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1
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Jensen L, Guo Z, Sun X, Jing X, Yang Y, Cao Y. Angiogenesis, signaling pathways, and animal models. Chin Med J (Engl) 2025; 138:1153-1162. [PMID: 40254738 PMCID: PMC12091601 DOI: 10.1097/cm9.0000000000003561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Indexed: 04/22/2025] Open
Abstract
ABSTRACT The vasculature plays a critical role in homeostasis and health as well as in the development and progression of a wide range of diseases, including cancer, cardiovascular diseases, metabolic diseases (and their complications), chronic inflammatory diseases, ophthalmic diseases, and neurodegenerative diseases. As such, the growth of the vasculature mediates normal development and physiology, as well as disease, when pathologically induced vessels are morphologically and functionally altered owing to an imbalance of angiogenesis-stimulating and angiogenesis-inhibiting factors. This review offers an overview of the angiogenic process and discusses recent findings that provide additional interesting nuances to this process, including the roles of intussusception and angiovasculogenesis, which may hold promise for future therapeutic interventions. In addition, we review the methodology, including those of in vitro and in vivo assays, which has helped build the vast amount of knowledge on angiogenesis available today and identify important remaining knowledge gaps that should be bridged through future research.
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Affiliation(s)
- Lasse Jensen
- Department of Health, Medical and Caring Sciences, Unit of Diagnostics and Specialist Medicine, Linköping University, Linköping SE-58183, Sweden
| | - Ziheng Guo
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xiaoting Sun
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vison and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325024, China
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna 17165, Sweden
| | - Xu Jing
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna 17165, Sweden
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna 17165, Sweden
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Lee C, Kim MJ, Kumar A, Lee HW, Yang Y, Kim Y. Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives. Signal Transduct Target Ther 2025; 10:170. [PMID: 40383803 PMCID: PMC12086256 DOI: 10.1038/s41392-025-02249-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/09/2025] [Accepted: 04/21/2025] [Indexed: 05/20/2025] Open
Abstract
Vascular endothelial growth factor (VEGF) signaling is a critical regulator of vasculogenesis, angiogenesis, and lymphangiogenesis, processes that are vital for the development of vascular and lymphatic systems, tissue repair, and the maintenance of homeostasis. VEGF ligands and their receptors orchestrate endothelial cell proliferation, migration, and survival, playing a pivotal role in dynamic vascular remodeling. Dysregulated VEGF signaling drives diverse pathological conditions, including tumor angiogenesis, cardiovascular diseases, and ocular disorders. Excessive VEGF activity promotes tumor growth, invasion, and metastasis, while insufficient signaling contributes to impaired wound healing and ischemic diseases. VEGF-targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have revolutionized the treatment of diseases involving pathological angiogenesis, offering significant clinical benefits in oncology and ophthalmology. These therapies inhibit angiogenesis and slow disease progression, but they often face challenges such as therapeutic resistance, suboptimal efficacy, and adverse effects. To further explore these issues, this review provides a comprehensive overview of VEGF ligands and receptors, elucidating their molecular mechanisms and regulatory networks. It evaluates the latest progress in VEGF-targeted therapies and examines strategies to address current challenges, such as resistance mechanisms. Moreover, the discussion includes emerging therapeutic strategies such as innovative drug delivery systems and combination therapies, highlighting the continuous efforts to improve the effectiveness and safety of VEGF-targeted treatments. This review highlights the translational potential of recent discoveries in VEGF biology for improving patient outcomes.
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Affiliation(s)
- Chunsik Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea.
| | - Myung-Jin Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea
| | - Anil Kumar
- Center for Research and Innovations, Adichunchanagiri University, Mandya, Karnataka, India
| | - Han-Woong Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yonghwan Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea.
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Hasegawa K, Nishio S, Yamamoto K, Fujiwara H, Itagaki H, Nagai T, Takano H, Yamaguchi S, Kudoh A, Suzuki Y, Nakamoto T, Kurosaki A, Kamio M, Kato K, Nakamura K, Takehara K, Yahata H, Kobayashi H, Saito M, Fujiwara K. Tegafur-uracil maintenance chemotherapy post-chemoradiotherapy for cervical cancer: Randomized trial. Eur J Cancer 2025; 219:115304. [PMID: 40010135 DOI: 10.1016/j.ejca.2025.115304] [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: 10/24/2024] [Revised: 01/31/2025] [Accepted: 02/01/2025] [Indexed: 02/28/2025]
Abstract
AIM Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer (LACC), but recurrence rates remain high. This multicenter phase-3 randomized trial (GOTIC-002) evaluated the efficacy of low-dose oral tegafur-uracil (UFT) as maintenance chemotherapy following curative CCRT for LACC. METHODS Between 2010 and 2018, 351 patients with stage Ib2-IVa cervical cancer were enrolled. After achieving complete or partial remission post-CCRT, patients were randomized 1:1 into observation (arm O) or UFT maintenance therapy (arm UFT). UFT doses were 300-400 mg/day based on body surface area for 2 years, disease progression or adverse effects occurred. The primary endpoint was progression-free survival (PFS), with overall survival (OS) and safety as secondary endpoints. RESULTS Patient characteristics were similar between the groups (n = 178 in arm O, n = 173 in arm UFT). During a median follow-up of 3 years, median PFS was not reached in either group. 5-year PFS rates were similar between them (arm O: 61.3 %, arm UFT: 62.0 %, hazard ratio: 0.92, P = .634). 5-year OS rates were also comparable (77.6 % vs 76.1 %, hazard ratio: 1.04, P = .869). Compliance with UFT ranged from 87.8 % to 98.8 %. Although adverse events were more frequent in arm UFT (93.5 % vs 73.9 %, odds ratio: 5.05), most were mild or moderate. Despite its tolerability, UFT did not improve PFS or OS. CONCLUSIONS These findings suggest the need to reconsider maintenance therapy strategies after CCRT for potentially shifting away from cytotoxic chemotherapy towards alternative methods to enhance survival outcomes in patients with LACC.
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Affiliation(s)
- Kosei Hasegawa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Japan.
| | - Shin Nishio
- Department of Obstetrics and Gynecology, Kurume University, Japan
| | - Kouji Yamamoto
- Department of Biostatistics, Yokohama City University, Japan
| | - Hiroyuki Fujiwara
- Department of Obstetrics and Gynecology, Jichi Medical University, Japan
| | - Hiroya Itagaki
- Department of Obstetrics and Gynecology, University of Tsukuba, Japan
| | - Tomonori Nagai
- Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University, Japan
| | - Hirokuni Takano
- Department of Obstetrics and Gynecology, Jikei University Kashiwa Hospital, Japan
| | | | - Akiko Kudoh
- Department of Obstetrics and Gynecology, Tottori University, Japan
| | - Yurina Suzuki
- Department of Gynecology, Saitama Cancer Center, Japan
| | - Tomoko Nakamoto
- Department of Obstetrics and Gynecology, The University of the Ryukyus, Japan
| | - Akira Kurosaki
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Japan
| | - Masaaki Kamio
- Department of Gynecologic Oncology, Kagoshima Medical Center, Japan
| | - Kazuyoshi Kato
- Department of Obstetrics and Gynecology, Kitasato University, Japan
| | - Kazuto Nakamura
- Department of Gynecologic Oncology, Gunma Prefectural Cancer Center, Japan
| | - Kazuhiro Takehara
- Department of Gynecologic Oncology, NHO Shikoku Cancer Center, Japan
| | - Hideaki Yahata
- Department of Obstetrics and Gynecology, Kyushu University, Japan
| | | | - Motoaki Saito
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Japan
| | - Keiichi Fujiwara
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Japan
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Guarini C, Santoro AN, Melaccio A, Lanotte L, Gadaleta-Caldarola G, Giuliani F, Pinto A, Fedele P. Metronomic chemotherapy and breast cancer: a critical evaluation of its role in the new landscape of therapeutics. Expert Opin Drug Saf 2025; 24:9-16. [PMID: 39422380 DOI: 10.1080/14740338.2024.2419547] [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: 04/29/2024] [Revised: 08/20/2024] [Accepted: 10/15/2024] [Indexed: 10/19/2024]
Abstract
INTRODUCTION Breast cancer (BC) remains a prevalent and challenging malignancy among women, with significant advancements in treatment strategies over the past decades. Traditional chemotherapy has been progressively supplemented by newer modalities, including Antibody-Drug Conjugates (ADCs), Immunotherapy (IO), and Targeted Therapies (TT). Despite these advancements, there remains a critical need for strategies that maintain efficacy while minimizing toxicity. AREAS COVERED This review delves into metronomic chemotherapy (MC), a novel approach involving the frequent administration of low-dose chemotherapy without prolonged breaks. We explore MC's impact across various breast cancer subtypes, such as Estrogen Receptor-Positive (ER+), HER2-Positive, and Triple-Negative Breast Cancer (TNBC). The literature reviewed highlights MC's mechanisms, including its anti-angiogenic, immunomodulatory, and antiproliferative effects, and its potential to improve treatment tolerability and address drug resistance. EXPERT OPINION MC represents a promising adjunct to existing therapies, particularly in advanced or resistant cases. Its unique dosing schedule could offer sustained antitumor activity with reduced toxicity, making it a viable option for long-term management. However, further research is warranted to establish optimal dosing regimens, identify predictive biomarkers, and delineate its role within combination treatment strategies. Clarifying these aspects could refine MC's application, potentially reshaping treatment paradigms and enhancing patient outcomes in breast cancer management.
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Affiliation(s)
- Chiara Guarini
- Medical Oncology Unit, 'Dario Camberlingo' Hospital, Francavilla Fontana, Brindisi, Italy
| | - Anna Natalizia Santoro
- Medical Oncology Unit, 'Dario Camberlingo' Hospital, Francavilla Fontana, Brindisi, Italy
| | | | - Laura Lanotte
- Medical Oncology Unit, 'Mons. Dimiccoli' Hospital, Barletta, Italy
| | | | | | - Antonello Pinto
- Medical Oncology Unit, 'Dario Camberlingo' Hospital, Francavilla Fontana, Brindisi, Italy
| | - Palma Fedele
- Medical Oncology Unit, 'Dario Camberlingo' Hospital, Francavilla Fontana, Brindisi, Italy
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Barranco MM, Zecchinati F, Perdomo VG, Habib MJ, Rico MJ, Rozados VR, Salazar M, Fusini ME, Scharovsky OG, Villanueva SSM, Mainetti LE, García F. Intestinal ABC transporters: Influence on the metronomic cyclophosphamide-induced toxic effect in an obese mouse mammary cancer model. Toxicol Appl Pharmacol 2024; 492:117130. [PMID: 39426530 DOI: 10.1016/j.taap.2024.117130] [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: 01/18/2024] [Revised: 09/26/2024] [Accepted: 10/16/2024] [Indexed: 10/21/2024]
Abstract
Metronomic chemotherapy (MCT) is a cancer therapeutic approach characterized by low dose drug chronic administration and limited or null toxicity. Obesity-induced metabolic alterations worsen cancer prognosis and influence the intestinal biochemical barrier, altering the Multidrug resistance-associated protein 2 (Mrp2) and Multidrug resistance protein-1 (Mdr-1), efflux pumps that transport chemotherapeutic drugs. Obesity and cancer are frequent co-morbidities; thus, our aim was to evaluate the effectiveness and toxicity of MCT with cyclophosphamide (Cy) in obese mice with metabolic alterations bearing a mammary adenocarcinoma. Simultaneously, the expression and activities of intestinal Mrp2 and Mdr-1 were assessed. CBi male mice, were fed with chow diet (C) or diet with 40 % of fat (HFD). After 16 weeks, metabolic alterations were confirmed by biochemical and morphological parameters. At that time-point, HFD group showed decreased expressions of Mrp2 mRNA (53 %) as well as Mdr-1a and Mdr-1b (42 % and 59 %, respectively), compared to C (P < 0.05). This result correlated with decreased intestinal Mrp2 and Mdr-1 efflux activities (64 % and 45 %, respectively), compared to C (P < 0.05). Ultimately, mice were challenged with M-406 mammary adenocarcinoma; when the tumor was palpable, mice were distributed into 4 groups. The % inhibition of tumor growth with Cy (30 mg/kg/day) in C + Cy was higher than that of HFD + Cy (P = 0.052). Besides, it was observed a 21 % diminution in body weight and leukopenia in the HFD + Cy group. Conclusion: Obesity-induced metabolic alterations impair intestinal Mrp2 and Mdr-1 functions, bringing about increments in Cy absorption, leading to toxicity; in addition, the antitumor effectiveness of MCT decreased in obese animals.
