational studies indicated that temsirolimus can reduce the shrew motor activity at 40 mg/kg, and subsequently, we examined the motor effects of its lower doses. At 10 and 20 mg/kg, it did not affect the spontaneous locomotor activity (distance moved) but attenuated the mean rearing frequency in a U-shaped manner at 10 mg/kg (p < 0.05). We then determined the broad-spectrum antiemetic potential of a 20 mg/kg (i.p.) dose of temsirolimus against diverse emetogens, including selective and nonselective agonists of 1) dopaminergic D2/3 receptors (apomorphine and quinpirole); 2) serotonergic 5-HT3 receptors [5-HT (serotonin) and 2-methyl-5-HT]; 3) cholinergic M1 receptors (pilocarpine and McN-A-343); 4) substance P neurokinin NK1 receptors (GR73632); 5) the L-type calcium (Ca2+) channel (LTCC) (FPL64176); 6) the sarcoplasmic endoplasmic reticulum Ca2+ ATPase inhibitor, thapsigargin; 7) the CB1 receptor inverse agonist/antagonist, SR141716A; and 8) the chemotherapeutic cisplatin. Temsirolimus prevented vomiting evoked by the aforementioned emetogens with varying degrees. The mechanisms underlying the pro- and antiemetic effects of temsirolimus evaluated by immunochemistry for c-fos expression demonstrated a c-fos induction in the AP and NTS, but not DMNX with the 10 mg/kg emetic dose of temsirolimus, whereas its larger antiemetic dose (20 mg/kg) had no significant effect. Our study is the first to provide preclinical evidence demonstrating the promising antiemetic potential of high doses of temsirolimus and possibly its analogs in least shrews.
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Affiliation(s)
| | | | - Nissar A. Darmani
- Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
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13
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Cutaneous toxicities from targeted therapies used in oncology: Literature review of clinical presentation and management. Int J Womens Dermatol 2022; 7:615-624. [PMID: 35024416 PMCID: PMC8721134 DOI: 10.1016/j.ijwd.2021.09.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 09/18/2021] [Accepted: 09/20/2021] [Indexed: 01/13/2023] Open
Abstract
Cutaneous toxicities are frequent with targeted therapies. Managing cutaneous toxicities is critical for life-saving treatment continuation. Dermatologists can provide a key input in preventing and managing these toxicities. With the development of molecular targeted therapies, a wide array of dermatologic toxicities is appearing. Their prevention, recognition, and management by dermatologists is critical to ensure antineoplastic treatment continuation. The objective of this study was to provide a literature review of the most common dermatologic toxicities due to targeted therapies in oncologic patients, including their clinical presentation, prevention, and management.
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14
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Jiménez JL, Niewczas J, Bore A, Burman CF. A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching. PLoS One 2021; 16:e0259178. [PMID: 34780488 PMCID: PMC8592474 DOI: 10.1371/journal.pone.0259178] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 10/15/2021] [Indexed: 11/18/2022] Open
Abstract
In confirmatory cancer clinical trials, overall survival (OS) is normally a primary endpoint in the intention-to-treat (ITT) analysis under regulatory standards. After the tumor progresses, it is common that patients allocated to the control group switch to the experimental treatment, or another drug in the same class. Such treatment switching may dilute the relative efficacy of the new drug compared to the control group, leading to lower statistical power. It would be possible to decrease the estimation bias by shortening the follow-up period but this may lead to a loss of information and power. Instead we propose a modified weighted log-rank test (mWLR) that aims at balancing these factors by down-weighting events occurring when many patients have switched treatment. As the weighting should be pre-specified and the impact of treatment switching is unknown, we predict the hazard ratio function and use it to compute the weights of the mWLR. The method may incorporate information from previous trials regarding the potential hazard ratio function over time. We are motivated by the RECORD-1 trial of everolimus against placebo in patients with metastatic renal-cell carcinoma where almost 80% of the patients in the placebo group received everolimus after disease progression. Extensive simulations show that the new test gives considerably higher efficiency than the standard log-rank test in realistic scenarios.
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Affiliation(s)
- José L. Jiménez
- Global Drug Development, Novartis Pharma A.G., Basel, Switzerland
| | - Julia Niewczas
- Statistical Innovation, Data Science & AI, AstraZeneca R&D, Gothenburg, Sweden
| | - Alexander Bore
- Statistical Innovation, Data Science & AI, AstraZeneca R&D, Gothenburg, Sweden
| | - Carl-Fredrik Burman
- Statistical Innovation, Data Science & AI, AstraZeneca R&D, Gothenburg, Sweden
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15
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Amin M, Gao F, Terrero G, Picus J, Wang-Gillam A, Suresh R, Ma C, Tan B, Baggstrom M, Naughton MJ, Trull L, Belanger S, Fracasso PM, Lockhart AC. Phase I Study of Docetaxel and Temsirolimus in Refractory Solid Tumors. Am J Clin Oncol 2021; 44:443-448. [PMID: 34310349 DOI: 10.1097/coc.0000000000000852] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, and plays a central role in cell proliferation, growth, differentiation, migration, and survival. Temsirolimus (CCI-779), a selective inhibitor of the mTOR, is an ester analog of rapamycin (sirolimus) with improved aqueous solubility and pharmacokinetic (PK) properties. Preclinical studies have confirmed additive and synergistic antitumor activity in cancer cell lines (breast, prostate cancer) with combinations of taxanes and mTOR inhibitors. We conducted a phase I open-label, dose-escalation study to determine the maximal tolerated dose (MTD) of docetaxel in combination with temsirolimus in patients with refractory solid tumors. PATIENTS AND METHODS Eligible patients had a diagnosis of a refractory solid malignancy, measurable disease, and adequate organ function. Patients were sequentially enrolled in 4 dose level intravenous combinations of docetaxel and temsirolimus. Temsirolimus was administered weekly with docetaxel administered every 3 weeks. Laboratory data for tumor markers and radiologic imaging were conducted prestudy and then after every 2 cycles of the treatment. Radiologic response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Blood samples for PK and pharmacodynamic analysis were planned to be drawn at MTD. Apart from the traditional 3+3 design, we also implemented Bayesian Optimal Interval design which uses isotonic regression method to select MTD. We proceeded with isotonic regression analysis by using 20% dose-limiting toxicity (DLT) rate as target. RESULTS Twenty-six patients were treated in this study in 4 cohorts and dose levels. Fourteen males and 12 females were enrolled with a median age of 50 years (range of 27 to 72 y) and median Eastern Cooperative Oncology Group performance score of 1. Tumor histologies included pancreas (6), colon (5), rectum (3), gallbladder (2), non-small cell lung (2), endometrium (1), neuroendocrine (1), esophagus (1), stomach (1), pharynx (1), small intestine (1), and duodenum (1). Stable disease was observed in 2/4 (50%), 3/7 (43%), 4/10 (40%), and 3/5 (60%) patients in cohorts 1, 2, 3, and 4, respectively. Dose escalation in cohorts 2, 3, and 4 was complicated by DLTs such as grade 4 neutropenia and grade 3 diarrhea and an inability for patients to tolerate treatments during and beyond cycle 1 without dose reductions. Therefore, we could not determine an MTD or recommended phase II dose using the traditional 3+3 study analysis. Blood samples for PK and pharmacodynamic analysis were not collected since MTD was not determined. By using 20% DLT rate closest to the target, isotonic regression analysis showed identical estimated DLT rates in dose -1 (docetaxel 50 mg/m2 and temsirolimus 15 mg/m2) and dose level 1 (docetaxel 60mg/m2 and temsirolimus 15 mg/m2). CONCLUSIONS Dose escalation of docetaxel and temsirolimus was limited by severe myelosuppressive toxicity in this phase I study. Most of the DLTs occurred after cycle 1 of therapy hence, we were unable to determine MTD or collect blood samples for PK and pharmacodynamic analysis. Our trial did not meet its objectives due to significant DLTs with this chemotherapy combination. Although our novel use of Bayesian Optimal Interval design using isotonic regression method to select MTD showed identical estimated DLT rates in dose levels 1 and -1, clinically our patients were not able to complete 2 cycles of this regimen without dose reductions due to myelosuppressive toxicity in either of these dose levels, and hence, escaped clinical validity. This combination regimen should not be studied further at the dose levels and schedules tested in our study.
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Affiliation(s)
- Manik Amin
- Division of Oncology, Dartmouth Hitchcock Medical Center, Lebanon, NH
| | - Feng Gao
- Division of Public Health Sciences, Washington University School of Medicine, Saint Louis, MO
| | - Gretel Terrero
- Division of Hematology/Oncology, Medical University of South Carolina, Hollings Cancer Center, Charleston, SC
| | - Joel Picus
- Division of Oncology, Dartmouth Hitchcock Medical Center, Lebanon, NH
| | | | - Rama Suresh
- Division of Oncology, Dartmouth Hitchcock Medical Center, Lebanon, NH
| | - Cynthia Ma
- Division of Oncology, Dartmouth Hitchcock Medical Center, Lebanon, NH
| | - Benjamin Tan
- Division of Oncology, Dartmouth Hitchcock Medical Center, Lebanon, NH
| | - Maria Baggstrom
- Division of Oncology, Dartmouth Hitchcock Medical Center, Lebanon, NH
| | - Michael J Naughton
- Division of Medical Oncology, Saint Francis Healthcare, Cape Girardeau, MO
| | - Lauren Trull
- Prelude Therapeutics Incorporated, Wilmington, DE
| | - Stephanie Belanger
- Clinical Research Operations at UNC Chapel Hill-Lineberger Comprehensive Cancer Center, Chapel Hill, NC
| | - Paula M Fracasso
- Department of Medicine and the UVA Cancer Center, University of Virginia, Charlottesville, VA
| | - Albert Craig Lockhart
- Division of Hematology/Oncology, Medical University of South Carolina, Hollings Cancer Center, Charleston, SC
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Programmed cell death, redox imbalance, and cancer therapeutics. Apoptosis 2021; 26:385-414. [PMID: 34236569 DOI: 10.1007/s10495-021-01682-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2021] [Indexed: 02/06/2023]
Abstract
Cancer cells are disordered by nature and thus featured by higher internal redox level than healthy cells. Redox imbalance could trigger programmed cell death if exceeded a certain threshold, rendering therapeutic strategies relying on redox control a possible cancer management solution. Yet, various programmed cell death events have been consecutively discovered, complicating our understandings on their associations with redox imbalance and clinical implications especially therapeutic design. Thus, it is imperative to understand differences and similarities among programmed cell death events regarding their associations with redox imbalance for improved control over these events in malignant cells as well as appropriate design on therapeutic approaches relying on redox control. This review addresses these issues and concludes by bringing affront cold atmospheric plasma as an emerging redox controller with translational potential in clinics.