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MESH Headings
- Animals
- Cyclophosphamide/toxicity
- Mice
- Obesity/metabolism
- Male
- Female
- Administration, Metronomic
- Multidrug Resistance-Associated Protein 2
- Antineoplastic Agents, Alkylating/toxicity
- Mammary Neoplasms, Experimental/metabolism
- Mammary Neoplasms, Experimental/drug therapy
- Mammary Neoplasms, Experimental/pathology
- Mammary Neoplasms, Experimental/chemically induced
- Mice, Obese
- Multidrug Resistance-Associated Proteins/metabolism
- Multidrug Resistance-Associated Proteins/genetics
- Intestinal Mucosa/drug effects
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/pathology
- Adenocarcinoma/pathology
- Adenocarcinoma/drug therapy
- Adenocarcinoma/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- ATP-Binding Cassette Transporters/metabolism
- ATP-Binding Cassette Transporters/genetics
- Diet, High-Fat
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Affiliation(s)
- María Manuela Barranco
- Laboratorio de Fisiología Metabólica, Facultad de Ciencias Médicas, Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina.; CONICET-Rosario. Rosario, Santa Fe, Argentina
| | - Felipe Zecchinati
- CONICET-Rosario. Rosario, Santa Fe, Argentina.; Instituto de Fisiología Experimental-CONICET. Rosario, Santa Fe, Argentina
| | - Virginia Gabriela Perdomo
- CONICET-Rosario. Rosario, Santa Fe, Argentina.; Facultad de Ciencias Bioquímicas y Farmacéuticas-Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina
| | - Martín José Habib
- Laboratorio de Fisiología Metabólica, Facultad de Ciencias Médicas, Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina
| | - María José Rico
- CONICET-Rosario. Rosario, Santa Fe, Argentina.; Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina
| | - Viviana Rosa Rozados
- CONICET-Rosario. Rosario, Santa Fe, Argentina.; Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina
| | - Mario Salazar
- CONICET-Rosario. Rosario, Santa Fe, Argentina.; Laboratorio de Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina
| | - Matías Ezequiel Fusini
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina
| | - Olga Graciela Scharovsky
- CONICET-Rosario. Rosario, Santa Fe, Argentina.; Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina.; CIC-UNR, Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina
| | | | - Leandro Ernesto Mainetti
- CONICET-Rosario. Rosario, Santa Fe, Argentina.; Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina
| | - Fabiana García
- Laboratorio de Fisiología Metabólica, Facultad de Ciencias Médicas, Universidad Nacional de Rosario. Rosario, Santa Fe, Argentina.; CONICET-Rosario. Rosario, Santa Fe, Argentina..
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6
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Guelfi S, Hodivala-Dilke K, Bergers G. Targeting the tumour vasculature: from vessel destruction to promotion. Nat Rev Cancer 2024; 24:655-675. [PMID: 39210063 DOI: 10.1038/s41568-024-00736-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2024] [Indexed: 09/04/2024]
Abstract
As angiogenesis was recognized as a core hallmark of cancer growth and survival, several strategies have been implemented to target the tumour vasculature. Yet to date, attempts have rarely been so diverse, ranging from vessel growth inhibition and destruction to vessel normalization, reprogramming and vessel growth promotion. Some of these strategies, combined with standard of care, have translated into improved cancer therapies, but their successes are constrained to certain cancer types. This Review provides an overview of these vascular targeting approaches and puts them into context based on our subsequent improved understanding of the tumour vasculature as an integral part of the tumour microenvironment with which it is functionally interlinked. This new knowledge has already led to dual targeting of the vascular and immune cell compartments and sets the scene for future investigations of possible alternative approaches that consider the vascular link with other tumour microenvironment components for improved cancer therapy.
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Affiliation(s)
- Sophie Guelfi
- Department of Oncology, VIB-KU Leuven Center for Cancer Biology and KU Leuven, Leuven, Belgium
| | - Kairbaan Hodivala-Dilke
- Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK.
| | - Gabriele Bergers
- Department of Oncology, VIB-KU Leuven Center for Cancer Biology and KU Leuven, Leuven, Belgium.
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7
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Quaggin SE. A half-century of VEGFA: from theory to practice. J Clin Invest 2024; 134:e184205. [PMID: 39087477 PMCID: PMC11290956 DOI: 10.1172/jci184205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2024] Open
Affiliation(s)
- Susan E. Quaggin
- Feinberg Cardiovascular & Renal Research Institute, and
- Division of Nephrology, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
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8
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Mpekris F, Panagi M, Charalambous A, Voutouri C, Stylianopoulos T. Modulating cancer mechanopathology to restore vascular function and enhance immunotherapy. Cell Rep Med 2024; 5:101626. [PMID: 38944037 PMCID: PMC11293360 DOI: 10.1016/j.xcrm.2024.101626] [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: 01/10/2024] [Revised: 04/12/2024] [Accepted: 06/07/2024] [Indexed: 07/01/2024]
Abstract
Solid tumor pathology, characterized by abnormalities in the tumor microenvironment (TME), challenges therapeutic effectiveness. Mechanical factors, including increased tumor stiffness and accumulation of intratumoral forces, can determine the success of cancer treatments, defining the tumor's "mechanopathology" profile. These abnormalities cause extensive vascular compression, leading to hypoperfusion and hypoxia. Hypoperfusion hinders drug delivery, while hypoxia creates an unfavorable TME, promoting tumor progression through immunosuppression, heightened metastatic potential, drug resistance, and chaotic angiogenesis. Strategies targeting TME mechanopathology, such as vascular and stroma normalization, hold promise in enhancing cancer therapies with some already advancing to the clinic. Normalization can be achieved using anti-angiogenic agents, mechanotherapeutics, immune checkpoint inhibitors, engineered bacterial therapeutics, metronomic nanomedicine, and ultrasound sonopermeation. Here, we review the methods developed to rectify tumor mechanopathology, which have even led to cures in preclinical models, and discuss their bench-to-bedside translation, including the derivation of biomarkers from tumor mechanopathology for personalized therapy.
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Affiliation(s)
- Fotios Mpekris
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
| | - Myrofora Panagi
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | - Antonia Charalambous
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | - Chrysovalantis Voutouri
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | - Triantafyllos Stylianopoulos
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
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9
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Kirti A, Simnani FZ, Jena S, Lenka SS, Kalalpitiya C, Naser SS, Singh D, Choudhury A, Sahu RN, Yadav A, Sinha A, Nandi A, Panda PK, Kaushik NK, Suar M, Verma SK. Nanoparticle-mediated metronomic chemotherapy in cancer: A paradigm of precision and persistence. Cancer Lett 2024; 594:216990. [PMID: 38801886 DOI: 10.1016/j.canlet.2024.216990] [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: 09/04/2023] [Revised: 03/05/2024] [Accepted: 05/23/2024] [Indexed: 05/29/2024]
Abstract
Current methods of cancer therapy have demonstrated enormous potential in tumor inhibition. However, a high dosage regimen of chemotherapy results in various complications which affect the normal body cells. Tumor cells also develop resistance against the prescribed drugs in the whole treatment regimen increasing the risk of cancer relapse. Metronomic chemotherapy is a modern treatment method that involves administering drugs at low doses continuously, allowing the drug sufficient time to take its effect. This method ensures that the toxicity of the drugs is to a minimum in comparison to conventional chemotherapy. Nanoparticles have shown efficacy in delivering drugs to the tumor cells in various cancer therapies. Combining nanoparticles with metronomic chemotherapy can yield better treatment results. This combination stimulates the immune system, improving cancer cells recognition by immune cells. Evidence from clinical and pre-clinical trials supports the use of metronomic delivery for drug-loaded nanoparticles. This review focuses on the functionalization of nanoparticles for improved drug delivery and inhibition of tumor growth. It emphasizes the mechanisms of metronomic chemotherapy and its conjunction with nanotechnology. Additionally, it explores tumor progression and the current methods of chemotherapy. The challenges associated with nano-based metronomic chemotherapy are outlined, paving the way for prospects in this dynamic field.
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Affiliation(s)
- Apoorv Kirti
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | | | - Snehasmita Jena
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | - Sudakshya S Lenka
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | | | | | - Dibyangshee Singh
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | - Anmol Choudhury
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | - Rudra Narayan Sahu
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | - Anu Yadav
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | - Adrija Sinha
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | - Aditya Nandi
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India; Instituto de Investigaciones en Materiales, UNAM, 04510, CDMX, Mexico
| | - Pritam Kumar Panda
- Condensed Matter Theory Group, Materials Theory Division, Department of Physics and Astronomy, Uppsala University, Box 516, SE-751 20, Uppsala, Sweden
| | - Nagendra Kumar Kaushik
- Plasma Bioscience Research Center, Department of Electrical and Biological Physics, Kwangwoon University, Seoul, 01897, Republic of Korea.
| | - Mrutyunjay Suar
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India.
| | - Suresh K Verma
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India.
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10
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Minichmayr IK, Knaack U, Gojo J, Senfter D, Haberler C, Azizi AA, Mayr L, Zeitlinger M, Peyrl A. Distribution of Bevacizumab into the Cerebrospinal Fluid of Children and Adolescents with Recurrent Brain Tumors. Paediatr Drugs 2024; 26:429-440. [PMID: 38587585 PMCID: PMC11192692 DOI: 10.1007/s40272-024-00624-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/04/2024] [Indexed: 04/09/2024]
Abstract
BACKGROUND To date, evidence has been lacking regarding bevacizumab pharmacokinetics in the cerebrospinal fluid (CSF). OBJECTIVE This study assessed the penetration of bevacizumab, as part of a metronomic antiangiogenic treatment regimen, into the CSF of children, adolescents, and young adults with recurrent brain tumors. PATIENTS AND METHODS Serum and CSF concentrations, malignant cells, and vascular endothelial growth factor A (VEGF-A) were analyzed in 12 patients (5-27 years) following 10 mg/kg bevacizumab intravenous biweekly administration (EudraCT number 2009-013024-23). A population pharmacokinetic model including body weight, albumin, and tumor type as influential factors was extended to quantify the CSF penetration of bevacizumab. RESULTS Apart from in serum (minimum concentration/maximum concentration [Cmin/Cmax] 77.0-305/267-612 mg/L, median 144/417 mg/L), bevacizumab could be quantified in the CSF (0.01-2.26 mg/L, median 0.35 mg/L). The CSF/serum ratio was 0.16 and highly variable between patients. Malignant cells could be detected in CSF before initiation of treatment in five of 12 patients; after treatment, the CSF was cleared in all patients. VEGF-A was detected in three patients before treatment (mean ± SD: 20 ± 11 pg/mL), and was still measurable in one of these patients despite treatment (16 pg/mL). CONCLUSIONS This pharmacokinetic pilot study indicated penetration of bevacizumab into the CSF in a population of children, adolescents, and young adults with recurrent brain tumors.
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Affiliation(s)
- Iris K Minichmayr
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Ursula Knaack
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Johannes Gojo
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Daniel Senfter
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Christine Haberler
- Department of Neurology, Division of Neuropathology and Neurochemistry, Medical University of Vienna, Vienna, Austria
| | - Amedeo A Azizi
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Lisa Mayr
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Markus Zeitlinger
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Andreas Peyrl
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
- Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.
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11
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Petrucci GN, Magalhães TR, Dias M, Queiroga FL. Metronomic chemotherapy: bridging theory to clinical application in canine and feline oncology. Front Vet Sci 2024; 11:1397376. [PMID: 38903691 PMCID: PMC11187343 DOI: 10.3389/fvets.2024.1397376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 05/22/2024] [Indexed: 06/22/2024] Open
Abstract
Veterinary oncology has experienced significant evolution over the last few decades, with chemotherapy being currently applied to several neoplasms with therapeutic success. Traditionally, chemotherapy protocols are based on classic cytostatic drugs under the concept of maximum tolerated dose (MTD), which has been associated with a greater risk of toxicity and resistance. Thus, new therapeutic alternatives have emerged, such as metronomic chemotherapy (MC), introducing a new paradigm in cancer treatment. MC consists of administering low doses of chemotherapy drugs continuously over a long period of time, modulating the tumour microenvironment (TME) due to the combination of cytotoxic, antiangiogenic and immunomodulatory effects. This multi-targeted therapy has been described as a treatment option in several canine and feline cancers since 2007, with positive results already published in the literature, particularly in mammary carcinomas and soft tissue sarcomas in dogs. The aim of this review article is to describe the current knowledge about the use of MC in small animal oncology, with emphasis on its mechanisms of action, the most commonly used drugs and clinical outcome.
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Affiliation(s)
- Gonçalo N. Petrucci
- Onevet Hospital Veterinário do Porto, Porto, Portugal
- Animal and Veterinary Department, University Institute of Health Sciences, CESPU, CRL, Gandra, Portugal
- Animal and Veterinary Research Centre (CECAV), University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
- Department of Veterinary Sciences, Center for Investigation Vasco da Gama (CIVG), Vasco da Gama University School (EUVG), Coimbra, Portugal
| | - Tomás Rodrigues Magalhães
- Animal and Veterinary Research Centre (CECAV), University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
| | - Márcia Dias
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
| | - Felisbina Luísa Queiroga
- Animal and Veterinary Research Centre (CECAV), University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
- Department of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
- Centre for the Study of Animal Science, CECA-ICETA, University of Porto, Porto, Portugal
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12
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Wu HL, Zhou HX, Chen LM, Wang SS. Metronomic chemotherapy in cancer treatment: new wine in an old bottle. Theranostics 2024; 14:3548-3564. [PMID: 38948068 PMCID: PMC11209710 DOI: 10.7150/thno.95619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 05/26/2024] [Indexed: 07/02/2024] Open
Abstract
Over the past two decades, metronomic chemotherapy has gained considerable attention and has demonstrated remarkable success in the treatment of cancer. Through chronic administration and low-dose regimens, metronomic chemotherapy is associated with fewer adverse events but still effectively induces disease control. The identification of its antiangiogenic properties, direct impact on cancer cells, immunomodulatory effects on the tumour microenvironment, and metabolic reprogramming ability has established the intrinsic multitargeted nature of this therapeutic approach. Recently, the utilization of metronomic chemotherapy has evolved from salvage treatment for metastatic disease to adjuvant maintenance therapy for high-risk cancer patients, which has been prompted by the success of several substantial phase III trials. In this review, we delve into the mechanisms underlying the antitumour effects of metronomic chemotherapy and provide insights into potential combinations with other therapies for the treatment of various malignancies. Additionally, we discuss health-economic advantages and candidates for the utilization of this treatment option.