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Yu L, Wei J, Liu P. Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer. Semin Cancer Biol 2021; 85:69-94. [PMID: 34175443 DOI: 10.1016/j.semcancer.2021.06.019] [Citation(s) in RCA: 318] [Impact Index Per Article: 79.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 06/10/2021] [Accepted: 06/22/2021] [Indexed: 02/08/2023]
Abstract
Cancer is the second leading cause of human death globally. PI3K/Akt/mTOR signaling is one of the most frequently dysregulated signaling pathways observed in cancer patients that plays crucial roles in promoting tumor initiation, progression and therapy responses. This is largely due to that PI3K/Akt/mTOR signaling is indispensable for many cellular biological processes, including cell growth, metastasis, survival, metabolism, and others. As such, small molecule inhibitors targeting major kinase components of the PI3K/Akt/mTOR signaling pathway have drawn extensive attention and been developed and evaluated in preclinical models and clinical trials. Targeting a single kinase component within this signaling usually causes growth arrest rather than apoptosis associated with toxicity-induced adverse effects in patients. Combination therapies including PI3K/Akt/mTOR inhibitors show improved patient response and clinical outcome, albeit developed resistance has been reported. In this review, we focus on revealing the mechanisms leading to the hyperactivation of PI3K/Akt/mTOR signaling in cancer and summarizing efforts for developing PI3K/Akt/mTOR inhibitors as either mono-therapy or combination therapy in different cancer settings. We hope that this review will facilitate further understanding of the regulatory mechanisms governing dysregulation of PI3K/Akt/mTOR oncogenic signaling in cancer and provide insights into possible future directions for targeted therapeutic regimen for cancer treatment, by developing new agents, drug delivery systems, or combination regimen to target the PI3K/Akt/mTOR signaling pathway. This information will also provide effective patient stratification strategy to improve the patient response and clinical outcome for cancer patients with deregulated PI3K/Akt/mTOR signaling.
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Affiliation(s)
- Le Yu
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | | | - Pengda Liu
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Systemic Sirolimus Therapy for Infants and Children With Pulmonary Vein Stenosis. J Am Coll Cardiol 2021; 77:2807-2818. [PMID: 34082911 DOI: 10.1016/j.jacc.2021.04.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 04/01/2021] [Accepted: 04/02/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND Anatomic interventions for pulmonary vein stenosis (PVS) in infants and children have been met with limited success. Sirolimus, a mammalian target of rapamycin inhibitor, has demonstrated promise as a primary medical therapy for PVS, but the impact on patient survival is unknown. OBJECTIVES The authors sought to investigate whether mTOR inhibition with sirolimus as a primary medical therapy would improve outcomes in high-risk infants and children with PVS. METHODS In this single-center study, patients with severe PVS were considered for systemic sirolimus therapy (SST) following a strict protocol while receiving standardized surveillance and anatomic therapies. The SST cohort was compared with a contemporary control group. The primary endpoint for this study was survival. The primary safety endpoint was adverse events (AEs) related to SST. RESULTS Between 2015 and 2020, our PVS program diagnosed and treated 67 patients with ≥moderate PVS. Of these, 15 patients were treated with sirolimus, whereas the remaining patients represent the control group. There was 100% survival in the SST group compared with 45% survival in the control group (log-rank p = 0.004). A sensitivity analysis was completed to address survival bias using median time from diagnosis of PVS to SST. A survival advantage persisted (log-rank p = 0.027). Two patients on sirolimus developed treatable AEs. Patients in the SST group underwent frequent transcatheter interventions with 3.7 catheterizations per person-year (25th to 75th percentile: 2.7 to 4.4 person-years). Median follow up time was 2.2 years (25th to 75th percentile: 1.2 to 2.9 years) in the SST group versus 0.9 years (25th to 75th percentile: 0.5 to 2.7 years) in the control group. CONCLUSIONS The authors found a survival benefit associated with SST in infants and children with moderate-to-severe PVS. This survival benefit persisted after adjusting the analysis for survival bias. There were 2 mild AEs associated with SST during the study period; both patients were able to resume therapy without recurrence.
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Zaryouh H, De Pauw I, Baysal H, Peeters M, Vermorken JB, Lardon F, Wouters A. Recent insights in the PI3K/Akt pathway as a promising therapeutic target in combination with EGFR-targeting agents to treat head and neck squamous cell carcinoma. Med Res Rev 2021; 42:112-155. [PMID: 33928670 DOI: 10.1002/med.21806] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 02/17/2021] [Accepted: 03/31/2021] [Indexed: 12/20/2022]
Abstract
Resistance to therapies targeting the epidermal growth factor receptor (EGFR), such as cetuximab, remains a major roadblock in the search for effective therapeutic strategies in head and neck squamous cell carcinoma (HNSCC). Due to its close interaction with the EGFR pathway, redundant or compensatory activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has been proposed as a major driver of resistance to EGFR inhibitors. Understanding the role of each of the main proteins involved in this pathway is utterly important to develop rational combination strategies able to circumvent resistance. Therefore, the current work reviewed the role of PI3K/Akt pathway proteins, including Ras, PI3K, tumor suppressor phosphatase and tensing homolog, Akt and mammalian target of rapamycin in resistance to anti-EGFR treatment in HNSCC. In addition, we summarize PI3K/Akt pathway inhibitors that are currently under (pre)clinical investigation with focus on overcoming resistance to EGFR inhibitors. In conclusion, genomic alterations in and/or overexpression of one or more of these proteins are common in both human papillomavirus (HPV)-positive and HPV-negative HNSCC tumors. Therefore, downstream effectors of the PI3K/Akt pathway serve as promising drug targets in the search for novel therapeutic strategies that are able to overcome resistance to anti-EGFR treatment. Co-targeting EGFR and the PI3K/Akt pathway can lead to synergistic drug interactions, possibly restoring sensitivity to EGFR inhibitors and hereby improving clinical efficacy. Better understanding of the predictive value of PI3K/Akt pathway alterations is needed to allow the identification of patient populations that might benefit most from these combination strategies.
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Affiliation(s)
- Hannah Zaryouh
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium
| | - Ines De Pauw
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium
| | - Hasan Baysal
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium
| | - Marc Peeters
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.,Department of Medical Oncology, Antwerp University Hospital, Antwerp, Belgium
| | - Jan Baptist Vermorken
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.,Department of Medical Oncology, Antwerp University Hospital, Antwerp, Belgium
| | - Filip Lardon
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium
| | - An Wouters
- Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium
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20
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Liu K, Gao R, Wu H, Wang Z, Han G. Single-cell analysis reveals metastatic cell heterogeneity in clear cell renal cell carcinoma. J Cell Mol Med 2021; 25:4260-4274. [PMID: 33759378 PMCID: PMC8093989 DOI: 10.1111/jcmm.16479] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 02/20/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022] Open
Abstract
Renal cell carcinoma (RCC) is one of the leading causes of cancer-related death worldwide. Tumour metastasis and heterogeneity lead to poor survival outcomes and drug resistance in patients with metastatic RCC (mRCC). In this study, we aimed to assess intratumoural heterogeneity (ITH) in mRCC cells by performing a combined analysis of bulk data and single-cell RNA-sequencing data, and develop novel biomarkers for prognosis prediction on the basis of the potential molecular mechanisms underlying tumorigenesis. Eligible single-cell cohorts related to mRCC were acquired using the Gene Expression Omnibus (GEO) dataset to identify potential mRCC subpopulations. We then performed gene set variation analysis to understand the differential function in primary RCC and mRCC samples. Subsequently, we applied weighted correlation network analysis to identify coexpressing gene modules that were related to the external trait of metastasis. Protein-protein interactions were used to screen hub subpopulation-difference (sub-dif) markers (ACTG1, IL6, CASP3, ACTB and RAP1B) that might be involved in the regulation of RCC metastasis and progression. Cox regression analysis revealed that ACTG1 was a protective factor (HR < 1), whereas the other four genes (IL6, CASP3, ACTB and RAP1B) were risk factors (HR > 1). Kaplan-Meier survival analysis suggested the potential prognostic value of these sub-dif markers. The expression of sub-dif markers in mRCC was further evaluated in clinical samples by immunohistochemistry (IHC). Additionally, the genetic features of sub-dif marker expression patterns, such as genetic variation profiles, correlations with tumour-infiltrating lymphocytes (TILs), and targeted signalling pathway activities, were assessed in bulk RNA-seq datasets. In conclusion, we established novel subpopulation markers as key prognostic factors affecting EMT-related signalling pathway activation in mRCC, which could facilitate the implementation of a treatment for mRCC patients.
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Affiliation(s)
- Kun Liu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Rui Gao
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hao Wu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhe Wang
- Department of Gastrointestinal Oncology, Cancer Hospital of China Medical University Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Guang Han
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China
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21
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Song MJ, Pan QZ, Ding Y, Zeng J, Dong P, Zhao JJ, Tang Y, Li J, Zhang Z, He J, Yang J, Huang Y, Peng R, Wang QJ, Gu JM, He J, Li YQ, Chen SP, Huang R, Zhou ZQ, Yang C, Han Y, Chen H, Liu H, Xia S, Wan Y, Weng DS, Xia L, Zhou FJ, Xia JC. The efficacy and safety of the combination of axitinib and pembrolizumab-activated autologous DC-CIK cell immunotherapy for patients with advanced renal cell carcinoma: a phase 2 study. Clin Transl Immunology 2021; 10:e1257. [PMID: 33717483 PMCID: PMC7927618 DOI: 10.1002/cti2.1257] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 01/15/2021] [Accepted: 02/01/2021] [Indexed: 12/22/2022] Open
Abstract
Objectives Although axitinib has achieved a preferable response rate for advanced renal cell carcinoma (RCC), patient survival remains unsatisfactory. In this study, we evaluated the efficacy and safety of a combination treatment of axitinib and a low dose of pembrolizumab‐activated autologous dendritic cells–co‐cultured cytokine‐induced killer cells in patients with advanced RCC. Methods All adult patients, including treatment‐naive or pretreated with VEGF‐targeted agents, were enrolled from May 2016 to March 2019. Patients received axitinib 5 mg twice daily and pembrolizumab‐activated dendritic cells–co‐cultured cytokine‐induced killer cells intravenously weekly for the first four cycles, every 2 weeks for the next four cycles, and every month thereafter. Results The 43 patients (22 untreated and 21 previously treated) showed a median progression‐free survival (mPFS) of 14.7 months (95% CI, 11.16–18.30). mPFS in treatment‐naive patients was 18.2 months, as compared with 14.4 months in pretreated patients (log‐rank P‐value = 0.07). Overall response rates were 25.6% (95% CI, 13.5–41.2%). Grade 3 or higher adverse events occurred in 5% of patients included hypertension (11.6%) and palmar‐plantar erythrodysesthesia (7.0%). Peripheral blood lymphocyte immunophenotype and serum cytokine profile analyses demonstrated increased antitumor immunity after combination treatment particularly in patients with a long‐term survival benefit, while those with a minimal survival benefit demonstrated an elevated proportion of peripheral CD8+TIM3+ T cells and lower serum‐level immunostimulatory cytokine profile. Conclusions The combination therapy was active and well tolerated for treatment of advanced RCC, either as first‐ or second‐line treatment following other targeted agents. Changes in immunophenotype and serum cytokine profile may be used as prognostic biomarkers.
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Affiliation(s)
- Meng-Jia Song
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Qiu-Zhong Pan
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Ya Ding
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Jianxiong Zeng
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Pei Dong
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Urology Sun Yat-sen University Cancer Center Guangzhou China
| | - Jing-Jing Zhao
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Yan Tang
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Jingjing Li
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Zhiling Zhang
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Urology Sun Yat-sen University Cancer Center Guangzhou China
| | - Junyi He
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Jieying Yang
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Yue Huang
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Ruiqing Peng
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Qi-Jing Wang
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Jia-Mei Gu
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Jia He
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Yong-Qiang Li
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Shi-Ping Chen
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Rongxing Huang
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Zi-Qi Zhou
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Chaopin Yang
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Yulong Han
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Hao Chen
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Heping Liu
- Guangzhou Yiyang Bio-technology Co., Ltd Guangzhou China
| | - Shangzhou Xia
- Guangzhou Yiyang Bio-technology Co., Ltd Guangzhou China
| | - Yang Wan
- Guangzhou Yiyang Bio-technology Co., Ltd Guangzhou China
| | - De-Sheng Weng
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
| | - Liming Xia
- Guangzhou Yiyang Bio-technology Co., Ltd Guangzhou China
| | - Fang-Jian Zhou
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Urology Sun Yat-sen University Cancer Center Guangzhou China
| | - Jian-Chuan Xia
- Collaborative Innovation Center for Cancer Medicine State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer Center Guangzhou China.,Department of Biotherapy Sun Yat-sen University Cancer Center Guangzhou China
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22
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Cherri S, Noventa S, Fanelli M, Calandra G, Prochilo T, Bnà C, Savelli G, Zaniboni A. Drug-Related Pneumonitis in Cancer Treatment during the COVID-19 Era. Cancers (Basel) 2021; 13:1052. [PMID: 33801385 PMCID: PMC7958630 DOI: 10.3390/cancers13051052] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 02/24/2021] [Indexed: 12/17/2022] Open
Abstract
Interstitial lung disease is recognized as a group of diseases with a different etiopathogenesis characterized by chronic lung inflammation with the accumulation of inflammatory cells, lymphocytes and macrophages, and the consequent release of proinflammatory cytokines. Various degrees of pulmonary fibrosis can be associated with this inflammatory condition. Interstitial lung disease related to oncological drugs is a relevant problem in clinical practice. The etiopathogenetic mechanisms underlying this adverse event are not completely known but can be partly explained by the mechanism of action of the drug involved. Therefore, knowledge of the relevance of this potentially fatal adverse event supported by the reported safety data of pivotal studies becomes fundamental in the management of patients. The prompt diagnosis of drug-related pneumonia and the consequent differential diagnosis with other forms of pneumonia allow a rapid suspension of treatment and the establishment of an immunosuppressive treatment if necessary. In the context of the health emergency related to SARS CoV2 infection and COVID-19-related interstitial lung disease, such knowledge holds decisive relevance in the conscious choice of cancer treatments. Our intent was to describe the oncological drugs most correlated with this adverse event by reporting, where possible, the percentages of insurgency in pivotal studies to provide an overview and therefore promote greater awareness of this important toxicity related to oncological treatment.
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Affiliation(s)
- Sara Cherri
- Unit of Medical Oncology, Department of Oncology, Fondazione Poliambulanza, 25124 Brescia, Italy; (S.N.); (T.P.); (A.Z.)
| | - Silvia Noventa
- Unit of Medical Oncology, Department of Oncology, Fondazione Poliambulanza, 25124 Brescia, Italy; (S.N.); (T.P.); (A.Z.)
| | - Martina Fanelli
- Medical Oncology Unit, University Hospital of Modena, 41124 Modena, Italy;
| | - Giulio Calandra
- Unit of Radiology, Department of Diagnostic Imaging, Fondazione Poliambulanza, 25124 Brescia, Italy; (G.C.); (C.B.)
| | - Tiziana Prochilo
- Unit of Medical Oncology, Department of Oncology, Fondazione Poliambulanza, 25124 Brescia, Italy; (S.N.); (T.P.); (A.Z.)
| | - Claudio Bnà
- Unit of Radiology, Department of Diagnostic Imaging, Fondazione Poliambulanza, 25124 Brescia, Italy; (G.C.); (C.B.)
| | - Giordano Savelli
- Nuclear Medicine Department, Fondazione Poliambulanza, 25124 Brescia, Italy;
| | - Alberto Zaniboni
- Unit of Medical Oncology, Department of Oncology, Fondazione Poliambulanza, 25124 Brescia, Italy; (S.N.); (T.P.); (A.Z.)
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23
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Trivedi ND, Armstrong S, Wang H, Hartley M, Deeken J, Ruth He A, Subramaniam D, Melville H, Albanese C, Marshall JL, Hwang J, Pishvaian MJ. A phase I trial of the mTOR inhibitor temsirolimus in combination with capecitabine in patients with advanced malignancies. Cancer Med 2021; 10:1944-1954. [PMID: 33638305 PMCID: PMC7957175 DOI: 10.1002/cam4.3672] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/18/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Temsirolimus is an mTOR antagonist with proven anticancer efficacy. Preclinical data suggest greater anticancer effect when mTOR inhibitors are combined with cytotoxic chemotherapy. We performed a Phase I assessment of the combination of temsirolimus and capecitabine in patients with advanced solid tumors. METHODS Patients were enrolled in an alternating dose escalation of temsirolimus (at 15 or 25 mg IV weekly) and capecitabine (at 750, 1000, and 1250 mg/m2 twice daily) in separate Q2-week and Q3-week cohorts. At the recommended Phase II doses (RP2Ds) of temsirolimus and capecitabine (Q2), seven patients were also treated with oxaliplatin (85 mg/m2 , day 1) to determine triplet combination safety and efficacy. RESULTS Forty-five patients were enrolled and 41 were evaluable for dose-limiting toxicities (DLTs). The most common adverse events (AEs) were mucositis, fatigue, and thrombocytopenia. The most common grade 3/4 AEs were hypophosphatemia and anemia. Five patients had DLTs, including hypophosphatemia, mucositis, and thrombocytopenia. The RP2Ds were temsirolimus 25 mg +capecitabine 1000 mg/m2 (Q2); and temsirolimus 25 mg +capecitabine 750 mg/m2 (Q3). Of the 38 patients evaluable for response, one had a partial response (PR) and 19 had stable disease (SD). The overall disease control rate was 52%. Five of the 20 patients with SD/PR maintained disease control for >6 months. CONCLUSIONS The combination of temsirolimus and capecitabine is safe on both a Q2-week and a Q3-week schedule. The combination demonstrated promising evidence of disease control in this highly refractory population and could be considered for testing in disease-specific phase II trials.