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Affiliation(s)
| | | | | | - Shu-sen Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China
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13
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Arora G, Bairagi N, Chatterjee S. A mathematical model to study low-dose metronomic scheduling for chemotherapy. Math Biosci 2024; 372:109186. [PMID: 38580078 DOI: 10.1016/j.mbs.2024.109186] [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: 12/15/2023] [Revised: 02/21/2024] [Accepted: 03/27/2024] [Indexed: 04/07/2024]
Abstract
Metronomic chemotherapy refers to the frequent administration of chemotherapeutic agents at a lower dose and presents an attractive alternative to conventional chemotherapy with encouraging response rates. However, the schedule of the therapy, including the dosage of the drug, is usually based on empiricism. The confounding effects of tumor-endothelial-immune interactions during metronomic administration of drugs have not yet been explored in detail, resulting in an incomplete assessment of drug dose and frequency evaluations. The present study aimed to gain a mechanistic understanding of different actions of metronomic chemotherapy using a mathematical model. We have established an analytical condition for determining the dosage and frequency of the drug depending on its clearance rate for complete tumor elimination. The model also brings forward the immune-mediated clearance of the tumor during the metronomic administration of the chemotherapeutic agent. The results from the global sensitivity analysis showed an increase in the sensitivity of drug and immune-mediated killing factors toward the tumor population during metronomic scheduling. Our results emphasize metronomic scheduling over the maximum tolerated dose (MTD) and define a model-based approach for approximating the optimal schedule of drug administration to eliminate tumors while minimizing harm to the immune cells and the patient's body.
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Affiliation(s)
- Garhima Arora
- Complex Analysis Group, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, 121001, India
| | - Nandadulal Bairagi
- Department of Mathematics, Centre for Mathematical Biology and Ecology, Jadavpur University, Kolkata, 700032, India
| | - Samrat Chatterjee
- Complex Analysis Group, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, 121001, India.
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14
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Basar OY, Mohammed S, Qoronfleh MW, Acar A. Optimizing cancer therapy: a review of the multifaceted effects of metronomic chemotherapy. Front Cell Dev Biol 2024; 12:1369597. [PMID: 38813084 PMCID: PMC11133583 DOI: 10.3389/fcell.2024.1369597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 04/29/2024] [Indexed: 05/31/2024] Open
Abstract
Metronomic chemotherapy (MCT), characterized by the continuous administration of chemotherapeutics at a lower dose without prolonged drug-free periods, has garnered significant attention over the last 2 decades. Extensive evidence from both pre-clinical and clinical settings indicates that MCT induces distinct biological effects than the standard Maximum Tolerated Dose (MTD) chemotherapy. The low toxicity profile, reduced likelihood of inducing acquired therapeutic resistance, and low cost of MCT render it an attractive chemotherapeutic regimen option. One of the most prominent aspects of MCT is its anti-angiogenesis effects. It has been shown to stimulate the expression of anti-angiogenic molecules, thereby inhibiting angiogenesis. In addition, MCT has been shown to decrease the regulatory T-cell population and promote anti-tumor immune response through inducing dendritic cell maturation and increasing the number of cytotoxic T-cells. Combination therapies utilizing MCT along with oncolytic virotherapy, radiotherapy or other chemotherapeutic regimens have been studied extensively. This review provides an overview of the current status of MCT research and the established mechanisms of action of MCT treatment and also offers insights into potential avenues of development for MCT in the future.
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Affiliation(s)
- Oyku Yagmur Basar
- Department of Biological Sciences, Middle East Technical University, Ankara, Türkiye
| | - Sawsan Mohammed
- Qatar University, QU Health, College of Medicine, Doha, Qatar
| | - M. Walid Qoronfleh
- Q3 Research Institute (QRI), Research and Policy Division, Ypsilanti, MI, United States
| | - Ahmet Acar
- Department of Biological Sciences, Middle East Technical University, Ankara, Türkiye
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15
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Stucchi E, Bartolini M, Airoldi M, Fazio R, Daprà V, Mondello G, Prete MG, Puccini A, Santoro A. Fruquintinib as new treatment option in metastatic colorectal cancer patients: is there an optimal sequence? Expert Opin Pharmacother 2024; 25:371-382. [PMID: 38568032 DOI: 10.1080/14656566.2024.2336069] [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: 01/23/2024] [Accepted: 03/25/2024] [Indexed: 04/30/2024]
Abstract
INTRODUCTION Available treatments for colorectal cancer are limited. However, in the last few years several advances and new treatment options became available and expanded the continuum of care in metastatic colorectal cancer (mCRC). AREAS COVERED Fruquintinib, a tyrosine kinase inhibitor, has been shown to be effective in heavily pretreated mCRC progressing to trifluridine-tipiracil (FTD/TPI) or regorafenib or both. Preclinical studies have shown that fruquintinib inhibits with high selectivity VEGFR 1-2-3, leading to a blockade in angiogenesis process, but also acts, with weak inhibition, on RET, FGFR-1, and c-kit kinases. Fruquintinib demonstrated good efficacy and tolerance in chemorefractory mCRC in two phase III trial: FRESCO and FRESCO 2. These results led to FDA approval of fruquintinib for pretreated mCRC patients who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. EXPERT OPINION Fruquintinib is a valid therapeutic option for heavily pretreated mCRC patients. However, an optimal sequence of treatments is yet to be defined. In this review, we propose an algorithm for later lines of treatment to integrate fruquintinib as a standard of care together with the new therapeutic combinations that recently showed clinical benefit for chemorefractory mCRC, in both molecularly selected (e.g. KRASG12C or HER2 amplification) and in non-oncogenic driven patients.
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Affiliation(s)
- Erika Stucchi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Michela Bartolini
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Marco Airoldi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Roberta Fazio
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Valentina Daprà
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Giuseppe Mondello
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Maria Giuseppina Prete
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Alberto Puccini
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Armando Santoro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
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Reni M, Peretti U, Macchini M, Orsi G, Militello A, Briccolani A, Falconi M, Cascinu S. Cyclophosphamide maintenance to extend combination chemotherapy-free interval in metastatic pancreatic ductal adenocarcinoma. Dig Liver Dis 2024; 56:509-513. [PMID: 37586911 DOI: 10.1016/j.dld.2023.07.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 07/27/2023] [Accepted: 07/27/2023] [Indexed: 08/18/2023]
Abstract
BACKGROUND Administering chemotherapy until progression to metastatic pancreatic ductal adenocarcinoma (PDAC) patients lacks of supporting evidence and causes cumulative toxicity. We explored the role of cyclophosphamide as maintenance therapy. METHODS PDAC germline BRCA1-2 wild-type patients who were progression-free after ≥6 months of any regimen and line of chemotherapy and received maintenance cyclophosphamide (mCTX) (50 mg/day), were included in the analysis. RESULTS 42 patients were included in the analysis. Thirty-nine patients had progression of disease. Median PFS was 3.5 (range 1.0-31+) months. PFS rates at 6 and 12 months were 26.2% and 11.9%. At a median follow-up of 20.0 months (range 12.1-31.0 months), 20 patients died and 22 are alive. Median OS was 20.0 months (range 2.2-31.0+). OS at 6 and 12 months was 97.6% (95%CI: 93.4-100), and 73.8% (95% CI: 61.1-86.5), respectively. Only 2 patients receiving mCTX had Grade 3 toxicity. CONCLUSIONS mCTX therapy yielded promising PFS and OS outcome in PDAC patients who were progression-free after induction chemotherapy, with unremarkable toxicity. Accordingly, this approach warrants further investigation.
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Affiliation(s)
- Michele Reni
- Department of Medical Oncology, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
| | - Umberto Peretti
- Department of Medical Oncology, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Marina Macchini
- Department of Medical Oncology, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Giulia Orsi
- Department of Medical Oncology, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Annamaria Militello
- Department of Medical Oncology, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Assunta Briccolani
- Department of Medical Oncology, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy
| | - Massimo Falconi
- Vita-Salute San Raffaele University, Milan, Italy; Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
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17
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Jan N, Sofi S, Qayoom H, Shabir A, Haq BU, Macha MA, Almilaibary A, Mir MA. Metronomic chemotherapy and drug repurposing: A paradigm shift in oncology. Heliyon 2024; 10:e24670. [PMID: 38314272 PMCID: PMC10837507 DOI: 10.1016/j.heliyon.2024.e24670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/03/2023] [Accepted: 01/11/2024] [Indexed: 02/06/2024] Open
Abstract
Cancer represents a significant global health and economic burden due to its high mortality rates. While effective in some instances, traditional chemotherapy often falls short of entirely eradicating various types of cancer. It can cause severe side effects due to harm to healthy cells. Two therapeutic approaches have risen to the forefront to address these limitations: metronomic chemotherapy (MCT) and drug repurposing. Metronomic chemotherapy is an innovative approach that breaks from traditional models. It involves the administration of chemotherapeutic regimens at lower doses, without long drug-free intervals that have previously been a hallmark of such treatments. This method offers a significant reduction in side effects and improved disease management. Simultaneously, drug repurposing has gained considerable attraction in cancer treatment. This approach involves utilizing existing drugs, initially developed for other therapeutic purposes, as potential cancer treatments. The application of known drugs in a new context accelerates the timeline from laboratory to patient due to pre-existing safety and dosage data. The intersection of these two strategies gives rise to a novel therapeutic approach named 'Metronomics.' This approach encapsulates the benefits of both MCT and drug repurposing, leading to reduced toxicity, potential for oral administration, improved patient quality of life, accelerated clinical implementation, and enhanced affordability. Numerous clinical studies have endorsed the efficacy of metronomic chemotherapy with tolerable side effects, underlining the potential of Metronomics in better cancer management, particularly in low- and middle-income countries. This review underscores the benefits and applications of metronomic chemotherapy and drug repurposing, specifically in the context of breast cancer, showcasing the promising results of pre-clinical and clinical studies. However, we acknowledge the necessity of additional clinical investigations to definitively establish the role of metronomic chemotherapy in conjunction with other treatments in comprehensive cancer management.
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Affiliation(s)
- Nusrat Jan
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
| | - Shazia Sofi
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
| | - Hina Qayoom
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
| | - Aisha Shabir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
| | - Burhan Ul Haq
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
| | - Muzaffar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Pulwama, India
| | - Abdullah Almilaibary
- Department of Family and Community Medicine, Faculty of Medicine, Al Baha University, Saudi Arabia
| | - Manzoor Ahmad Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar-190006, India
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18
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Liu H, Zheng Q, Li M, Kou J, Wei J, Feng W. Dose-dependent bidirectional pharmacological effects of vinorelbine-based metronomic combination chemotherapy on tumor growth and metastasis and mechanisms in melanoma mouse model. Fundam Clin Pharmacol 2024; 38:99-112. [PMID: 37458143 DOI: 10.1111/fcp.12939] [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: 02/07/2023] [Revised: 03/25/2023] [Accepted: 06/26/2023] [Indexed: 07/18/2023]
Abstract
BACKGROUND There is evidence that the empirical setting of doses and schedules of antineoplastic agents in metronomic chemotherapy (MC) might lead to undesirable outcomes, such as promoting tumor growth or metastasis at certain low doses. However, details about the dose effect of antineoplastic agents in MC have not been fully known yet. OBJECTIVES Vinorelbine combined with cisplatin or fluorouracil (VNR/CDDP or VNR/FU) was selected to investigate its effects on tumor growth or metastasis as well as mechanisms. METHODS Experimental techniques, including immunohistochemistry, western blot, immunofluorescence, and flow cytometry, were used to explore the mechanisms, along with cell proliferation, apoptosis, migration, and invasion. RESULTS The results showed that VNR/CDDP or VNR/FU promoted tumor growth and metastasis at low doses and inhibited them at high ones. Except that expressions of apoptotic proteins were elevated at both low and high doses, low-dose treatments enhanced angiogenesis and promoted the mobilization and recruitment of myeloid-derived suppressor cells (MDSCs), while high-dose treatments reversed these effects. Additionally, low concentrations of VNR/CDDP or VNR/FU stimulated tumor cell functions such as anti-apoptosis, migration, and invasion, but high concentrations only suppressed cell proliferation and increased apoptosis. CONCLUSION This study elucidated a bidirectional action mode regulated by multiple mechanisms at different doses in MC and also highlighted the risks of low-dose metronomic administration of antineoplastic agents in the clinic. More preclinical and clinical studies focusing on the dose-effect of metronomic regimens are urgently needed because an effective therapeutic regimen should be an optimal setting of drugs, doses, schedules, or combinations.
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Affiliation(s)
- Hua Liu
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Qiaowei Zheng
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Min Li
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Jianrong Kou
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Junsong Wei
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Weiyi Feng
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
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Liu J, Han X, Hu X, He Y, Shao Y, Yang Y, Wang K, Zhao Y. An epidermal growth factor receptor-mutated lung adenocarcinoma patient with brain lesions resisted to osimertinib monotherapy but achieved more than 4 years of survival in osimertinib plus bevacizumab metronomic treatment. Heliyon 2024; 10:e24378. [PMID: 38298673 PMCID: PMC10827756 DOI: 10.1016/j.heliyon.2024.e24378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 12/18/2023] [Accepted: 01/08/2024] [Indexed: 02/02/2024] Open
Abstract
Background Epidermal growth factor receptor (EGFR) mutations have been identified as promising therapeutic targets for non-small cell lung cancer. Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor-targeting drug, has good anti-tumor ability and excellent intracranial effects. However, management of osimertinib resistance is a clinical challenge. The clinical benefit of osimertinib combined with the antiangiogenic drug, bevacizumab, remains to be determined. Case presentation A 40-year-old female with right lung adenocarcinoma (cT2aN3M1c, IVb) was confirmed positive for EGFR exon 19 deletion mutation (c.2235_2249del, 1.3%). After receiving 5 months of osimertinib (80 mg, qd) therapy, the patient's disease progressed and she subsequently accepted treatment with osimertinib (80 mg, qd) plus bevacizumab (15 mg/kg, q21d) and achieved notable clinical remission for 23 months until renal impairment occurred, after which bevacizumab was discontinued. The patient had 6 months of remission before progression, after which bevacizumab was added again. To date, the disease has been under control. The brain lesion showed partial response again, and the side effects of bevacizumab were tolerable. The overall survival time exceeded 4 years. Conclusion This case report describes a treatment strategy for osimertinib-resistant patients with EGFR exon 19 deletion mutations. Metronomic treatment with osimertinib plus bevacizumab was achieved for more than 4 years.