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Affiliation(s)
- Neel D Trivedi
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Samantha Armstrong
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Hongkun Wang
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Marion Hartley
- The Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - John Deeken
- Inova Schar Cancer Institute, Inova Health System, Falls Church, VA, USA
| | - A Ruth He
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Deepa Subramaniam
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Heather Melville
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Chris Albanese
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - John L Marshall
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Jimmy Hwang
- Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA
| | - Michael J Pishvaian
- Department of Oncology, Johns Hopkins University School of Medicine, SKCC, Washington, DC, USA
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24
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Gkolfinopoulos S, Psyrri A, Bamias A. Clear-cell renal cell carcinoma - A comprehensive review of agents used in the contemporary management of advanced/metastatic disease. Oncol Rev 2021; 15:530. [PMID: 33747368 PMCID: PMC7967495 DOI: 10.4081/oncol.2021.530] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 12/28/2020] [Indexed: 01/05/2023] Open
Abstract
Renal cell carcinoma represents the most common malignancy of the kidney and the majority of cases are categorized as clear cell carcinomas. The elucidation of the specific alterations in key molecular and metabolic pathways responsible for cancer development and progression have prompted the rationalization of our classification of this disease and have provided specific targetable molecules implicated in carcinogenesis. Although immunotherapy has been an established option in the treatment of metastatic renal cell cancer for many years, its role has been renewed and upgraded with the implementation of anti-angiogenic agents and immune checkpoint inhibitors in our treatment armamentarium. The future holds promise, as newer agents become available and combination regimens of immunotherapy with anti-angiogenic agents have become the standard of care in the management of metastatic disease and are currently being evaluated in earlier settings. Proper patient selection and individualization of our treatment strategies are of utmost importance in order to provide optimal care to patients suffering from renal cell carcinoma.
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Affiliation(s)
- Stavros Gkolfinopoulos
- 2 Propaedeutic Dept. of Internal Medicine, National & Kapodistrian University of Athens, ATTIKON University Hospital, Athens, Greece
| | - Amanda Psyrri
- 2 Propaedeutic Dept. of Internal Medicine, National & Kapodistrian University of Athens, ATTIKON University Hospital, Athens, Greece
| | - Aristotelis Bamias
- 2 Propaedeutic Dept. of Internal Medicine, National & Kapodistrian University of Athens, ATTIKON University Hospital, Athens, Greece
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25
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Zhong R, Li JQ, Wu SW, He XM, Xuan JC, Long H, Liu HQ. Transcriptome analysis reveals possible antitumor mechanism of Chlorella exopolysaccharide. Gene 2021; 779:145494. [PMID: 33588036 DOI: 10.1016/j.gene.2021.145494] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 01/18/2021] [Accepted: 02/03/2021] [Indexed: 12/13/2022]
Abstract
Microalgae, one of the most important classes of biomass producers, can produce exopolysaccharides similar to bacteria. The exopolysaccharide from Chlorella (CEPS) displays remarkable anticancer activity the mechanism of which remains to be elucidated. In this study, we analyzed the inhibitory effect of CEPS on the growth of HeLa cells. The results showed that CEPS inhibited the proliferation, decreased the viability, and changed the morphology of HeLa cells. Transcriptome analysis showed that 1894 genes were differentially expressed in the CEPS-treated group compared with the control group, including 1076 genes that were upregulated and 818 genes that were downregulated. The results of gene function enrichment analysis showed that the differentially expressed genes (DEGs) were significantly enriched in apoptosis and tumor-related biological processes and participated in several cancer and apoptosisrelated signaling pathways, including the MAPK signaling pathway, TNF signaling pathway, and the PI3K-Akt signaling pathway. The protein-protein interaction network identified 13 DEGs including PTPN11, RSAD2, ISG15, IFIT1, MX2, IFIT2, OASL, OAS1, JUN, OAS2, XAF1, ISG20, and IRF9 as hub genes. Our results suggest that CEPS is a promising therapeutic drug for the follow-up interventional therapy of cancer.
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Affiliation(s)
- Run Zhong
- Guangxi University for Nationalities, School of Marine Sciences and Biotechnology, Guangxi Key Laboratory of Polysaccharide Materials and Their Modification, Nanning 530007, China
| | - Jie-Qiong Li
- Guangxi Botanical Garden of Medicinal Plants, Nanning 530023, China
| | - Si-Wei Wu
- Guangxi University for Nationalities, School of Marine Sciences and Biotechnology, Guangxi Key Laboratory of Polysaccharide Materials and Their Modification, Nanning 530007, China
| | - Xiu-Miao He
- Guangxi University for Nationalities, School of Marine Sciences and Biotechnology, Guangxi Key Laboratory of Polysaccharide Materials and Their Modification, Nanning 530007, China
| | - Jin-Cai Xuan
- Guangxi University for Nationalities, School of Marine Sciences and Biotechnology, Guangxi Key Laboratory of Polysaccharide Materials and Their Modification, Nanning 530007, China
| | - Han Long
- Guangxi University for Nationalities, School of Marine Sciences and Biotechnology, Guangxi Key Laboratory of Polysaccharide Materials and Their Modification, Nanning 530007, China
| | - Hong-Quan Liu
- Guangxi University for Nationalities, School of Marine Sciences and Biotechnology, Guangxi Key Laboratory of Polysaccharide Materials and Their Modification, Nanning 530007, China.
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26
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Deutsch A, Leboeuf NR, Lacouture ME, McLellan BN. Dermatologic Adverse Events of Systemic Anticancer Therapies: Cytotoxic Chemotherapy, Targeted Therapy, and Immunotherapy. Am Soc Clin Oncol Educ Book 2021; 40:485-500. [PMID: 32421446 DOI: 10.1200/edbk_289911] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Over the past 2 decades, rapid advancement in systemic anticancer therapeutics has led to astounding improvement in survival rates of patients with cancer. However, this celebrated progress has brought with it an evolving spectrum of drug toxicities that limit their prodigious capabilities. Cutaneous adverse events are of the most frequent of these toxicities, with substantial impact on quality of life and commonly resulting in dose reduction or change in therapy. Thus, familiarity with the array of dermatologic manifestations caused by these drugs is prudent for patient treatment. As such, the advent of dedicated oncodermatologists, and their introduction into multidisciplinary cancer care, has been crucial in optimizing treatment through therapeutic achievement and overall well-being. This review will address the epidemiology, clinical presentations, and management strategies of the major dermatologic adverse events of systemic anticancer agents, including cytotoxic chemotherapy, targeted therapy, and immunotherapy.
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Affiliation(s)
- Alana Deutsch
- Division of Dermatology, Department of Internal Medicine, Albert Einstein College of Medicine, Bronx, NY
| | - Nicole R Leboeuf
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.,Department of Cutaneous Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Mario E Lacouture
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Beth N McLellan
- Division of Dermatology, Department of Internal Medicine, Albert Einstein College of Medicine, Bronx, NY
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27
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Jeong JH, Ojha U, Lee YM. Pathological angiogenesis and inflammation in tissues. Arch Pharm Res 2020; 44:1-15. [PMID: 33230600 PMCID: PMC7682773 DOI: 10.1007/s12272-020-01287-2] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 11/13/2020] [Indexed: 12/12/2022]
Abstract
The role of angiogenesis in the growth of organs and tumors is widely recognized. Vascular-organ interaction is a key mechanism and a concept that enables an understanding of all biological phenomena and normal physiology that is essential for human survival under pathological conditions. Recently, vascular endothelial cells have been classified as a type of innate immune cells that are dependent on the pathological situations. Moreover, inflammatory cytokines and signaling regulators activated upon exposure to infection or various stresses play crucial roles in the pathological function of parenchymal cells, peripheral immune cells, stromal cells, and cancer cells in tissues. Therefore, vascular-organ interactions as a vascular microenvironment or tissue microenvironment under physiological and pathological conditions are gaining popularity as an interesting research topic. Here, we review vascular contribution as a major factor in microenvironment homeostasis in the pathogenesis of normal as well as cancerous tissues. Furthermore, we suggest that the normalization strategy of pathological angiogenesis could be a promising therapeutic target for various diseases, including cancer.
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Affiliation(s)
- Ji-Hak Jeong
- College of Pharmacy, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, Daegu, 41566, Republic of Korea.,College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Uttam Ojha
- College of Pharmacy, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, Daegu, 41566, Republic of Korea
| | - You Mie Lee
- College of Pharmacy, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, Daegu, 41566, Republic of Korea. .,College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
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28
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Farhan M, Silva M, Li S, Yan F, Fang J, Peng T, Hu J, Tsao M, Little P, Zheng W. The role of FOXOs and autophagy in cancer and metastasis-Implications in therapeutic development. Med Res Rev 2020; 40:2089-2113. [PMID: 32474970 PMCID: PMC7586888 DOI: 10.1002/med.21695] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 04/21/2020] [Accepted: 05/16/2020] [Indexed: 12/17/2022]
Abstract
Autophagy is a highly conserved intracellular degradation process that plays a crucial role in cell survival and stress reactions as well as in cancer development and metastasis. Autophagy process involves several steps including sequestration, fusion of autophagosomes with lysosomes and degradation. Forkhead box O (FOXO) transcription factors regulate the expression of genes involved in cellular metabolic activity and signaling pathways of cancer growth and metastasis. Recent evidence suggests that FOXO proteins are also involved in autophagy regulation. The relationship among FOXOs, autophagy, and cancer has been drawing attention of many who work in the field. This study summarizes the role of FOXO proteins and autophagy in cancer growth and metastasis and analyzes their potential roles in cancer disease management.
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Affiliation(s)
- Mohd Farhan
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Marta Silva
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Shuai Li
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Fengxia Yan
- Department of MedicineJinan UniversityGuangzhouChina
| | - Jiankang Fang
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Tangming Peng
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
| | - Jim Hu
- Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoOntarioCanada
| | - Ming‐Sound Tsao
- Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoOntarioCanada
| | - Peter Little
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of QueenslandWoolloongabbaQueenslandAustralia
| | - Wenhua Zheng
- Faculty of Health SciencesCentre of Reproduction, Development and Aging, Institute of Translational Medicine, University of MacauTaipaMacau SARChina
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Hofmann F, Hwang EC, Lam TB, Bex A, Yuan Y, Marconi LS, Ljungberg B. Targeted therapy for metastatic renal cell carcinoma. Cochrane Database Syst Rev 2020; 10:CD012796. [PMID: 33058158 PMCID: PMC8094280 DOI: 10.1002/14651858.cd012796.pub2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review. OBJECTIVES To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy. SEARCH METHODS We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020. SELECTION CRITERIA We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI-based targeted therapy. DATA COLLECTION AND ANALYSIS Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression-free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health-related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random-effects model and rated the certainty of evidence according to the GRADE approach. MAIN RESULTS We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This abstract focuses on the primary outcomes of select comparisons. 1. Pazopanib versus sunitinib Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low-certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants. 2. Sunitinib versus avelumab and axitinib Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low-certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low-certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants. 3. Sunitinib versus pembrolizumab and axitinib Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 months, this corresponds to 125 fewer participants experiencing PFS (95% CI 195 fewer to 56 fewer) per 1000 participants. Sunitinib probably reduces OS (HR 1.90, 95% CI 1.36 to 2.65; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 880 per 1000 in this trial at 12 months, this would result in 96 fewer OSs (95% CI 167 fewer to 40 fewer) per 1000 participants. Sunitinib may reduce SAEs as compared to pembrolizumab plus axitinib (RR 0.90, 95% CI 0.81 to 1.02; 1 study, 854 participants; low-certainty evidence) although the CI includes the possibility of no effect. Based on the control event risk of 604 per 1000 in this trial, this corresponds to 60 fewer SAEs (95% CI 115 fewer to 12 more) per 1000 participants. 4. Sunitinib versus nivolumab and ipilimumab Sunitinib may reduce PFS as compared to nivolumab plus ipilimumab (HR 1.30, 95% CI 1.11 to 1.52; 1 study, 847 participants; low-certainty evidence). Based on the control event risk of 280 per 1000 in this trial at 30 months' follow-up, this corresponds to 89 fewer PFSs (95% CI 136 fewer to 37 fewer) per 1000 participants. Sunitinib reduces OS (HR 1.52, 95% CI 1.23 to 1.89; 1 study, 847 participants; high-certainty evidence). Based on the control event risk 600 per 1000 in this trial at 30 months, this would result in 140 fewer OSs (95% CI 219 fewer to 67 fewer) per 1000 participants. Sunitinib probably increases SAEs (RR 1.37, 95% CI 1.22 to 1.53; 1 study, 1082 participants; moderate-certainty evidence). Based on the control event risk of 457 per 1000 in this trial, this corresponds to 169 more SAEs (95% CI 101 more to 242 more) per 1000 participants. AUTHORS' CONCLUSIONS Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.
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Key Words
- adult
- humans
- antibodies, monoclonal, humanized
- antibodies, monoclonal, humanized/adverse effects
- antibodies, monoclonal, humanized/therapeutic use
- antineoplastic agents
- antineoplastic agents/adverse effects
- antineoplastic agents/therapeutic use
- antineoplastic agents, immunological
- antineoplastic agents, immunological/therapeutic use
- axitinib
- axitinib/adverse effects
- axitinib/therapeutic use
- bevacizumab
- bevacizumab/adverse effects
- bevacizumab/therapeutic use
- bias
- carcinoma, renal cell
- carcinoma, renal cell/drug therapy
- carcinoma, renal cell/mortality
- everolimus
- everolimus/adverse effects
- everolimus/therapeutic use
- indazoles
- ipilimumab
- ipilimumab/adverse effects
- ipilimumab/therapeutic use
- kidney neoplasms
- kidney neoplasms/drug therapy
- kidney neoplasms/mortality
- kidney neoplasms/pathology
- phenylurea compounds
- phenylurea compounds/adverse effects
- phenylurea compounds/therapeutic use
- progression-free survival
- protein kinase inhibitors
- protein kinase inhibitors/adverse effects
- protein kinase inhibitors/therapeutic use
- pyrimidines
- pyrimidines/adverse effects
- pyrimidines/therapeutic use
- quality of life
- quinolines
- quinolines/adverse effects
- quinolines/therapeutic use
- randomized controlled trials as topic
- receptors, vascular endothelial growth factor
- receptors, vascular endothelial growth factor/antagonists & inhibitors
- sirolimus
- sirolimus/adverse effects
- sirolimus/analogs & derivatives
- sirolimus/therapeutic use
- sorafenib
- sorafenib/adverse effects
- sorafenib/therapeutic use
- sulfonamides
- sulfonamides/adverse effects
- sulfonamides/therapeutic use
- sunitinib
- sunitinib/adverse effects
- sunitinib/therapeutic use
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Affiliation(s)
- Fabian Hofmann
- Department of Urology, Sunderby Sjukhus, Umeå University, Luleå, Sweden
| | - Eu Chang Hwang
- Department of Urology, Chonnam National University Medical School, Chonnam National University Hwasun Hospital, Hwasun, Korea, South
| | - Thomas Bl Lam
- Academic Urology Unit, University of Aberdeen, Aberdeen, UK
| | - Axel Bex
- Department of Urology and UCL Division of Surgery and Interventional Science, Royal Free London NHS Foundation Trust, London, UK
| | - Yuhong Yuan
- Department of Medicine, Division of Gastroenterology, McMaster University, Hamilton, Canada
| | - Lorenzo So Marconi
- Department of Urology and Renal Transplantation, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal
| | - Börje Ljungberg
- Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
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Lu Z, Shi X, Gong F, Li S, Wang Y, Ren Y, Zhang M, Yu B, Li Y, Zhao W, Zhang J, Hou G. RICTOR/mTORC2 affects tumorigenesis and therapeutic efficacy of mTOR inhibitors in esophageal squamous cell carcinoma. Acta Pharm Sin B 2020; 10:1004-1019. [PMID: 32642408 PMCID: PMC7332809 DOI: 10.1016/j.apsb.2020.01.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 11/01/2019] [Accepted: 12/24/2019] [Indexed: 02/06/2023] Open
Abstract
Dysregulation of mTORC1/mTORC2 pathway is observed in many cancers and mTORC1 inhibitors have been used clinically in many tumor types; however, the mechanism of mTORC2 in tumorigenesis is still obscure. Here, we mainly explored the potential role of mTORC2 in esophageal squamous cell carcinoma (ESCC) and its effects on the sensitivity of cells to mTOR inhibitors. We demonstrated that RICTOR, the key factor of mTORC2, and p-AKT (Ser473) were excessively activated in ESCC and their overexpression is related to lymph node metastasis and the tumor-node-metastasis (TNM) phase of ESCC patients. Furthermore, we found that mTORC1/ mTORC2 inhibitor PP242 exhibited more efficacious anti-proliferative effect on ESCC cells than mTORC1 inhibitor RAD001 due to RAD001-triggered feedback activation of AKT signal. Another, we demonstrated that down-regulating expression of RICTOR in ECa109 and EC9706 cells inhibited proliferation and migration as well as induced cell cycle arrest and apoptosis. Noteworthy, knocking-down stably RICTOR significantly suppresses RAD001-induced feedback activation of AKT/PRAS40 signaling, and enhances inhibition efficacy of PP242 on the phosphorylation of AKT and PRAS40, thus potentiates the antitumor effect of RAD001 and PP242 both in vitro and in vivo. Our findings highlight that selective targeting mTORC2 could be a promising therapeutic strategy for future treatment of ESCC.
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Key Words
- 4EBP-1, E binding protein-1
- AKT
- AKT, protein kinase B (PKB)
- ESCC, esophageal squamous cell carcinoma
- Esophageal squamous cell carcinoma
- FDA, U.S. Food and Drug Administration
- H&E staining, hematoxylin and eosin staining
- IC50, half maximal inhibitory concentration
- PI3K, phosphatidylinositol 3 kinase
- RAD001
- RICTOR
- RICTOR, rapamycin-insensitive companion of mTOR
- TNM, tumor-node-metastasis
- TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling
- mTOR, mammalian target of rapamycin
- mTORC1, mTOR complex 1
- mTORC2, mTOR complex 2
- p70S6K, p70 ribosomal S6 kinase-1
- pp242
- rapalogs, rapamycin and its analogs
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Antoch MP, Wrobel M, Gillard B, Kuropatwinski KK, Toshkov I, Gleiberman AS, Karasik E, Moser MT, Foster BA, Andrianova EL, Chernova OV, Gudkov AV. Superior cancer preventive efficacy of low versus high dose of mTOR inhibitor in a mouse model of prostate cancer. Oncotarget 2020; 11:1373-1387. [PMID: 32341756 PMCID: PMC7170500 DOI: 10.18632/oncotarget.27550] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 03/14/2020] [Indexed: 12/15/2022] Open
Abstract
The mechanistic target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation and survival in response to the availability of energy sources and growth factors. Cancer development and progression is often associated with constitutive activation of the mTOR pathway, thus justifying mTOR inhibition as a promising approach to cancer treatment and prevention. However, development of previous rapamycin analogues has been complicated by their induction of adverse side effects and variable efficacy. Since mTOR pathway regulation involves multiple feedback mechanisms that may be differentially activated depending on the degree of mTOR inhibition, we investigated whether rapamycin dosing could be adjusted to achieve chemopreventive efficacy without side effects. Thus, we tested the efficacy of two doses of a novel, highly bioavailable nanoformulation of rapamycin, Rapatar, in a mouse prostate cancer model (male mice with prostate epithelium-specific Pten-knockout). We found that the highest efficacy was achieved by the lowest dose of Rapatar used in the study. While both doses tested were equally effective in suppressing proliferation of prostate epithelial cells, higher dose resulted in activation of feedback circuits that reduced the drug’s tumor preventive efficacy. These results demonstrate that low doses of highly bioavailable mTOR inhibitor, Rapatar, may provide safe and effective cancer prevention.