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Affiliation(s)
- Jie Liu
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Xiao Han
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xiufeng Hu
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Yuange He
- Geneplus-Beijing, Beijing ,102206, China
| | - Yijia Shao
- Geneplus-Beijing, Beijing ,102206, China
| | | | - Kai Wang
- Geneplus-Beijing, Beijing ,102206, China
| | - Yanqiu Zhao
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
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20
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Sambath J, Noronha V, Manda SS, Mishra R, Chandrani P, Patil V, Menon N, Chougule A, Ramachandran V, Limaye S, Kuriakose MA, Banavali SD, Kumar P, Prabhash K. Whole exome sequencing uncovers HRAS mutations as potential mediators of resistance to metronomic chemotherapy. Gene 2024; 893:147952. [PMID: 37918550 DOI: 10.1016/j.gene.2023.147952] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 10/11/2023] [Accepted: 10/30/2023] [Indexed: 11/04/2023]
Abstract
OBJECTIVES The aim of this pilot study is to identify the genetic factors that contribute to the response of metronomic chemotherapy in head and neck squamous cell carcinoma (HNSCC) patients using whole-exome sequencing (WES). This study would facilitate the identification of predictive biomarkers, which would enable personalized treatment strategies and improve treatment outcomes for patients with HNSCC. MATERIALS AND METHODS We have selected patients with recurrent head and neck cancer who underwent metronomic chemotherapy. Sequential tumor biopsies were collected from the patients at different stages of treatment to capture the genomic alterations and tumor evolution during metronomic chemotherapy and sequenced using WES. RESULTS We identified several known HNSCC hallmark genes reported in COSMIC, including KMT2B, NOTCH1, FAT1, TP53, HRAS, CASP8, and CDKN2A. Copy number alteration analysis revealed amplifications and deletions in several oncogenic and tumor suppressor genes. COSMIC Mutational Signature 15 associated with defective DNA mismatch repair was enriched in 73% of HNSCC samples. Further, the comparison of genomic alterations between responders and non-responders identified HRAS gene uniquely mutated in non-responders that could potentially contribute to resistance against metronomic chemotherapy. DISCUSSION Our findings corroborate the molecular heterogeneity of recurrent HNSCC tumors and establish an association between HRAS mutations and resistance to metronomic chemotherapy, suggesting HRAS as a potential therapeutic target. Combining HRAS inhibitors with metronomic regimens could improve treatment sensitivity in HRAS-mutated HNSCC patients. Further studies are needed to fully elucidate the genomic mechanisms underlying the response to metronomic chemotherapy.
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Affiliation(s)
- Janani Sambath
- Institute of Bioinformatics, Bangalore, India; Manipal Academy of Higher Education (MAHE), Manipal, India
| | | | - Srikanth S Manda
- Karkinos Foundation, Mumbai, India; Karkinos Healthcare Pvt Ltd., Mumbai, India
| | | | | | | | | | | | | | - Sewanti Limaye
- Division of Medical and Precision Oncology, Sir H.N. Reliance Foundation Hospital and Research Centre, Mumbai, India
| | - Moni A Kuriakose
- Karkinos Foundation, Mumbai, India; Karkinos Healthcare Pvt Ltd., Mumbai, India
| | | | - Prashant Kumar
- Karkinos Foundation, Mumbai, India; Karkinos Healthcare Pvt Ltd., Mumbai, India.
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Huang X, Ren Q, Yang L, Cui D, Ma C, Zheng Y, Wu J. Immunogenic chemotherapy: great potential for improving response rates. Front Oncol 2023; 13:1308681. [PMID: 38125944 PMCID: PMC10732354 DOI: 10.3389/fonc.2023.1308681] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 11/15/2023] [Indexed: 12/23/2023] Open
Abstract
The activation of anti-tumor immunity is critical in treating cancers. Recent studies indicate that several chemotherapy agents can stimulate anti-tumor immunity by inducing immunogenic cell death and durably eradicate tumors. This suggests that immunogenic chemotherapy holds great potential for improving response rates. However, chemotherapy in practice has only had limited success in inducing long-term survival or cure of cancers when used either alone or in combination with immunotherapy. We think that this is because the importance of dose, schedule, and tumor model dependence of chemotherapy-activated anti-tumor immunity is under-appreciated. Here, we review immune modulation function of representative chemotherapy agents and propose a model of immunogenic chemotherapy-induced long-lasting responses that rely on synergetic interaction between killing tumor cells and inducing anti-tumor immunity. We comb through several chemotherapy treatment schedules, and identify the needs for chemotherapy dose and schedule optimization and combination therapy with immunotherapy when chemotherapy dosage or immune responsiveness is too low. We further review tumor cell intrinsic factors that affect the optimal chemotherapy dose and schedule. Lastly, we review the biomarkers indicating responsiveness to chemotherapy and/or immunotherapy treatments. A deep understanding of how chemotherapy activates anti-tumor immunity and how to monitor its responsiveness can lead to the development of more effective chemotherapy or chemo-immunotherapy, thereby improving the efficacy of cancer treatment.
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Affiliation(s)
- Xiaojun Huang
- Cancer Center, Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Qinghuan Ren
- Alberta Institute, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Leixiang Yang
- Cancer Center, The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Center for Reproductive Medicine, Department of Genetic and Genomic Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Di Cui
- Cancer Center, The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Chenyang Ma
- Department of Internal Medicine of Traditional Chinese Medicine, The Second People’s Hospital of Xiaoshan District, Hangzhou, Zhejiang, China
| | - Yueliang Zheng
- Cancer Center, Emergency and Critical Care Center, Department of Emergency Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Junjie Wu
- Cancer Center, The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Center for Reproductive Medicine, Department of Genetic and Genomic Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
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22
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Garg V, Kumar L. Metronomic chemotherapy in ovarian cancer. Cancer Lett 2023; 579:216469. [PMID: 37923056 DOI: 10.1016/j.canlet.2023.216469] [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: 09/04/2023] [Revised: 10/15/2023] [Accepted: 10/27/2023] [Indexed: 11/07/2023]
Abstract
Translational research and the development of targeted therapies have transformed the therapeutic landscape in epithelial ovarian cancer over the last decade. However, recurrent ovarian cancer continues to pose formidable challenges to therapeutic interventions, necessitating innovative strategies to optimize treatment outcomes. Current research focuses on the development of pharmaceuticals that target potential resistance pathways to DNA repair pathways. However, the cost and toxicity of some of these therapies are prohibitive and majority of patients lack access to clinical trials. Metronomic chemotherapy, characterized by the continuous administration of low doses of chemotherapeutic agents without long treatment breaks, has emerged as a promising approach with potential implications beyond recurrent setting. It acts primarily by inhibition of angiogenesis and activation of host immune system. We here review the mechanism of action of metronomic chemotherapy, as well as its current role, limitations, and avenues for further research in the management of epithelial ovarian cancer.
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Affiliation(s)
- Vikas Garg
- Clinical Research Fellow, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 700 University Avenue, 7th Floor, Station 7W386, M5G 1Z5, Toronto, ON, Canada.
| | - Lalit Kumar
- Oncology and BMT, Department of Medical Oncology, Artemis Hospital, Gurugram, India.
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23
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Bravetti G, Falvo P, Talarico G, Orecchioni S, Bertolini F. Metronomic chemotherapy, dampening of immunosuppressive cells, antigen presenting cell activation, and T cells. A quartet against refractoriness and resistance to checkpoint inhibitors. Cancer Lett 2023; 577:216441. [PMID: 37806515 DOI: 10.1016/j.canlet.2023.216441] [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: 08/03/2023] [Revised: 10/04/2023] [Accepted: 10/06/2023] [Indexed: 10/10/2023]
Abstract
Chemotherapeutic agents have profound effects on cancer, stroma and immune cells that - in most cases - depend upon the dosage and schedule of administration. Preclinical and clinical studies summarized and discussed in the present review have demonstrated that maximum tolerable dosage (MTD) vs low-dosage, continuous (metronomic) administration of most chemotherapeutics have polarized effects on immune cells. In particular, metronomic schedules might be associated - among others effects - with activation of antigen presenting cells and generation of new T cell clones to enhance the activity of several types of immunotherapies. Ongoing and planned clinical trials in different types of cancer will confirm or dismiss this hypothesis and provide candidate biomarker data for the selection of patients who are likely to benefit from these combinatorial strategies.
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Affiliation(s)
- Giulia Bravetti
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20137, Milan, Italy; Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Paolo Falvo
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20137, Milan, Italy; Medical University of Vienna, (MUW), Borschkegasse 8A 1090, Wien, Austria
| | - Giovanna Talarico
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20137, Milan, Italy; Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Stefania Orecchioni
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20137, Milan, Italy; Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy
| | - Francesco Bertolini
- Laboratory of Hematology-Oncology, European Institute of Oncology IRCCS, Via Ripamonti 435, 20137, Milan, Italy; Onco-Tech Lab, European Institute of Oncology IRCCS and Politecnico di Milano, Milan, Italy.
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24
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Strobl MAR, Gallaher J, Robertson-Tessi M, West J, Anderson ARA. Treatment of evolving cancers will require dynamic decision support. Ann Oncol 2023; 34:867-884. [PMID: 37777307 PMCID: PMC10688269 DOI: 10.1016/j.annonc.2023.08.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 08/01/2023] [Accepted: 08/21/2023] [Indexed: 10/02/2023] Open
Abstract
Cancer research has traditionally focused on developing new agents, but an underexplored question is that of the dose and frequency of existing drugs. Based on the modus operandi established in the early days of chemotherapies, most drugs are administered according to predetermined schedules that seek to deliver the maximum tolerated dose and are only adjusted for toxicity. However, we believe that the complex, evolving nature of cancer requires a more dynamic and personalized approach. Chronicling the milestones of the field, we show that the impact of schedule choice crucially depends on processes driving treatment response and failure. As such, cancer heterogeneity and evolution dictate that a one-size-fits-all solution is unlikely-instead, each patient should be mapped to the strategy that best matches their current disease characteristics and treatment objectives (i.e. their 'tumorscape'). To achieve this level of personalization, we need mathematical modeling. In this perspective, we propose a five-step 'Adaptive Dosing Adjusted for Personalized Tumorscapes (ADAPT)' paradigm to integrate data and understanding across scales and derive dynamic and personalized schedules. We conclude with promising examples of model-guided schedule personalization and a call to action to address key outstanding challenges surrounding data collection, model development, and integration.
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Affiliation(s)
- M A R Strobl
- Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa; Translational Hematology and Oncology Research, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, USA
| | - J Gallaher
- Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa
| | - M Robertson-Tessi
- Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa
| | - J West
- Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa
| | - A R A Anderson
- Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa.
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25
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Bisogno G, Minard-Colin V, Jenney M, Ferrari A, Chisholm J, Di Carlo D, Hjalgrim LL, Orbach D, Merks JHM, Casanova M. Maintenance Chemotherapy for Patients with Rhabdomyosarcoma. Cancers (Basel) 2023; 15:4012. [PMID: 37568826 PMCID: PMC10417571 DOI: 10.3390/cancers15154012] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 07/28/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
Maintenance chemotherapy (MC) defines the administration of prolonged relatively low-intensity chemotherapy with the aim of "maintaining" tumor complete remission. This paper aims to report an update of the RMS2005 trial, which demonstrated better survival for patients with high-risk localized rhabdomyosarcoma (RMS) when MC with vinorelbine and low-dose cyclophosphamide was added to standard chemotherapy, and to discuss the published experience on MC in RMS. In the RMS2005 study, the outcome for patients receiving MC vs. those who stopped the treatment remains superior, with a 5-year disease-free survival of 78.1% vs. 70.1% (p = 0.056) and overall survival of 85.0% vs. 72.4% (p = 0.008), respectively. We found seven papers describing MC in RMS, but only one randomized trial that did not demonstrate any advantage when MC with eight courses of trofosfamide/idarubicine alternating with trofosfamide/etoposide has been employed in high-risk RMS. The use of MC showed better results in comparison to high-dose chemotherapy in non-randomized studies, including metastatic patients, and demonstrated feasibility and tolerability in relapsed RMS. Many aspects of MC in RMS need to be investigated, including the best drug combination and the optimal duration. The ongoing EpSSG trial will try to answer some of these questions.
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Affiliation(s)
- Gianni Bisogno
- Department of Women’s and Children’s Health, University of Padua, 35128 Padua, Italy;
- Pediatric Hematology Oncology Division, University Hospital of Padua, 35128 Padua, Italy
| | - Veronique Minard-Colin
- Department of Pediatric and Adolescent Oncology, Institut Gustave-Roussy, Université Paris-Saclay, 94800 Villejuif, France;
| | - Meriel. Jenney
- Department of Paediatric Oncology, Children’s Hospital for Wales, Heath Park, Cardiff CF14 4XW, UK;
| | - Andrea Ferrari
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy; (A.F.); (M.C.)
| | - Julia Chisholm
- Children and Young People’s Unit, Royal Marsden Hospital and Institute of Cancer Research, Sutton SM2 5PT, UK;
| | - Daniela Di Carlo
- Department of Women’s and Children’s Health, University of Padua, 35128 Padua, Italy;
| | - Lisa Lyngsie Hjalgrim
- Department of Paediatric and Adolescent Medicine, University Hospital Copenhagen, 2100 Copenhagen, Denmark;
| | - Daniel Orbach
- SIREDO Oncology Centre (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), Institut Curie, Paris Sciences et Lettres L University, 75005 Paris, France;
| | - Johannes Hendrikus Maria Merks
- Princess Máxima Centre for Pediatric Oncology, 3584 CS Utrecht, The Netherlands;
- Division of Imaging and Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Michela Casanova
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy; (A.F.); (M.C.)