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Affiliation(s)
- Marina P Antoch
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | | | - Bryan Gillard
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Karen K Kuropatwinski
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | | | | | - Ellen Karasik
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Michael T Moser
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Barbara A Foster
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | | | | | - Andrei V Gudkov
- Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
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Das H, Rodriguez R. Health Care Disparities in Urologic Oncology: A Systematic Review. Urology 2020; 136:9-18. [DOI: 10.1016/j.urology.2019.09.058] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 09/12/2019] [Accepted: 09/23/2019] [Indexed: 12/21/2022]
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Santoni M, Cimadamore A, Cheng L, Lopez-Beltran A, Scarpelli M, Battelli N, Montironi R. Targeted Treatment of Renal Cell Carcinoma. KIDNEY CANCER 2020. [DOI: 10.1007/978-3-030-28333-9_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Whiting D, Sriprasad S. Molecular biology and targeted therapy in metastatic renal cell carcinoma. JOURNAL OF CLINICAL UROLOGY 2020. [DOI: 10.1177/2051415819849322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The treatment of metastatic renal cell carcinoma is challenging as it has proven to be relatively resistant to conventional oncological treatments. An improved understanding of the molecular biology of renal cell carcinoma has led to the development of a number of targeted therapies in metastatic renal cell carcinoma. This includes vascular endothelial growth factor inhibitors, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors and most recently immune checkpoint inhibitors. This article will review the mechanisms of development and progression of renal cell carcinoma as well as the mechanisms of current approved treatments in metastatic disease.Level of evidence: Not applicable for this multicentre audit.
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Affiliation(s)
- D Whiting
- Department of Urology, Darent Valley Hospital, UK
| | - S Sriprasad
- Department of Urology, Darent Valley Hospital, UK
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35
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Xu Z, Li X, Qi F, Hu X, Zheng Y, Cai H, Xu T, Yu B, Zou Q. A new strategy for the treatment of sorafenib-refractory metastatic renal cell carcinoma in China: combination with intermittent chemotherapy. Transl Androl Urol 2019; 8:339-345. [PMID: 31555557 DOI: 10.21037/tau.2019.06.25] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background This study assesses the clinical safety and efficacy of Gemcitabine and S-1 combination chemotherapy in sorafenib-refractory metastatic renal cell carcinoma (RCC) patients. Methods The baseline characteristics and survival outcomes of 19 patients suffering from metastatic and progressive sorafenib-refractory RCC were retrospectively collected and analyzed from January 2010 to April 2014. Patients were treated by combining Gemcitabine (1,000 mg/m2, day 1 and day 8 of every cycle of 21 days) and S-1 (40 mg/m2, twice a day for 14 days, followed by the rest period of 7 days), with a continual treatment of sorafenib 400 mg twice a day in a cycle of 28 days. Results After combination chemotherapy, the disease control rate was 68.4%. Among them, 6 patients (31.6%) had progressive disease (PD), 5 patients (26.3%) had stable disease (SD) and 8 patients (42.1%) had partial response (PR). The median time to progression (TTP) was 6.3 months (range, 2.0-32.7 months), and the median overall survival (OS) was 19.7 months (range, 5.7-45.0 months). In the survival analysis, comparing PD group, disease control (PR + SD) group showed an obviously longer TTP (median TTP: 9.5 vs. 2.0 months, 95% CI, 7.7-11.3 months, P<0.001) and OS (median OS: 21.0 vs. 8.3 months, 95% CI, 14.5-24.9 months, P<0.001). In univariate and multivariate analysis, TTP and OS were significantly associated with disease control condition. Side-effects were found in all patients at different degree, but only 3 patients suffered grade 3/4 toxicities (15.8%). No death related to treatment was observed. Conclusions The combination chemotherapy could be a promising treatment option for advanced metastatic RCC (mRCC) patients after sorafenib refractory.
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Affiliation(s)
- Zicheng Xu
- Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
| | - Xiao Li
- Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
| | - Feng Qi
- Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China.,Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xin Hu
- Department of Urology, First Clinical Medical College of Nanjing Medical University, Nanjing 210029, China
| | - Yuxiao Zheng
- Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
| | - Hongzhou Cai
- Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
| | - Ting Xu
- Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
| | - Bin Yu
- Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
| | - Qing Zou
- Department of Urologic Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
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Mak DW, Li S, Minchom A. Challenging the recalcitrant disease—developing molecularly driven treatments for small cell lung cancer. Eur J Cancer 2019; 119:132-150. [DOI: 10.1016/j.ejca.2019.04.037] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 04/11/2019] [Accepted: 04/26/2019] [Indexed: 12/29/2022]
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Willemsen AECAB, Tol J, van Erp NP, Jonker MA, de Boer M, Meek B, de Jong PC, van Moorsel C, Gerritsen WR, Grutters JC, van Herpen CML. Prospective Study of Drug-induced Interstitial Lung Disease in Advanced Breast Cancer Patients Receiving Everolimus Plus Exemestane. Target Oncol 2019; 14:441-451. [PMID: 31325105 PMCID: PMC6684805 DOI: 10.1007/s11523-019-00656-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Everolimus-related interstitial lung disease (ILD) (also: pneumonitis) poses a difficulty for physicians, as it is hard to discriminate ILD from other causes of respiratory symptoms and to decide on safe treatment continuation. OBJECTIVE We investigated the capability of pulmonary function tests (PFT), plasma biomarkers, everolimus pharmacokinetics, and FDG-PET to discriminate between everolimus-related ILD and other causes of respiratory problems and to predict the severity of ILD. PATIENTS AND METHODS Women starting treatment with everolimus plus exemestane for advanced breast cancer were included. At baseline and during the first 3 months, respiratory symptoms, PFT with diffusion capacity of the lungs for carbon monoxide corrected for hemoglobin (DLCOc) and forced vital capacity, serum plasma biomarkers (including SP-D and YKL-40), everolimus trough concentration, and 18F-FDG-PET were prospectively recorded. RESULTS Twenty-seven (out of 29 included) patients were evaluable for analysis. Fifteen patients (56%) developed everolimus-related respiratory signs or symptoms and four patients (15%) needed everolimus discontinuation and received corticosteroids. Change in DLCOc differentiated ILD from alternative diagnoses with 0.91 sensitivity and 0.78 specificity. Decrease in DLCOc (non-significant) was greatest in patients who needed everolimus discontinuation. Serum SP-D and YKL-40 could differentiate ILD from alternative diagnoses with 0.83 and 0.83 sensitivity, and 0.85 and 0.62 specificity, respectively. 18F-FDG-PET abnormalities did not precede clinical symptoms. No relationship between ILD and everolimus trough concentration was found. CONCLUSIONS This study shows that everolimus-related ILD occurs frequently. Prospective monitoring of DLCOc in combination with measurement of serum SP-D and YKL-40 appear useful to discriminate ILD from other causes of respiratory symptoms. Clinicaltrials.gov identifier: NCT01978171.
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Affiliation(s)
- Annelieke E C A B Willemsen
- Department of Medical Oncology, Radboud university medical center, route 452, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Jolien Tol
- Department of Medical Oncology, Jeroen Bosch Hospital, P.O. Box 90153, 5200 ME, 's Hertogenbosch, The Netherlands
| | - Nielka P van Erp
- Department of Pharmacy, Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Marianne A Jonker
- Department for Health Evidence, Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Maaike de Boer
- Division of Medical Oncology Department of Internal Medicine, GROW-School of Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Bob Meek
- Department of Pulmonology, St. Antonius Hospital, Centre of Interstitial Lung Diseases, Nieuwegein, The Netherlands
| | - Paul C de Jong
- Department of Medical Oncology, St. Antonius Hospital, Nieuwegein, The Netherlands
| | - Coline van Moorsel
- Department of Pulmonology, St. Antonius Hospital, Centre of Interstitial Lung Diseases, Nieuwegein, The Netherlands
- Division Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Winald R Gerritsen
- Department of Medical Oncology, Radboud university medical center, route 452, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Jan C Grutters
- Department of Pulmonology, St. Antonius Hospital, Centre of Interstitial Lung Diseases, Nieuwegein, The Netherlands
- Division Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Carla M L van Herpen
- Department of Medical Oncology, Radboud university medical center, route 452, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
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Wu JB, Tang YL, Liang XH. Targeting VEGF pathway to normalize the vasculature: an emerging insight in cancer therapy. Onco Targets Ther 2018; 11:6901-6909. [PMID: 30410348 PMCID: PMC6200071 DOI: 10.2147/ott.s172042] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Vascular normalization is a new concept of targeting angiogenesis to restore vessel structure and function and to increase blood perfusion and delivery of drugs. It has been confirmed that vascular normalization can decrease relapse and benefit other cancer therapy, including chemotherapy, radiotherapy, and immune cell therapy. The key point of this therapy is to inhibit pro-angiogenic factors and make it be balanced with anti-angiogenic factors, resulting in a mature and normal vessel characteristic. Vascular endothelial growth factor (VEGF) is a key player in the process of tumor angiogenesis, and inhibiting VEGF is a primary approach to tumor vessel normalization. Herein, we review newly uncovered mechanisms governing angiogenesis and vascular normalization of cancer and place emphasis on targeting VEGF pathway to normalize the vasculature. Also, important methods to depress VEGF pathway and make tumor vascular are discussed.
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Affiliation(s)
- Jing-Biao Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan, People's Republic of China, ;
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan, People's Republic of China, ;
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan, People's Republic of China, ;
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Tsuchiya N. Molecular-targeted therapy in advanced renal cell carcinoma based on pharmacokinetics, pharmacodynamics and pharmacogenetics: A proposed strategy. Int J Urol 2018; 26:48-56. [DOI: 10.1111/iju.13805] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 08/20/2018] [Indexed: 01/16/2023]
Affiliation(s)
- Norihiko Tsuchiya
- Department of Urology; Yamagata University Faculty of Medicine; Yamagata Japan
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Li X, Tang Y, Yu F, Sun Y, Huang F, Chen Y, Yang Z, Ding G. Inhibition of Prostate Cancer DU-145 Cells Proliferation by Anthopleura anjunae Oligopeptide (YVPGP) via PI3K/AKT/mTOR Signaling Pathway. Mar Drugs 2018; 16:E325. [PMID: 30208576 PMCID: PMC6165336 DOI: 10.3390/md16090325] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 09/06/2018] [Indexed: 12/12/2022] Open
Abstract
We investigated the antitumor mechanism of Anthopleura anjunae oligopeptide (AAP-H, YVPGP) in prostate cancer DU-145 cells in vitro and in vivo. Results indicated that AAP-H was nontoxic and exhibited antitumor activities. Cell cycle analysis indicated that AAP-H may arrest DU-145 cells in the S phase. The role of the phosphatidylinositol 3-kinase/protein kinase B/mammalian rapamycin target protein (PI3K/AKT/mTOR) signaling pathway in the antitumor mechanism of APP-H was investigated. Results showed that AAP-H treatment led to dose-dependent reduction in the levels of p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448), whereas t-AKT and t-PI3K levels remained unaltered compared to the untreated DU-145 cells. Inhibition of PI3K/AKT/mTOR signaling pathway in the DU-145 cells by employing inhibitor LY294002 (10 μM) or rapamycin (20 nM) effectively attenuated AAP-H-induced phosphorylation of AKT and mTOR. At the same time, inhibitor addition further elevated AAP-H-induced cleaved-caspase-3 levels. Furthermore, the effect of AAP-H on tumor growth and the role of the PI3K/AKT/mTOR signaling pathway in nude mouse model were also investigated. Immunohistochemical analysis showed that activated AKT, PI3K, and mTOR levels were reduced in DU-145 xenografts. Western blotting showed that AAP-H treatment resulted in dose-dependent reduction in p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448) levels, whereas t-AKT and t-PI3K levels remained unaltered. Similarly, Bcl-xL levels decreased, whereas that of Bax increased after AAP-H treatment. AAP-H also increased initiator (caspase 8 and 9) and executor caspase (caspase 3 and 7) levels. Therefore, the antitumor mechanism of APP-H on DU-145 cells may involve regulation of the PI3K/AKT/mTOR signaling pathway, which eventually promotes apoptosis via mitochondrial and death receptor pathways. Thus, the hydrophobic oligopeptide (YVPGP) can be developed as an adjuvant for the prevention or treatment of prostate cancer in the future.
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Affiliation(s)
- Xiaojuan Li
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316022, China.
| | - Yunping Tang
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316022, China.
| | - Fangmiao Yu
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316022, China.
| | - Yu Sun
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, Zhejiang Ocean University Donghai Science and Technology College, Zhoushan 316000, China.
| | - Fangfang Huang
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316022, China.
| | - Yan Chen
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316022, China.
| | - Zuisu Yang
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316022, China.
| | - Guofang Ding
- Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316022, China.
- Zhejiang Marine Fisheries Research Institution, Zhoushan 316021, China.
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Visalli T, Bower N, Kokate T, Andrews PA. Lack of value of juvenile animal toxicity studies for supporting the safety of pediatric oncology phase I trials. Regul Toxicol Pharmacol 2018; 96:167-177. [PMID: 29763632 DOI: 10.1016/j.yrtph.2018.05.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/07/2018] [Accepted: 05/11/2018] [Indexed: 02/04/2023]
Abstract
Toxicity studies in juvenile animals (JAS) are sometimes performed to support clinical trials in pediatric oncology patients, and there are differing conclusions on the value of JAS for pediatric drug development. This manuscript provides a review of the pediatric clinical data for 25 molecularly-targeted and 4 biologic anticancer therapeutics. Other publications that evaluated the value of JAS in pediatric drug development focus on differences in toxicity between juvenile animals and adult animals. The present paper examines pediatric-specific clinical findings to focus on dose setting in pediatric oncology patients and safety monitoring in terms of the potential value of JAS. Our assessment demonstrates that pediatric starting doses were safe for all 29 therapeutics examined in that no life-threatening toxicities occurred in the first cohort, and overall the ratio of the pediatric maximum tolerated dose (MTD) to the recommended adult dose was close to 1. In addition, the 4 serious adverse events (SAEs) that weren't detectable with standard monitoring plans for pediatric oncology trials would not have been detectable in a standard JAS. This review demonstrates that safe starting doses in pediatric oncology patients for these therapeutics could have been solely based on adult doses without any knowledge of findings in JAS.
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Affiliation(s)
- Thomas Visalli
- Eisai Inc., Global Nonclinical Regulatory Affairs, 155 Tice Boulevard, Woodcliff Lake, NJ 07677, United States.
| | - Nancy Bower
- Eisai Inc., Global Nonclinical Regulatory Affairs, 155 Tice Boulevard, Woodcliff Lake, NJ 07677, United States
| | - Tushar Kokate
- Eisai Inc., Global Nonclinical Regulatory Affairs, 155 Tice Boulevard, Woodcliff Lake, NJ 07677, United States
| | - Paul A Andrews
- Eisai Inc., Global Nonclinical Regulatory Affairs, 155 Tice Boulevard, Woodcliff Lake, NJ 07677, United States
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Abstract
Mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. mTORC1 and mTORC2 play key physiological roles as they control anabolic and catabolic processes in response to external cues in a variety of tissues and organs. However, mTORC1 and mTORC2 activities are deregulated in widespread human diseases, including cancer. Cancer cells take advantage of mTOR oncogenic signaling to drive their proliferation, survival, metabolic transformation, and metastatic potential. Therefore, mTOR lends itself very well as a therapeutic target for innovative cancer treatment. mTOR was initially identified as the target of the antibiotic rapamycin that displayed remarkable antitumor activity in vitro Promising preclinical studies using rapamycin and its derivatives (rapalogs) demonstrated efficacy in many human cancer types, hence supporting the launch of numerous clinical trials aimed to evaluate the real effectiveness of mTOR-targeted therapies. However, rapamycin and rapalogs have shown very limited activity in most clinical contexts, also when combined with other drugs. Thus, novel classes of mTOR inhibitors with a stronger antineoplastic potency have been developed. Nevertheless, emerging clinical data suggest that also these novel mTOR-targeting drugs may have a weak antitumor activity. Here, we summarize the current status of available mTOR inhibitors and highlight the most relevant results from both preclinical and clinical studies that have provided valuable insights into both their efficacy and failure.
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Alvarez RH, Bechara RI, Naughton MJ, Adachi JA, Reuben JM. Emerging Perspectives on mTOR Inhibitor-Associated Pneumonitis in Breast Cancer. Oncologist 2018; 23:660-669. [PMID: 29487226 DOI: 10.1634/theoncologist.2017-0343] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 01/03/2018] [Indexed: 01/14/2023] Open
Abstract
Substantial improvements in the early detection and treatment of breast cancer have led to improvements in survival, but breast cancer remains a significant cause of morbidity and mortality in women. In 2012, the mammalian target of rapamycin (mTOR) inhibitor everolimus was approved by the U.S. Food and Drug Administration for the treatment of advanced breast cancer in patients resistant to endocrine therapy. Although everolimus is generally well tolerated, mTOR inhibitor-associated pneumonitis is one of the most common adverse drug events leading to treatment discontinuation. To date, the underlying pathophysiology of this toxicity is unclear, and this uncertainty may hinder the optimization of management strategies. However, experiences from breast cancer and renal cell carcinoma clinical trials indicate that mTOR inhibitor-associated pneumonitis can be effectively managed by early detection, accurate diagnosis, and prompt intervention that generally involves everolimus dose reductions, interruptions, or discontinuation. Management can be achieved by a multidisciplinary approach that involves the collaborative efforts of nurses, oncologists, radiologists, infectious disease specialists, pulmonologists, clinical pharmacists, and pathologists. Comprehensive education must be provided to all health care professionals involved in managing patients receiving everolimus therapy. Although general recommendations on the management of mTOR inhibitor-associated pneumonitis have been published, there is a lack of consensus on the optimal management of this potentially serious complication. This article provides an overview of mTOR inhibitor-associated pneumonitis, with a focus on the detection, accurate diagnosis, and optimal management of this class-related complication of mTOR inhibitor therapy. IMPLICATIONS FOR PRACTICE This article summarizes the pathogenesis, clinical presentation, incidence, detection, and optimal management of everolimus-related noninfectious pneumonitis in breast cancer. In particular, this article provides a detailed overview of the important aspects of the detection, accurate diagnosis, and appropriate management of mammalian target of rapamycin inhibitor-associated pneumonitis. In addition, this article emphasizes that effective management of this adverse drug event in patients with breast cancer will require a multidisciplinary approach and collaboration among various health care professionals.