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26
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Fante MA, Harrer DC, Zartner B, Lüke F, Mayer S, Menhart K, Reichle A, Herr W, Vogelhuber M, Heudobler D. All-oral low-dose chemotherapy TEPIP is effective and well-tolerated in patients with peripheral T-cell lymphoma. Front Oncol 2023; 13:1177330. [PMID: 37305564 PMCID: PMC10250661 DOI: 10.3389/fonc.2023.1177330] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 04/24/2023] [Indexed: 06/13/2023] Open
Abstract
Purpose Peripheral T-cell lymphoma (PTCL) is a rare and heterogenous hematologic malignancy with poor prognosis especially in elderly and frail patients who are not eligible for intensive treatment. The resulting palliative setting necessitates tolerable but effective schedules for outpatient treatment. TEPIP is a locally developed, all-oral low-dose regimen comprising trofosfamide, etoposide, procarbazine, idarubicin, and prednisolone. Methods In this observational retrospective, single-center study, the safety and efficacy of TEPIP was evaluated in 12 patients (pts.) with PTCL treated at the University Medical Center Regensburg between 2010 and 2022. The endpoints were overall response rate (ORR) and overall survival (OS), and adverse events were individually reported according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria. Results The enrolled cohort was characterized by advanced age (median 70 years), extensive disease (100% Ann Arbor ≥stage 3), and poor prognosis (75% high/high-intermediate international prognostic index). The most common subtype was angioimmunoblastic T-cell lymphoma (8/12), and 11/12 patients had relapsed or refractory disease at TEPIP onset with a median of 1.5 prior treatment regimens. After a median of 2.5 TEPIP cycles (total of 83 cycles), the ORR was 42% (complete remission 25%), and the OS reached a median of 185 days. Any grade of adverse event (AE) occurred in 8/12 patients, with four patients showing AE ≥CTCAE grade 3 (33%), and the AEs were mainly non-hematological. Conclusion TEPIP demonstrated competitive efficacy with a tolerable safety profile in a highly palliative cohort of patients with difficult-to-treat PTCL. The all-oral application, which makes outpatient treatment possible, is particularly noteworthy.
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Affiliation(s)
- Matthias A. Fante
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Dennis C. Harrer
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Barbara Zartner
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Florian Lüke
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
- Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine, Regensburg, Germany
| | - Stephanie Mayer
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Karin Menhart
- Department of Nuclear Medicine, University Hospital Regensburg, Regensburg, Germany
| | - Albrecht Reichle
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Wolfgang Herr
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Martin Vogelhuber
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Daniel Heudobler
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), University Hospital Regensburg, Regensburg, Germany
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27
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Davis JT, Ghosh TM, Mazumder S, Mitra A, Bird RC, Arnold RD. Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial-Mesenchymal Transition. Int J Mol Sci 2023; 24:ijms24108490. [PMID: 37239838 DOI: 10.3390/ijms24108490] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 05/28/2023] Open
Abstract
Maximum tolerable dosing (MTD) of chemotherapeutics has long been the gold standard for aggressive malignancies. Recently, alternative dosing strategies have gained traction for their improved toxicity profiles and unique mechanisms of action, such as inhibition of angiogenesis and stimulation of immunity. In this article, we investigated whether extended exposure (EE) topotecan could improve long-term drug sensitivity by preventing drug resistance. To achieve significantly longer exposure times, we used a spheroidal model system of castration-resistant prostate cancer. We also used state-of-the-art transcriptomic analysis to further elucidate any underlying phenotypic changes that occurred in the malignant population following each treatment. We determined that EE topotecan had a much higher barrier to resistance relative to MTD topotecan and was able to maintain consistent efficacy throughout the study period (EE IC50 of 54.4 nM (Week 6) vs. MTD IC50 of 2200 nM (Week 6) vs. 83.8 nM IC50 for control (Week 6) vs. 37.8 nM IC50 for control (Week 0)). As a possible explanation for these results, we determined that MTD topotecan stimulated epithelial-mesenchymal transition (EMT), upregulated efflux pumps, and produced altered topoisomerases relative to EE topotecan. Overall, EE topotecan resulted in a more sustained treatment response and maintained a less aggressive malignant phenotype relative to MTD topotecan.
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Affiliation(s)
- Joshua T Davis
- Department of Drug Discovery and Development, Auburn University, Auburn, AL 36849, USA
| | - Taraswi Mitra Ghosh
- Department of Drug Discovery and Development, Auburn University, Auburn, AL 36849, USA
- Department of Urology Research, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Suman Mazumder
- Department of Drug Discovery and Development, Auburn University, Auburn, AL 36849, USA
- UAB O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35233, USA
| | - Amit Mitra
- Department of Drug Discovery and Development, Auburn University, Auburn, AL 36849, USA
- UAB O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35233, USA
- Center for Pharmacogenomics and Single-Cell Omics (AUPharmGx), Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Richard Curtis Bird
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
| | - Robert D Arnold
- Department of Drug Discovery and Development, Auburn University, Auburn, AL 36849, USA
- UAB O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35233, USA
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
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28
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Panthi VK, Dua K, Singh SK, Gupta G, Hansbro PM, Paudel KR. Nanoformulations-Based Metronomic Chemotherapy: Mechanism, Challenges, Recent Advances, and Future Perspectives. Pharmaceutics 2023; 15:pharmaceutics15041192. [PMID: 37111677 PMCID: PMC10146318 DOI: 10.3390/pharmaceutics15041192] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/30/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Cancer-related death is a significant health and economic burden worldwide, and some conventional chemotherapy is associated with limited effectiveness in completely curing various cancers, severe adverse effects, and destruction of healthy cells. To overcome the complications associated with conventional treatment, metronomic chemotherapy (MCT) is extensively suggested. In this review, we aim to highlight the importance of MCT over conventional chemotherapeutic approach with emphasis on nanoformulations-based MCT, their mechanism, challenges, recent advances, and future perspectives. Nanoformulations-based MCT revealed remarkable antitumor activity in both preclinical and clinical settings. For example, the metronomic scheduling of oxaliplatin-loaded nanoemulsion and polyethylene glycol-coated stealth nanoparticles incorporating paclitaxel were proven very effective in tumor-bearing mice and rats, respectively. Additionally, several clinical studies have demonstrated the benefit of MCT with acceptable tolerance. Moreover, metronomic might be a promising treatment strategy for improving cancer care in low- and middle-income nations. However, an appropriate alternative to a metronomic regimen for an individual ailment, suitable combinational delivery and scheduling, and predictive biomarkers are certain parts that remain unanswered. Further clinical-based comparative research studies are mandatory to be performed before entailing this treatment modality in clinical practice as alternative maintenance therapy or in place of transferring to therapeutic management.
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Affiliation(s)
- Vijay Kumar Panthi
- Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia
- Faculty of Health, Australian Research Centre in Complementary & Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Sachin Kumar Singh
- Faculty of Health, Australian Research Centre in Complementary & Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur 302017, India
| | - Philip M Hansbro
- Centre for Inflammation, Faculty of Science, School of Life Sciences, Centenary Institute and University of Technology Sydney, Sydney, NSW 2050, Australia
| | - Keshav Raj Paudel
- Centre for Inflammation, Faculty of Science, School of Life Sciences, Centenary Institute and University of Technology Sydney, Sydney, NSW 2050, Australia
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Retrospective National "Real Life" Experience of the SFCE with the Metronomic MEMMAT and MEMMAT-like Protocol. J Clin Med 2023; 12:jcm12041415. [PMID: 36835950 PMCID: PMC9967517 DOI: 10.3390/jcm12041415] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/02/2023] [Accepted: 02/08/2023] [Indexed: 02/12/2023] Open
Abstract
BACKGROUND Relapses in pediatric high-risk brain tumors remain unmet medical needs. Over the last 15 years, metronomic chemotherapy has gradually emerged as an alternative therapeutic approach. PATIENTS AND METHODS This is a national retrospective study of patients with relapsing pediatric brain tumors treated according to the MEMMAT or MEMMAT-like regimen from 2010 to 2022. Treatment consisted of daily oral thalidomide, fenofibrate, and celecoxib, and alternating 21-day cycles of metronomic etoposide and cyclophosphamide associated with bevacizumab and intraventricular chemotherapy. RESULTS Forty-one patients were included. The most frequent malignancies were medulloblastoma (22) and ATRT (8). Overall, the best responses were CR in eight patients (20%), PR in three patients (7%), and SD in three patients (7%), for a clinical benefit rate of 34%. The median overall survival was 26 months (IC95% = 12.4-42.7), and median EFS was 9.7 months (IC95% = 6.0-18.6). The most frequent grade ¾ toxicities were hematological. Dose had to be adjusted in 27% of the cases. There was no statistical difference in outcome between full or modified MEMMAT. The best setting seems to be when MEMMAT is used as a maintenance and at first relapse. CONCLUSIONS The metronomic MEMMAT combination can lead to sustained control of relapsed high-risk pediatric brain tumors.
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30
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Sarabi N, Chamani R, Assareh E, Saberi O, Asghari SM. Combination Therapy in Cancer: Doxorubicin in Combination with an N-terminal Peptide of Endostatin Suppresses Angiogenesis and Stimulates Apoptosis in the Breast Cancer. INTERNATIONAL JOURNAL OF MOLECULAR AND CELLULAR MEDICINE 2023; 12:120-134. [PMID: 38313376 PMCID: PMC10837914 DOI: 10.22088/ijmcm.bums.12.2.120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 10/12/2023] [Accepted: 11/12/2023] [Indexed: 02/06/2024]
Abstract
The combination of chemotherapy drugs with angiogenesis inhibitors improves response and survival and reduces the cytotoxic side effects and drug resistance in patients compared to chemotherapy alone. Here, we investigated the efficacy of the concomitant administration of doxorubicin and a peptide derived from the N-terminal domain of Endostatin (called ES-SS) in the 4T1 mammary carcinoma tumor model. Tumor-bearing mice were divided into the control and three treatment groups, including ES-SS, doxorubicin, and the combination. Injections were performed daily for two weeks and tumor volumes were measured during the treatment. Immunohistochemical analysis of Ki-67, CD31, CD34, Bcl-2, p53 expression, and TUNEL assay were performed on tumor tissues at the end of treatment. Besides, molecular dynamics and docking simulations were performed. It was demonstrated that tumor growth was inhibited in mice treated with peptide plus doxorubicin more significantly than in each treatment alone (P<0.05). No weight loss or adverse effects were observed. Moreover, combination therapy was more effective in tumor angiogenesis suppression and apoptosis stimulation (P<0.05). Docking simulations by ClusPro server demonstrated that ES-SS binds to integrin α5β1, Transglu-taminase 2, and Matrix metalloproteinase 2 with more negative binding energy and hydrogen bonds compared to the native peptide. Generally, we proposed that ES-SS can augment the therapeutic efficacy of doxorubicin through angiogenesis prevention and apoptosis induction in breast tumor. Owing to the advantages of peptides to recombinant proteins or monoclonal antibodies, further preclinical and clinical evaluations of this combination strategy are worth taking into consideration.
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Affiliation(s)
- Narges Sarabi
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
| | | | - Elham Assareh
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
| | - Omid Saberi
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
| | - S. Mohsen Asghari
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
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31
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Li M, Lin C, Lin J, Chen S, Weng L, He Z. Efficacy of Osimertinib Continuation Plus Metronomic Oral Vinorelbine for EGFRmutant Advanced NSCLC Beyond Limited Progression on Osimertinib. Anticancer Agents Med Chem 2023; 23:2095-2101. [PMID: 37534792 DOI: 10.2174/1871520623666230803142758] [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: 01/17/2023] [Revised: 06/03/2023] [Accepted: 06/15/2023] [Indexed: 08/04/2023]
Abstract
BACKGROUND Treatment options for advanced non-small-cell lung cancer (NSCLC) after osimertinib failure are limited, and osimertinib continuation is recommended for selected patients. Metronomic oral vinorelbine is an effective treatment with less toxicity for advanced NSCLC. OBJECTIVE The objective of the study was to investigate the effects of osimertinib plus metronomic oral vinorelbine on epidermal growth factor receptor (EGFR)-mutant advanced NSCLC beyond limited progression on osimertinib. METHODS We have reviewed the medical records of 28 patients with EGFR-mutant advanced NSCLC who had received osimertinib continuation plus metronomic oral vinorelbine beyond limited progression on osimertinib. We also evaluated the clinicopathological characteristics of enrolled patients, as well as the efficacy and toxicity of the treatment. RESULTS After a median follow-up period of 14.1 months, 57.1% (16/28) of cases showed NSCLC progression. The median progression-free survival (PFS) period under osimertinib plus metronomic oral vinorelbine was 9.4 months (95% confidence interval, 1.562-17.238 months), with a disease control rate of 89.3% and objective response rate of 17.9%. PFS did not differ between patients who had previously received osimertinib as first- (n = 16) and second-line (n = 12) therapy (median, 11.4 and 4.7 months, P = 0.391). In addition, the median PFS duration did not differ according to the efficacy (PFS2 ≥ 6 months vs. <6 months) of previous osimertinib monotherapy (median, 5.8 and 9.4 months, P = 0.677). CONCLUSIONS Osimertinib continuation in conjunction with metronomic oral vinorelbine may enable overcoming TKI resistance and prolong the survival of patients with EGFR-mutant advanced NSCLC beyond limited progression on osimertinib treatment.