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Affiliation(s)
| | | | - Michael J Naughton
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Javier A Adachi
- The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - James M Reuben
- The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Grut H, Solberg S, Seierstad T, Revheim ME, Egge TS, Larsen SG, Line PD, Dueland S. Growth rates of pulmonary metastases after liver transplantation for unresectable colorectal liver metastases. Br J Surg 2018; 105:295-301. [PMID: 29168565 DOI: 10.1002/bjs.10651] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 06/21/2017] [Accepted: 06/23/2017] [Indexed: 02/11/2025]
Abstract
BACKGROUND The previously reported SECA study demonstrated a dramatic 5-year survival improvement in patients with unresectable colorectal liver metastases (CLM) treated with liver transplantation (LT) compared with chemotherapy. The objective of this study was to assess whether immunosuppressive therapy accelerates the growth of pulmonary metastases in patients transplanted for unresectable CLM. METHODS Chest CT scans from 11 patients in the SECA study resected for 18 pulmonary metastases were reviewed retrospectively. Tumour diameter, volume and CT characteristics were registered and tumour volume doubling time was calculated. Findings in the SECA group were compared with those of a control group consisting of 12 patients with non-transplanted rectal cancer resected for 26 pulmonary metastases. Disease-free survival (DFS) and overall survival (OS) after first pulmonary resection were determined. RESULTS Median doubling time based on tumour diameter and volume in the SECA and control groups were 125 and 130 days (P = 0·658) and 110 and 129 days (P = 0·632) respectively. The metastases in both groups were distributed to all lung lobes and were mostly peripheral. Median DFS after LT in the SECA group and after primary pelvic surgery in the control group was 17 (range 6-42) and 18 (2-57) months respectively (P = 0·532). In the SECA group, estimated 5-year DFS and OS rates after first pulmonary resection were 39 and 51 per cent respectively. CONCLUSION Patients treated by LT for unresectable CLM have a good prognosis following resection of pulmonary metastases. Doubling time did not appear to be worse with the immunosuppression used after LT.
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Affiliation(s)
- H Grut
- Division of Radiology and Nuclear Medicine, University of Oslo, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - S Solberg
- Department of Thoracic Surgery, University of Oslo, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - T Seierstad
- Division of Radiology and Nuclear Medicine, University of Oslo, Oslo, Norway
| | - M E Revheim
- Division of Radiology and Nuclear Medicine, University of Oslo, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - T S Egge
- Division of Radiology and Nuclear Medicine, University of Oslo, Oslo, Norway
| | - S G Larsen
- Department of Gastroenterological Surgery, University of Oslo, Oslo, Norway
| | - P D Line
- Department of Transplantation Medicine, University of Oslo, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - S Dueland
- Department of Oncology, Oslo University Hospital, Oslo, Norway
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Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus. Oncotarget 2018; 7:23227-38. [PMID: 26933802 PMCID: PMC5029622 DOI: 10.18632/oncotarget.7594] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 02/05/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Bevacizumab and temsirolimus are active agents in advanced solid tumors. Temsirolimus inhibits mTOR in the PI3 kinase/AKT/mTOR pathway as well as CYP2A, which may be a resistance mechanism for cetuximab. In addition, temsirolimus attenuates upregulation of HIF-1α levels, which may be a resistance mechanism for bevacizumab. RESULTS The median age of patients was 60 years (range, 23-80 years). The median number of prior systemic therapies was 3 (range, 1-6). The maximum tolerated dose (MTD) was determined to be bevacizumab 10 mg/kg biweekly, temsirolimus 5 mg weekly and cetuximab 100/75 mg/m2 weekly. Grade 3 or 4 toxicities were seen in 52% of patients with the highest prevalence being hyperglycemia (14%) and hypophosphatemia (14%). Eighteen of the 21 patients were evaluable for response. Three patients were taken off the study before restaging for toxicities. Partial response (PR) was observed in 2/18 patients (11%) and stable disease (SD) lasting ≥ 6 months was observed in 4/18 patients (22%) (total = 6/18 (33%)). In 8 evaluable patients with squamous cell carcinoma of the head and neck (HNSCC) there were partial responses in 2/8 (25%) patients and SD ≥ 6 months in 1/8 (13%) patients (total = 3/8, (38%)). PATIENTS AND METHODS We analyzed safety and responses in 21 patients with advanced solid tumors treated with bevacizumab, cetuximab, and temsirolimus. CONCLUSION The combination of bevacizumab, cetuximab, and temsirolimus showed activity in HNSCC; however, there were numerous toxicities reported, which will require careful management for future clinical development.
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Satoh T, Koie T, Horiguchi H, Tokui N, Narita S, Ohyama C. Longer recurrence-free survival in a patient with metastatic renal cell carcinoma treated with temsirolimus. Clin Case Rep 2017; 5:1950-1953. [PMID: 29225833 PMCID: PMC5715416 DOI: 10.1002/ccr3.1181] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 08/03/2017] [Accepted: 08/22/2017] [Indexed: 01/05/2023] Open
Abstract
Temsirolimus did not demonstrate an efficacy advantage compared with sorafenib as second-line therapy in patients with metastatic renal cell carcinoma (mRCC). Only a few patients achieved complete responses, and the median progression-free survival rate remains short. We report one patient with mRCC who had a continuing response to temsirolimus.
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Affiliation(s)
- Tendo Satoh
- Department of UrologyOdate Municipal General HospitalOdateJapan
| | - Takuya Koie
- Department of UrologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Hirotaka Horiguchi
- Department of UrologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Noriko Tokui
- Department of UrologyOdate Municipal General HospitalOdateJapan
| | - Satoshi Narita
- Department of UrologyOdate Municipal General HospitalOdateJapan
| | - Chikara Ohyama
- Department of UrologyHirosaki University Graduate School of MedicineHirosakiJapan
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Sánchez-Gastaldo A, Kempf E, González del Alba A, Duran I. Systemic treatment of renal cell cancer: A comprehensive review. Cancer Treat Rev 2017; 60:77-89. [DOI: 10.1016/j.ctrv.2017.08.010] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Revised: 08/26/2017] [Accepted: 08/26/2017] [Indexed: 12/27/2022]
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Ghidini M, Petrelli F, Ghidini A, Tomasello G, Hahne JC, Passalacqua R, Barni S. Clinical development of mTor inhibitors for renal cancer. Expert Opin Investig Drugs 2017; 26:1229-1237. [DOI: 10.1080/13543784.2017.1384813] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Michele Ghidini
- Oncology Unit, Oncology Department, ASST Ospedale di Cremona, Cremona, Italy
| | - Fausto Petrelli
- Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio, Italy
| | | | - Gianluca Tomasello
- Oncology Unit, Oncology Department, ASST Ospedale di Cremona, Cremona, Italy
| | - Jens Claus Hahne
- Laboratory of Gastrointestinal Cancer Biology and Genomics, Division of Molecular Pathology, The Institute of Cancer Research, Sutton, UK
| | - Rodolfo Passalacqua
- Oncology Unit, Oncology Department, ASST Ospedale di Cremona, Cremona, Italy
| | - Sandro Barni
- Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio, Italy
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50
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Briggs JW, Ren L, Chakrabarti KR, Tsai YC, Weissman AM, Hansen RJ, Gustafson DL, Khan YA, Dinman JD, Khanna C. Activation of the unfolded protein response in sarcoma cells treated with rapamycin or temsirolimus. PLoS One 2017; 12:e0185089. [PMID: 28926611 PMCID: PMC5605117 DOI: 10.1371/journal.pone.0185089] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 09/06/2017] [Indexed: 01/21/2023] Open
Abstract
Activation of the unfolded protein response (UPR) in eukaryotic cells represents an evolutionarily conserved response to physiological stress. Here, we report that the mTOR inhibitors rapamycin (sirolimus) and structurally related temsirolimus are capable of inducing UPR in sarcoma cells. However, this effect appears to be distinct from the classical role for these drugs as mTOR inhibitors. Instead, we detected these compounds to be associated with ribosomes isolated from treated cells. Specifically, temsirolimus treatment resulted in protection from chemical modification of several rRNA residues previously shown to bind rapamycin in prokaryotic cells. As an application for these findings, we demonstrate maximum tumor cell growth inhibition occurring only at doses which induce UPR and which have been shown to be safely achieved in human patients. These results are significant because they challenge the paradigm for the use of these drugs as anticancer agents and reveal a connection to UPR, a conserved biological response that has been implicated in tumor growth and response to therapy. As a result, eIF2 alpha phosphorylation and Xbp-1 splicing may serve as useful biomarkers of treatment response in future clinical trials using rapamycin and rapalogs.
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Affiliation(s)
- Joseph W. Briggs
- Tumor Metastasis Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
- * E-mail:
| | - Ling Ren
- Tumor Metastasis Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Kristi R. Chakrabarti
- Tumor Metastasis Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Yien Che Tsai
- Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America
| | - Allan M. Weissman
- Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America
| | - Ryan J. Hansen
- Colorado State University Flint Animal Cancer Center, Fort Collins, Colorado, United States of America
| | - Daniel L. Gustafson
- Colorado State University Flint Animal Cancer Center, Fort Collins, Colorado, United States of America
| | - Yousuf A. Khan
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America
| | - Jonathan D. Dinman
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland, United States of America
| | - Chand Khanna
- Tumor Metastasis Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
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