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Affiliation(s)
- Meifang Li
- Department of Thoracic Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Cheng Lin
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Jinghui Lin
- Department of Thoracic Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Shijie Chen
- Department of Thoracic Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Lihong Weng
- Department of Thoracic Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
| | - Zhiyong He
- Department of Thoracic Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China
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Adil M, Kanwal S, Rasheed S, Iqbal M, Abbas G. Cancer Chemoresistance; Recent Challenges and Future Considerations. Cancer Treat Res 2023; 185:237-253. [PMID: 37306912 DOI: 10.1007/978-3-031-27156-4_12] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Cancer remains one of the serious health hazards and major causes of human mortality across the world. Despite the development of many typical antineoplastic drugs and introduction of novel targeted agents, chemoresistance constitutes a major challenge in the effective therapeutic management of cancer. Drug inactivation, efflux of anticancer agents, modification of target sites, enhanced repair of DNA damage, apoptosis failure and induction of epithelial-mesenchymal transition are the principal mechanisms of cancer chemoresistance. Moreover, epigenetics, cell signaling, tumor heterogeneity, stem cells, microRNAs, endoplasmic reticulum, tumor microenvironment and exosomes have also been implicated in the multifaceted phenomenon of anticancer drug resistance. The tendency of resistance is either intrinsically possessed or subsequently acquired by cancerous cells. From clinical oncology standpoint, therapeutic failure and tumor progression are the most probable consequences of cancer chemoresistance. Combination therapy can help to overcome the issue of drug resistance, and therefore, the development of such treatment regimens is recommended for counteracting the emergence and dissemination of cancer chemoresistance. This chapter outlines the current knowledge on underlying mechanisms, contributory biological factors and likely consequences of cancer chemoresistance. Besides, prognostic biomarkers, diagnostic methods and potential approaches to overcome the emergence of antineoplastic drug resistance have also been described.
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Affiliation(s)
- Muhammad Adil
- Pharmacology and Toxicology Section, University of Veterinary and Animal Sciences, Lahore, Jhang Campus, Jhang, 35200, Pakistan.
| | - Shamsa Kanwal
- Microbiology Section, University of Veterinary and Animal Sciences, Lahore, Jhang Campus, Jhang, 35200, Pakistan
| | - Sarmad Rasheed
- Microbiology Section, University of Veterinary and Animal Sciences, Lahore, Jhang Campus, Jhang, 35200, Pakistan
| | - Mavara Iqbal
- Microbiology Section, University of Veterinary and Animal Sciences, Lahore, Jhang Campus, Jhang, 35200, Pakistan
| | - Ghazanfar Abbas
- Microbiology Section, University of Veterinary and Animal Sciences, Lahore, Jhang Campus, Jhang, 35200, Pakistan
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Ahmad A, Nawaz MI. Molecular mechanism of VEGF and its role in pathological angiogenesis. J Cell Biochem 2022; 123:1938-1965. [PMID: 36288574 DOI: 10.1002/jcb.30344] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 09/12/2022] [Accepted: 10/13/2022] [Indexed: 12/24/2022]
Abstract
Over the last seven decades, a significant scientific contribution took place in the delineation of the implications of vascular endothelial-derived growth factor (VEGF) in the processes of angiogenesis. Under pathological conditions, mainly in response to hypoxia or ischemia, elevated VEGF levels promote vascular damage and the growth of abnormal blood vessels. Indeed, the development of VEGF biology has revolutionized our understanding of its role in pathological conditions. Hence, targeting VEGF or VEGF-mediated molecular pathways could be an excellent therapeutic strategy for managing cancers and intraocular neovascular disorders. Although anti-VEGF therapies, such as monoclonal antibodies and small-molecule tyrosine kinase inhibitors, have limited clinical efficacy, they can still significantly improve the overall survival rate. This thus demands further investigation through the development of alternative strategies in the management of VEGF-mediated pathological angiogenesis. This review article focuses on the recent developments toward the delineation of the functional biology of VEGF and the role of anti-VEGF strategies in the management of tumor and eye pathologies. Moreover, therapeutic angiogenesis, an exciting frontier for the treatment of ischemic disorders, is highlighted in this review, including wound healing.
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Affiliation(s)
- Ajmal Ahmad
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Dr. Nasser Al-Rashid Research Chair in Ophthalmology, Abdulaziz University Hospital, Riyadh, Saudi Arabia
| | - Mohd Imtiaz Nawaz
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Dr. Nasser Al-Rashid Research Chair in Ophthalmology, Abdulaziz University Hospital, Riyadh, Saudi Arabia
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Liu J, He M, Wang Z, Li Q, Xu B. Current Research Status of Metronomic Chemotherapy in Combination Treatment of Breast Cancer. Oncol Res Treat 2022; 45:681-692. [PMID: 35988534 PMCID: PMC9677858 DOI: 10.1159/000526481] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 08/02/2022] [Indexed: 08/27/2023]
Abstract
BACKGROUND Metronomic chemotherapy (MCT), termed sustained low-dose administration with minimal toxicity, is a new modality of conventional chemotherapy, a verified therapy alternative, and has acquired significant recognition and interest in oncology. Numerous clinical trials of MCT in combination with other treatments, including targeted therapies, biologics, and endocrine therapy, are in progress to obtain better results. SUMMARY We comprehensively described the clinical benefits of MCT in combination with other treatments in different molecular subtypes of breast cancer and assessed the feasibility of its adoption in varying phases of treatment. Due to the promising preclinical and clinical investigations, it is expected that MCT in combination with other treatments will enhance the advantages of this strategy and apply it to clinical practice. KEY MESSAGE MCT, in combination with other therapeutic interventions, will fully exploit the benefits of this strategy, ushering in a new paradigm in oncology treatment and driving the transformation of cancer into a more manageable chronic disease using newly developed treatment approaches.
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Affiliation(s)
| | | | | | - Qiao Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Binghe Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Cohen IJ, Ash S. New Approaches Promise to Improve Local Ewing Sarcoma Results. J Pediatr Hematol Oncol 2022; 44:280-284. [PMID: 35537008 DOI: 10.1097/mph.0000000000002481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 03/31/2022] [Indexed: 11/26/2022]
Abstract
The study by Whelan and colleagues showed that addition of busulfan and melphalan conditioning and autologous stem cell rescue to conventional EURO-E.W.I.N.G STUDY chemotherapy in local nonmetastatic Ewing sarcoma improves prognosis. However, almost 30% of these study patients will have relapsed before this stage of therapy is reached, and 78% of his patients were at high risk because of inadequate response to the initial chemotherapy given. Further improvement could be achieved by the integration of other novel advances with this approach. Ash and colleagues have shown that the separation of such cases into high- and low-risk groups by using CD56 negativity of the tumor cells is an improvement over current methods with a 100% 10-year progression-free survival in CD56- nonpelvic local isolated Ewing sarcoma patients. Their patients were treated on the SCMCIE 94 protocol, associated with no relapses before 30 months in 24 consecutive patients independent of the CD status. Integration of these novel approaches in diagnosis and treatment would allow truly high-risk patients, who would benefit from the procedure, to reach the busulfan and melphalan stage of therapy and delineate those patients who can be cured without such therapy. Details of the SCMCIE 94 protocol are given and the possible reasons for the different relapse patterns are discussed.
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Affiliation(s)
- Ian J Cohen
- Rina Zaizov Department of Pediatric Hematology‑Oncology, Schneider Children's Medical Center of Israel, Petach Tikva
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv
| | - Shifra Ash
- Joan and Sanford Weill Pediatric Hematology Oncology and Bone Marrow Transplantation Division, Ruth Rappaport Children's Hospital, Rambam Health Care Campus
- Technion Israel Institute of Technology, The Ruth and Bruce Rappaport Faculty of Medicine, Haifa, Israel
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Xun X, Cao Q, Hong P, Rai S, Zhou Y, Liu R, Hu H. Efficacy and Safety of Capecitabine for Triple-Negative Breast Cancer: A Meta-Analysis. Front Oncol 2022; 12:899423. [PMID: 35875141 PMCID: PMC9300946 DOI: 10.3389/fonc.2022.899423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 06/02/2022] [Indexed: 11/21/2022] Open
Abstract
Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited treatment options and poor prognosis. Capecitabine, as a novel adjuvant chemotherapy for TNBCs, remains controversial. Therefore, we conducted this meta-analysis to assess the efficacy and safety of capecitabine for early-stage TNBCs combined with neo-/adjuvant chemotherapy. Methods We searched Medline, Embase, Web of Science, and Cochrane databases updated on Mar 18, 2022 for relevant RCTs. In all, 11 RCTs with 5,175 patients were included. We used hazard ratios (HRs) and odds ratios (ORs) to assess the differences between disease-free survival (DFS), overall survival (OS), and adverse events. Results Our study demonstrated significance differences in both DFS and OS (DFS: HR=0.77; 95% CI 0.68–0.86; OS: HR=0.73, 95% CI 0.63–0.85). In subgroup analysis, the lower dosage group showed higher DFS (HR=0.79, 95% CI 0.69–0.91), higher frequency (HR=0.72, 95%CI 0.62–0.83), and adjuvant chemotherapy (HR=0.74, 95% CI 0.65–0.84). However, capecitabine was also associated with a higher risk of diarrhea (OR=3.10, 95% CI 2.32–4.15), hand–foot syndrome (OR=25.79, 95% CI 15.32–43.42), and leukopenia (OR=2.08, 95% CI 1.13–3.84). Conclusion The addition of capecitabine to early-stage TNBC patients receiving standard adjuvant chemotherapy showed significant DFS and OS improvement with tolerable adverse events. The lower dosage and higher frequency of capecitabine combined with adjuvant chemotherapy demonstrated a better survival outcome.
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Affiliation(s)
- Xueqiong Xun
- Department of Thyroid and Breast Surgery, First People’s Hospital of Qujing, Qujing, China
| | - Qinguang Cao
- Department of Thyroid and Breast Surgery, First People’s Hospital of Qujing, Qujing, China
| | - Pan Hong
- Department of Orthopaedic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Saroj Rai
- Department of Orthopaedics and Trauma Surgery, Blue Cross Hospital, Kathmandu, Nepal
- Department of Orthopaedics and Trauma Surgery, Karama Medical Center, Dubai, United Arab Emirates
| | - Yeming Zhou
- Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ruikang Liu
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Ruikang Liu, ; Huiyong Hu,
| | - Huiyong Hu
- Department of Thyroid and Breast Surgery, First People’s Hospital of Qujing, Qujing, China
- *Correspondence: Ruikang Liu, ; Huiyong Hu,
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Zhao X, Joshi JJ, Aird D, Karr C, Yu K, Huang C, Colombo F, Virrankoski M, Prajapati S, Selvaraj A. Combined inhibition of FGFR4 and VEGFR signaling enhances efficacy in FGF19 driven hepatocellular carcinoma. Am J Cancer Res 2022; 12:2733-2743. [PMID: 35812049 PMCID: PMC9251677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 04/07/2022] [Indexed: 06/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive liver malignancy that is difficult to treat with no approved biomarker based targeted therapies. FGF19-FGFR4 signaling blockade has been recently identified as a promising avenue for treatment of a subset of HCC patients. Using HCC relevant xenograft and PDX models, we show that Lenvatinib, an approved multi-kinase inhibitor, strongly enhanced the efficacy of FGFR4 inhibitor H3B-6527. This enhanced combination effect is not due to enhanced FGFR4 inhibition and it is likely due to cell non-autonomous VEGFR activity of Lenvatinib. This cell non-autonomous mode of action was further supported by strong in vivo combination efficacy with the mouse specific VEGFR2 antibody, DC101, which cannot cell-autonomously inhibit pathways in human xenografts. Mechanistic studies showed that the combination resulted in enhanced efficacy through increased anti-angiogenic and anti-tumorigenic activities. Overall, our results indicate that this combination can be a highly effective treatment option for FGF19 driven HCC patients, and provide preclinical validation of a combination that can be readily tested in the clinical setting.
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ChemoSensitivity Assay Guided Metronomic Chemotherapy Is Safe and Effective for Treating Advanced Pancreatic Cancer. Cancers (Basel) 2022; 14:cancers14122906. [PMID: 35740571 PMCID: PMC9220997 DOI: 10.3390/cancers14122906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 06/09/2022] [Accepted: 06/11/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Innovative chemotherapy regimens and tools to guide therapy in advanced pancreatic cancer are greatly needed. We present results of a study combining an innovative, metronomic chemotherapy strategy together with a blood-based pharmacogenomic tool to guide effective drug therapy. This study provides proof of principle that guided, metronomic chemotherapy for treatment of pancreatic cancer is a promising approach. Abstract Cytotoxic chemotherapy remains the mainstay of treatment for advanced pancreatic adenocarcinoma (PDAC). Emerging studies support metronomic chemotherapy (MCT) as effective, challenging established paradigms of dosing and schedules. The blood-based ChemoSensitivity Assay has been shown to predict response and survival in advanced PDAC patients treated with standard chemotherapy. The current study combines these concepts for a highly personalized treatment approach. This was a retrospective analysis; a pilot (n = 50) and validation cohort (n = 45) were studied. The ChemoSensitivity Assay was performed at baseline and during therapy; results were correlated to drugs administered and patient outcomes. MCT was administered based on the assay results at the treating physician′s discretion. Patients in the pilot cohort experienced favorable survival compared with historical controls (median overall survival (mOS) 16.8 mo). Patients whose treatment closely matched the ChemoSensitivity Assay predictions experienced longer median time on lines of therapy (5.3 vs. 3.3 mo, p = 0.02) and showed a trend for longer mOS (20.9 vs. 12.5 mo, p = 0.055) compared with those not closely matched. These findings were confirmed in the validation cohort. Overall, patients treated with MCT closely matching Assay results experienced a remarkable mOS of 27.7 mo. ChemoSensitivity profiling-guided MCT is a promising approach for personalized therapy in advanced PDAC.
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Wyss J, Frank NA, Soleman J, Scheinemann K. Novel Pharmacological Treatment Options in Pediatric Glioblastoma-A Systematic Review. Cancers (Basel) 2022; 14:2814. [PMID: 35681794 PMCID: PMC9179254 DOI: 10.3390/cancers14112814] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 05/30/2022] [Accepted: 05/31/2022] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Pediatric glioblastoma (GBM) is an aggressive central nervous system tumor in children that has dismal prognosis. Standard of care is surgery with subsequent irradiation and temozolomide. We aimed to outline currently available data on novel pharmacological treatments for pediatric GBM. METHODS We conducted a systematic literature search in PubMed and Embase, including reports published in English from 2010 to 2021. We included randomized trials, cohort studies and case series. Phase I trials were not analyzed. We followed PRISMA guidelines, assessed the quality of the eligible reports using the Newcastle-Ottawa scale (NOS) and the RoB-2 tool and registered the protocol on PROSPERO. RESULTS We included 6 out of 1122 screened reports. All six selected reports were prospective, multicenter phase II trials (five single-arm and one randomized controlled trial). None of the investigated novel treatment modalities showed any benefit regarding overall or progression free survival. CONCLUSIONS To date, the role of pharmacological approaches regarding pediatric GBM remains unclear, since no novel treatment approach could provide a significant impact on overall or progression free survival. Further research should aim to combine different treatment strategies in large international multicenter trials with central comprehensive diagnostics regarding subgrouping. These novel treatment approaches should include targeted and immunotherapeutic treatments, potentially leading to a more successful outcome.
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Affiliation(s)
- Johanna Wyss
- Division of Oncology-Hematology, Department of Pediatrics, Kantonsspital Aarau, 5001 Aarau, Switzerland;
- Division of Pediatric Oncology-Hematology, University Children’s Hospital of Basel, 4056 Basel, Switzerland
| | - Nicole Alexandra Frank
- Department of Neurosurgery, University Hospital of Basel, 4031 Basel, Switzerland; (N.A.F.); (J.S.)
| | - Jehuda Soleman
- Department of Neurosurgery, University Hospital of Basel, 4031 Basel, Switzerland; (N.A.F.); (J.S.)
- Department of Pediatric Neurosurgery, University Children’s Hospital of Basel, 4056 Basel, Switzerland
- Faculty of Medicine, University of Basel, 4056 Basel, Switzerland
| | - Katrin Scheinemann
- Division of Oncology-Hematology, Department of Pediatrics, Kantonsspital Aarau, 5001 Aarau, Switzerland;
- Department of Health Sciences and Medicine, University of Lucerne, 6002 Lucerne, Switzerland
- Department of Pediatrics, McMaster University Hamilton, Hamilton, ON L8S 4K1, Canada
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Fante MA, Felsenstein M, Mayer S, Gerken M, Klinkhammer-Schalke M, Herr W, Vogelhuber M, Reichle A, Heudobler D. All-Oral Low-Dose Chemotherapy TEPIP is Effective and Well-Tolerated in Relapsed/Refractory Patients With Aggressive B-Cell Lymphoma. Front Oncol 2022; 12:852987. [PMID: 35619924 PMCID: PMC9127443 DOI: 10.3389/fonc.2022.852987] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 04/07/2022] [Indexed: 12/24/2022] Open
Abstract
Purpose Treatment options in patients (pts.) with advanced relapsed and refractory aggressive B-cell lymphoma are limited. Palliative all-oral chemotherapy regimens reduce in-patient visits and contribute to quality of life. The all-oral low-dose chemotherapy regimen TEPIP comprises the conventional chemotherapy agents trofosfamide, etoposide, procarbazine, idarubicin and prednisolone. Methods Safety and efficacy of TEPIP was evaluated in an observational retrospective, single-center study at the University Medical Center Regensburg between 2010 and 2020. Treatment with TEPIP was applied for 7 or 10 days during a 28-days period. In a subgroup of fit and therapy-motivated pts. rituximab was added. End points were overall survival (OS) and progression free survival (PFS). Adverse events ≥ CTCAE grade III were reported. Results 35 highly pre-treated pts. with aggressive B-cell lymphoma were enrolled. Median age at TEPIP start was 67 years and 85% of pts. received TEPIP as ≥ third treatment line. Overall response rate (ORR) was 23% (CR 17%). Pts. benefited from additional rituximab administration (ORR 67%) and a lower number of pre-treatments (ORR 41%). The OS was 3.3 months (m) with a 1y-OS of 25.7% and the PFS amounted to 1.3 m with a 1y-PFS of 8.8%. OS and PFS were significantly prolonged in pts. that responded to treatment or additionally received rituximab. Adverse events were mainly hematological and occurred in 49% of pts. Conclusion TEPIP was well-tolerated and induced respectable response in a difficult-to-treat patient cohort. In particular, the all-oral administration enables out-patient use with palliative intent.
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Affiliation(s)
- Matthias A Fante
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Mona Felsenstein
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Stephanie Mayer
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Michael Gerken
- Bavarian Cancer Registry, Regional Centre Regensburg, Bavarian Health and Food Safety Authority, Regensburg, Germany.,Tumor Center - Institute for Quality Management and Health Services Research, University of Regensburg, Regensburg, Germany
| | - Monika Klinkhammer-Schalke
- Bavarian Cancer Registry, Regional Centre Regensburg, Bavarian Health and Food Safety Authority, Regensburg, Germany.,Tumor Center - Institute for Quality Management and Health Services Research, University of Regensburg, Regensburg, Germany
| | - Wolfgang Herr
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Martin Vogelhuber
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Albrecht Reichle
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Daniel Heudobler
- Department of Internal Medicine III, Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany.,Bavarian Cancer Research Center (BZKF), University Hospital Regensburg, Regensburg, Germany
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Carcamo B, Francia G. Cyclic Metronomic Chemotherapy for Pediatric Tumors: Six Case Reports and a Review of the Literature. J Clin Med 2022; 11:jcm11102849. [PMID: 35628975 PMCID: PMC9144744 DOI: 10.3390/jcm11102849] [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: 03/14/2022] [Revised: 04/06/2022] [Accepted: 05/13/2022] [Indexed: 12/03/2022] Open
Abstract
We report a retrospective case series of six Hispanic children with tumors treated with metronomic chemotherapy. The six cases comprised one rhabdoid tumor of the kidney, one ependymoma, two medulloblastomas, one neuroblastoma, and a type II neurocytoma of the spine. Treatment included oral cyclophosphamide daily for 21 days alternating with oral etoposide daily for 21 days in a backbone of daily valproic acid and celecoxib. In one case, celecoxib was substituted with sulindac. Of the six patients, three showed complete responses, and all patients showed some response to metronomic therapy with only minor hematologic toxicity. One patient had hemorrhagic gastritis likely associated with NSAIDs while off prophylactic antacids. These data add to a growing body of evidence suggesting that continuous doses of valproic acid and celecoxib coupled with alternating metronomic chemotherapy of agents such as etoposide and cyclophosphamide can produce responses in pediatric tumors relapsing to conventional dose chemotherapy.
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Affiliation(s)
- Benjamin Carcamo
- Department of Pediatric Hematology Oncology, El Paso Children’s Hospital, El Paso, TX 79905, USA
- Department of Pediatrics, Texas Tech University Health Science Center, El Paso, TX 79430, USA
- Correspondence: (B.C.); (G.F.); Tel.: +1-915-479-8970 (B.C.); +1-915-747-8025 (G.F.); Fax: +1-915-242-8437 (B.C.); +1-915-747-5808 (G.F.)
| | - Giulio Francia
- Border Biomedical Research Center, University of Texas at El Paso (UTEP), El Paso, TX 79968, USA
- Correspondence: (B.C.); (G.F.); Tel.: +1-915-479-8970 (B.C.); +1-915-747-8025 (G.F.); Fax: +1-915-242-8437 (B.C.); +1-915-747-5808 (G.F.)
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Pharmacokinetics of metronomic temozolomide in cerebrospinal fluid of children with malignant central nervous system tumors. Cancer Chemother Pharmacol 2022; 89:617-627. [PMID: 35355137 PMCID: PMC9054874 DOI: 10.1007/s00280-022-04424-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 03/13/2022] [Indexed: 11/24/2022]
Abstract
Purpose Although temozolomide is widely used in the treatment of childhood central nervous system (CNS) tumors, information on its pharmacokinetic profile in the brain or cerebrospinal fluid (CSF) is sparse. This study aimed at investigating whether measurable and clinically relevant concentrations of temozolomide are reached and maintained in CSF for continuous oral administration in pediatric patients. A population pharmacokinetic model was developed to quantify CSF penetration of temozolomide. Methods Eleven pediatric CNS tumor patients (aged 4–14 years) treated with oral temozolomide using a metronomic schedule (24–77 mg/m2/day) were included. Temozolomide concentrations in 28 plasma samples and 64 CSF samples were analyzed by high-performance liquid chromatography. Population pharmacokinetic modeling and simulations were performed using non-linear mixed effects modeling (NONMEM 7.4.2). Results Median temozolomide concentrations in plasma and CSF were 0.96 (range 0.24–5.99) µg/ml and 0.37 (0.06–1.76) µg/ml, respectively. A two-compartment model (central/plasma [1], CSF [2]) with first-order absorption, first-order elimination, and a transit compartment between CSF and plasma adequately described the data. Population mean estimates for clearance (CL) and the volume of distribution in the central compartment (Vc) were 3.29 L/h (95% confidence interval (CI) 2.58–3.95) and 10.5 L (8.17–14.32), respectively. Based on simulations, we found a median area under the concentration vs. time curve ratio (AUCCSF / AUCplasma ratio) of 37%. Conclusion Metronomic oral temozolomide penetrates into the CSF in pediatric patients, with even higher concentration levels compared to adults. Supplementary Information The online version contains supplementary material available at 10.1007/s00280-022-04424-4.
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Qian J, Tao D, Shan X, Xiao X, Chen C. Role of angiogenesis in beta-cell epithelial-mesenchymal transition in chronic pancreatitis-induced diabetes. J Transl Med 2022; 102:290-297. [PMID: 34764436 DOI: 10.1038/s41374-021-00684-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 09/30/2021] [Accepted: 10/01/2021] [Indexed: 11/08/2022] Open
Abstract
Clinical evidence suggests that patients with chronic pancreatitis (CP) are prone to development of diabetes (chronic pancreatitis-related diabetes; CPRD), whereas the underlying mechanisms are not fully determined. Recently, we showed that the gradual loss of functional beta-cells in a mouse model for CPRD, partial pancreatic duct ligation (PDL), results from a transforming growth factor β1 (TGFβ1)-triggered beta-cell epithelial-mesenchymal transition (EMT), rather than from apoptotic beta-cell death. Here, the role of angiogenesis in CPRD-associated beta-cell EMT was addressed. We detected enhanced angiogenesis in the inflamed pancreas from CP patients by bioinformatic analysis and from PDL-mice. Inhibition of angiogenesis by specific antisera for vascular endothelial growth factor receptor 2 (VEGFR2), DC101, did not alter the loss of beta-cells and the fibrotic process in PDL-pancreas. However, DC101-mediated inhibition of angiogenesis abolished pancreatitis-induced beta-cell EMT and rendered it to apoptotic beta-cell death. Thus, our data suggest that angiogenesis promotes beta-cell survival in the inflamed pancreas, while suppression of angiogenesis turns beta-cell EMT into apoptotic beta-cell death. This finding could be informative during development of intervention therapies for CPRD.
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MESH Headings
- Animals
- Antibodies, Monoclonal/pharmacology
- Apoptosis/drug effects
- Apoptosis/genetics
- Diabetes Mellitus/etiology
- Diabetes Mellitus/genetics
- Diabetes Mellitus/metabolism
- Disease Models, Animal
- Epithelial-Mesenchymal Transition/drug effects
- Epithelial-Mesenchymal Transition/genetics
- Female
- Gene Expression Profiling/methods
- Humans
- Insulin/metabolism
- Insulin-Secreting Cells/drug effects
- Insulin-Secreting Cells/metabolism
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/prevention & control
- Pancreatitis, Chronic/complications
- Pancreatitis, Chronic/genetics
- Pancreatitis, Chronic/metabolism
- Platelet Endothelial Cell Adhesion Molecule-1/metabolism
- Mice
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Affiliation(s)
- Jieqi Qian
- Department of Pediatric Endocrinology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA
| | - Dongdong Tao
- Department of Pediatric Surgery, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Xiaoou Shan
- Department of Pediatric Endocrinology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Xiangwei Xiao
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA.
| | - Congde Chen
- Department of Pediatric Endocrinology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA.
- Department of Pediatric Surgery, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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44
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Efficacy of Sequential Capecitabine on Adjuvant Chemotherapy of Triple-Negative Breast Cancer. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:7430775. [PMID: 35265304 PMCID: PMC8901322 DOI: 10.1155/2022/7430775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 01/29/2022] [Indexed: 11/30/2022]
Abstract
This paper aims to evaluate the efficacy of capecitabine as extended adjuvant treatment after anthracycline and paclitaxel combined adjuvant chemotherapy for women with early triple-negative breast cancer (TNBC). The patients with early TNBC were randomly assigned to capecitabine sequential treatment for 4 cycles and without any sequential treatment in the control group after anthracycline and paclitaxel combined adjuvant chemotherapy. The primary end point was disease-free survival (DFS). The secondary end point was overall survival (OS). One hundred patients were enrolled in this study between June 2013 and February 2015. Median age was 49 years ranging from 25 to 66 years and treatment was well tolerance. The median follow-up time after random allocation was 58 months (range: 11–62 months). There was no significant difference in DFS and OS between the two groups (hazard ratio (HR) of DFS was 0.50; 95% CI, 0.24–1.05; P=0.066). Our study shows that although the addition of four cycles capecitabine after anthracycline and paclitaxel combining adjuvant chemotherapy does not improve DFS and OS, but the trend of DFS is improved. The possible reason is that the four-cycle treatment of capecitabine is not enough, and another possible reason is that the number of cases is not enough.
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45
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Jaiswal V, Jain E, Hitawala G, Loh H, Patel S, Thada P, Nandwana V, Pandey S, Quinonez J, Naz S, Stein JD, Cueva W. Bevacizumab and Sinus Venous Thrombosis: A Literature Review. Cureus 2021; 13:e19471. [PMID: 34912612 PMCID: PMC8665695 DOI: 10.7759/cureus.19471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2021] [Indexed: 11/05/2022] Open
Abstract
Pediatric glioma treatment can be confounded by eloquent anatomical location and pathologic and genetic characteristics. Current literature suggests that the vascular endothelial growth factor (VEGF) inhibitor bevacizumab has been linked to enhancing disease control; however, its safety and effectiveness are unknown. Bevacizumab has been linked with an increased incidence of intratumoral hemorrhage as well as arterial and venous thromboembolism. A rare adverse effect of chemotherapeutic treatment with bevacizumab is sinus venous thrombosis (SVT), with only a few cases reported to date. This review highlights the pathophysiology of bevacizumab, its rare and life-threatening side effect of SVT, and future recommendations.
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Affiliation(s)
- Vikash Jaiswal
- Research and Academic Affairs, Larkin Community Hospital, South Miami, USA
| | - Esha Jain
- Medicine, American University of Antigua, St. John's, ATG
| | | | - Hanyou Loh
- Medicine, National University of Singapore, Singapore, SGP
| | - Suyog Patel
- Medicine, B J Medical College, Ahmedabad, IND
| | - Pawan Thada
- Research, Larkin Community Hospital, South Miami, USA
| | | | - Shreya Pandey
- Research, Larkin Community Hospital, South Miami, USA
| | - Jonathan Quinonez
- Neurology/Osteopathic Neuromuscular Medicine, Larkin Community Hospital, South Miami, USA
| | - Sidra Naz
- Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Joel D Stein
- Osteopathic Neuromusculoskeletal Manipulative Medicine, Family Medicine, Sports Medicine, Pain Medicine, Lake Erie College of Osteopathic Medicine Bradenton, Bradenton, USA.,Pain Mangement, Osteopathic Neuromusculoskeletal Manipulative Medicine, Sports Medicine, Larkin Community Hospital, South Miami, USA
| | - Wilson Cueva
- Neurology, Larkin Community Hospital, South Miami, USA
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46
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Adeola HA, Sabiu S, Aruleba RT, Adekiya TA, Adefuye AO, Adefuye OJ, Oyinloye BE. Phytodentistry in Africa: prospects for head and neck cancers. CLINICAL PHYTOSCIENCE 2021. [DOI: 10.1186/s40816-021-00254-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Orthodox dentistry has undergone significant changes in recent times with the introduction of various omics and molecular targeted therapies both at the experimental/trial and clinical implementation level. Although, significant milestones have been achieved in the molecular dentistry field in the past decade, there remains a dearth of application of phytopharmacological innovation in personalized and targeted therapies for dental diseases.
Main body
From time immemorial, plant products have long been an integral aspect of dental practice ranging from chewing sticks/herbal kinds of toothpaste to dental/impression materials. The current era of precision medicine seeks to apply a multipronged molecular and bio-computational approaches to solve fundamental medical problems that have hitherto remained difficult. Remarkable changes in the molecular/omics era, have transformed empirical therapies into personalized/individualized ones. Furthermore, the combinatorial application and the widespread introduction of high-throughput molecular tools such as pharmacogenomics, phytopharmacology, metabolomics, mathematical modelling, and genetic engineering inter alia, has tremendously improved the diagnostic and therapeutic landscape of medicine. Additionally, the variable molecular epidemiology of diseases among different population and emerging molecular evidence warrants the use of customized novel theranostic techniques. Unfortunately, the footprint of such emerging application is sparse in dental diseases such as maxillofacial cancers.
Conclusion
Hence, this review seeks to evaluate the potential application of phytopharmacological approaches to head and neck cancers in a resource-limited environment, such as Africa.
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Park M, Kim J, Kim T, Kim S, Park W, Ha KS, Cho SH, Won MH, Lee JH, Kwon YG, Kim YM. REDD1 is a determinant of low-dose metronomic doxorubicin-elicited endothelial cell dysfunction through downregulation of VEGFR-2/3 expression. Exp Mol Med 2021; 53:1612-1622. [PMID: 34697389 PMCID: PMC8568908 DOI: 10.1038/s12276-021-00690-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/21/2021] [Accepted: 06/29/2021] [Indexed: 01/10/2023] Open
Abstract
Low-dose metronomic chemotherapy (LDMC) inhibits tumor angiogenesis and growth by targeting tumor-associated endothelial cells, but the molecular mechanism has not been fully elucidated. Here, we examined the functional role of regulated in development and DNA damage responses 1 (REDD1), an inhibitor of mammalian target of rapamycin complex 1 (mTORC1), in LDMC-mediated endothelial cell dysfunction. Low-dose doxorubicin (DOX) treatment induced REDD1 expression in cultured vascular and lymphatic endothelial cells and subsequently repressed the mRNA expression of mTORC1-dependent translation of vascular endothelial growth factor receptor (Vegfr)-2/3, resulting in the inhibition of VEGF-mediated angiogenesis and lymphangiogenesis. These regulatory effects of DOX-induced REDD1 expression were additionally confirmed by loss- and gain-of-function studies. Furthermore, LDMC with DOX significantly suppressed tumor angiogenesis, lymphangiogenesis, vascular permeability, growth, and metastasis in B16 melanoma-bearing wild-type but not Redd1-deficient mice. Altogether, our findings indicate that REDD1 is a crucial determinant of LDMC-mediated functional dysregulation of tumor vascular and lymphatic endothelial cells by translational repression of Vegfr-2/3 transcripts, supporting the potential therapeutic properties of REDD1 in highly progressive or metastatic tumors.
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Affiliation(s)
- Minsik Park
- grid.412010.60000 0001 0707 9039Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341 Republic of Korea
| | - Joohwan Kim
- grid.412010.60000 0001 0707 9039Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341 Republic of Korea
| | - Taesam Kim
- grid.412010.60000 0001 0707 9039Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341 Republic of Korea
| | - Suji Kim
- grid.412010.60000 0001 0707 9039Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341 Republic of Korea
| | - Wonjin Park
- grid.412010.60000 0001 0707 9039Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341 Republic of Korea
| | - Kwon-Soo Ha
- grid.412010.60000 0001 0707 9039Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341 Republic of Korea
| | - Sung Hwan Cho
- grid.412010.60000 0001 0707 9039Kangwon Institute of Inclusive Technology, Kangwon National University, Chuncheon, Gangwon-do 24341 Republic of Korea
| | - Moo-Ho Won
- grid.412010.60000 0001 0707 9039Department of Neurobiology, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341 Republic of Korea
| | - Jeong-Hyung Lee
- grid.412010.60000 0001 0707 9039Department of Biochemistry, Kangwon National University, Chuncheon, Gangwon-Do 24341 Republic of Korea
| | - Young-Guen Kwon
- grid.15444.300000 0004 0470 5454Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722 Republic of Korea
| | - Young-Myeong Kim
- grid.412010.60000 0001 0707 9039Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Gangwon-do 24341 Republic of Korea ,grid.412010.60000 0001 0707 9039Kangwon Institute of Inclusive Technology, Kangwon National University, Chuncheon, Gangwon-do 24341 Republic of Korea
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48
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Khoobchandani M, Khan A, Katti KK, Thipe VC, Al-Yasiri AY, MohanDoss DKD, Nicholl MB, Lugão AB, Hans CP, Katti KV. Green nanotechnology of MGF-AuNPs for immunomodulatory intervention in prostate cancer therapy. Sci Rep 2021; 11:16797. [PMID: 34408231 PMCID: PMC8373987 DOI: 10.1038/s41598-021-96224-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 08/05/2021] [Indexed: 02/07/2023] Open
Abstract
Men with castration-resistant prostate cancer (CRPC) face poor prognosis and increased risk of treatment-incurred adverse effects resulting in one of the highest mortalities among patient population globally. Immune cells act as double-edged sword depending on the tumor microenvironment, which leads to increased infiltration of pro-tumor (M2) macrophages. Development of new immunomodulatory therapeutic agents capable of targeting the tumor microenvironment, and hence orchestrating the transformation of pro-tumor M2 macrophages to anti-tumor M1, would substantially improve treatment outcomes of CRPC patients. We report, herein, Mangiferin functionalized gold nanoparticulate agent (MGF-AuNPs) and its immunomodulatory characteristics in treating prostate cancer. We provide evidence of immunomodulatory intervention of MGF-AuNPs in prostate cancers through observations of enhanced levels of anti-tumor cytokines (IL-12 and TNF-α) with concomitant reductions in the levels of pro-tumor cytokines (IL-10 and IL-6). In the MGF-AuNPs treated groups, IL-12 was elevated to ten-fold while TNF-α was elevated to about 50-fold, while IL-10 and IL-6 were reduced by two-fold. Ability of MGF-AuNPs to target splenic macrophages is invoked via targeting of NF-kB signaling pathway. Finally, therapeutic efficacy of MGF-AuNPs, in treating prostate cancer in vivo in tumor bearing mice, is described taking into consideration various immunomodulatory interventions triggered by this green nanotechnology-based nanomedicine agent.
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Affiliation(s)
- Menka Khoobchandani
- Department of Radiology, Institute of Green Nanotechnology, University of Missouri, Columbia, MO, 65212, USA
- Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park Ave, St. Louis, MO, 63108, USA
| | - Aslam Khan
- Department of Biochemistry, University of Missouri, Columbia, MO, 65212, USA
| | - Kavita K Katti
- Department of Radiology, Institute of Green Nanotechnology, University of Missouri, Columbia, MO, 65212, USA
| | - Velaphi C Thipe
- Laboratório de Ecotoxicologia, Centro de Química e Meio Ambiente, Instituto de Pesquisas Energéticas e Nucleares (IPEN), Comissão Nacional de Energia Nuclear, IPEN/CNEN-SP, Butantã, São Paulo, SP, Brasil
| | - Amal Y Al-Yasiri
- Nuclear Science and Engineering Institute (NSEI), University of Missouri, Columbia, MO, 65211, USA
- College of Dentistry, University of Baghdad, Baghdad, Iraq
| | - Darsha K D MohanDoss
- Dhanvantari Nano Ayushadi Pvt Ltd, No. 8/34, Neelakanta Mehta Street, T. Nagar, Chennai, 600017, India
| | | | - Ademar B Lugão
- Laboratório de Ecotoxicologia, Centro de Química e Meio Ambiente, Instituto de Pesquisas Energéticas e Nucleares (IPEN), Comissão Nacional de Energia Nuclear, IPEN/CNEN-SP, Butantã, São Paulo, SP, Brasil
| | - Chetan P Hans
- Department of Medicine-Cardiology, University of Missouri, Columbia, MO, 65212, USA
| | - Kattesh V Katti
- Department of Radiology, Institute of Green Nanotechnology, University of Missouri, Columbia, MO, 65212, USA.
- Department of Physics, University of Missouri, Columbia, MO, 65212, USA.
- University of Missouri Research Reactor (MURR), University of Missouri, Columbia, MO, 65212, USA.
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49
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Gulia S, Ghosh J, Bajpai J, Rath S, Maheshwari A, Shylasree TS, Deodhar K, Thakur M, Gupta S. Pazopanib and Oral Cyclophosphamide in Women With Platinum-Resistant or -Refractory Epithelial Ovarian Cancer. JCO Glob Oncol 2021; 6:542-547. [PMID: 32228315 PMCID: PMC7113132 DOI: 10.1200/jgo.19.00331] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Women with recurrent, multiply-treated epithelial ovarian cancer (EOC) have unfavorable prognosis with limited treatment options after failure of platinum-based regimens. We report here a retrospective analysis of women with recurrent, platinum-resistant EOC treated with an oral regimen of pazopanib and cyclophosphamide. PATIENTS AND METHODS Women with recurrent platinum-resistant or -refractory EOC were treated with pazopanib (600 mg orally daily in 2 divided doses, 400 and 200 mg) and cyclophosphamide (50 mg orally daily for 21 days every 28 days) until disease progression or unacceptable toxicity. RESULTS Twenty patients (17 with platinum-resistant and 3 with platinum-refractory disease) were treated between April 2014 and April 2018. Patients had a median age of 52 years (range, 40-60 years) and median of 4 previous lines of chemotherapy (range, 2-8 previous lines), including 3 patients with progressive disease on bevacizumab. Patients received a median of 6 cycles (range, 2-48 cycles) of pazopanib and cyclophosphamide, with best responses of partial response in 9 patients (45%, including 1 of 3 patients treated previously with bevacizumab), stable disease in 6 patients (30%), and disease progression in 5 patients (25%). The median progression-free survival time was 5.5 months, and median overall survival was 9.5 months. Common adverse events (grade 3 or 4) were fatigue (25%), diarrhea (15%), hand-foot syndrome (10%), mucositis (10%), transaminitis (5%), and hypertension (5%). Dose reduction as a result of toxicity was required in 14 patients (70%), and no patient stopped treatment as a result of toxicity. CONCLUSION Pazopanib plus oral cyclophosphamide is a well-tolerated regimen with clinically relevant benefit in patients with platinum-resistant or -refractory EOC.
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Affiliation(s)
- Seema Gulia
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Jaya Ghosh
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Jyoti Bajpai
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Sushmita Rath
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Amita Maheshwari
- Department of Surgical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - T S Shylasree
- Department of Surgical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Kedar Deodhar
- Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Meenakshi Thakur
- Department of Radiology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Sudeep Gupta
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
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50
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Kerbel RS, Andre N. Adjuvant metronomic chemotherapy for locoregionally advanced nasopharyngeal carcinoma. Lancet 2021; 398:278-279. [PMID: 34111417 DOI: 10.1016/s0140-6736(21)01240-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 12/20/2022]
Affiliation(s)
- Robert S Kerbel
- Department of Medical Biophysics, Biological Sciences Platform, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5, Canada.
| | - Nicolas Andre
- Metronomic Global Health Initiative, Children Hospital of La Timone, AP-HM, Aix Marseille Université, Marseille, France
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