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Boegemann M, Schlack K, Rink M, Bernhardt S, Moran M, Hubbe M, Bergmann L, Schmid M, Strauss A. Effect of comorbidities/comedications on sunitinib outcomes for metastatic renal cell carcinoma: the STAR-TOR registry. Future Oncol 2020; 16:2939-2948. [PMID: 33021843 DOI: 10.2217/fon-2020-0548] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Aim: Examine the effects of baseline hypertension (HTN) and statin or proton pump inhibitor (PPI) use on sunitinib treatment outcomes in STAR-TOR, a real-world registry. Materials & methods: Presence or absence of HTN and use or nonuse of statins or PPIs were determined at registry entry. End points included overall survival (OS) and progression-free survival (PFS). Results: Data were from 557 patients. Presence or absence of HTN did not affect OS or PFS. PFS (median [95% CI]) was longer in statin users (9.4 [6.5-13.6] months) versus nonusers (6.9 [5.7-8.2] months) (p = 0.0442). OS was shorter in PPI users (20.2 [14.9-28.3] months) versus nonusers (25.7 [22.7-33.0] months) (p = 0.0212). Conclusion: Comorbidities and comedications may affect real-world sunitinib treatment outcomes. Clinical Trial Registration: NCT00700258 (ClinicalTrials.gov).
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Affiliation(s)
- Martin Boegemann
- Klinik für Urologie und Kinderurologie, Universitätsklinikum Münster, Münster, Germany, & West German Cancer Center, University Hospital of Muenster, Muenster, Germany
| | - Katrin Schlack
- Klinik für Urologie und Kinderurologie, Universitätsklinikum Münster, Münster, Germany, & West German Cancer Center, University Hospital of Muenster, Muenster, Germany
| | - Michael Rink
- Klinik und Poliklinik für Urologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | | | | | | | - Lothar Bergmann
- Medizinische Klinik 2, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Marianne Schmid
- Klinik für Urologie, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Arne Strauss
- Klinik für Urologie, Universitätsmedizin Göttingen, Göttingen, Germany
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Li J, Wang M, Zhang B, Wu X, Lin TL, Liu XF, Zhou Y, Zhang XH, Xu H, Shen LJ, Zou J, Lu P, Zhang D, Gu WJ, Zhang MX, Pan J, Cao H. Chinese consensus on management of tyrosine kinase inhibitor-associated side effects in gastrointestinal stromal tumors. World J Gastroenterol 2018; 24:5189-5202. [PMID: 30581268 PMCID: PMC6295840 DOI: 10.3748/wjg.v24.i46.5189] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 11/04/2018] [Accepted: 11/07/2018] [Indexed: 02/06/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) have improved the overall survival of patients with gastrointestinal stromal tumors (GISTs), but their side effects can impact dose intensity and, consequently, the clinical benefit. To date, no guideline or consensus has been published on the TKI-associated adverse reactions. Therefore, the Chinese Society of Surgeons for Gastrointestinal Stromal Tumor of the Chinese Medical Doctor Association organized an expert panel discussion involving representatives from gastrointestinal surgery, medical oncology, cardiology, dermatology, nephrology, endocrinology, and ophthalmology to consider the systemic clinical symptoms, molecular and cellular mechanisms, and treatment recommendations of GISTs. Here, we present the resultant evidence- and experience-based consensus to guide the management of TKI-associated side events in clinical practice.
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Affiliation(s)
- Jian Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Ming Wang
- Department of Gastrointestinal Surgery, Reiji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Bo Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Wu
- Department of General Surgery, the General Hospital of the People’s Liberation Army, Beijing 100853, China
| | - Tian-Long Lin
- Department of Gastrointestinal Surgery, Reiji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Xiu-Feng Liu
- Department of Oncology, The Chinese People’s Liberation Army 81st Hospital, Nanjing 210031, Jiangsu Province, China
| | - Ye Zhou
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Xin-Hua Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Hao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 320100, Jiangsu Province, China
| | - Li-Jing Shen
- Department of Hematology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, China
| | - Jing Zou
- Department of Respirology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, China
| | - Ping Lu
- Department of Dermatology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200240, China
| | - Dong Zhang
- Department of Nephrology, The General Hospital of the People’s Liberation Army, Beijing 100853, China
| | - Wei-Jun Gu
- Department of Endocrinology, The General Hospital of the People’s Liberation Army, Beijing 100853, China
| | - Mei-Xia Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jian Pan
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hui Cao
- Department of Gastrointestinal Surgery, Reiji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
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Abstract
Tyrosine kinase inhibitors like sunitinib, sorafenib, pazopanib or axintinib are regarded the standard of care in the systemic therapy of metastatic renal cell carcinoma. However, the many side effects associated with this therapy pose challenges for the treating physician and the patient. This review offers an overview of the classification and the treatment of hypertension, which is one of the major side effects induced by all tyrosine kinase inhibitors, in order to improve treatment efficacy and patient compliance.
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Ma Y, Zhou W, He S, Xu W, Xiao J. Tyrosine kinase inhibitor sunitinib therapy is effective in the treatment of bone metastasis from cancer of unknown primary: Identification of clinical and immunohistochemical biomarkers predicting survival. Int J Cancer 2017; 139:1423-30. [PMID: 27164264 DOI: 10.1002/ijc.30176] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 04/14/2016] [Accepted: 05/03/2016] [Indexed: 11/06/2022]
Abstract
Bone metastasis from cancer of unknown primary (BMCUP) brings poor survival prognosis and its management remains controversial. Sunitinib (SUTENT) proved effective in many sorts of solid tumors but has never been applied for patients with occult primary cancers, and there is no study to identify sensitive or resistant biomarkers for sunitinib therapy in CUP patients. An analysis was carried out to investigate the efficacy of sunitinib by multivariate survival analysis of 286 patients with BMCUP. We further carried out multivariate analysis to identify histological and clinical biomarkers that could predict sensitivity or resistance for sunitinib therapy. Of the 286 patients included from January 2011 to March 2016, sunitinib therapy proved effective to prolong survival in patients with BMCUP. Sensitive and resistant biomarkers were identified in histological specimen of patients receiving sunitinib therapy. Clinical factors were also identified that predict poor survival prognosis for sunitinib therapy. Sunitinib therapy proved effective to prolong survival in patients with BMCUP. Sensitive markers for sunitinib therapy include KDR positivity and early-developed treatment-induced hypertension. Resistance factors for sunitinib include VEGF positivity, CAIX positivity and squamous cell carcinoma pathology type. Prolonged symptom time and severe weight loss before therapy seemed to be associated with poor survival prognosis for sunitinib therapy.
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Affiliation(s)
- Yifei Ma
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wang Zhou
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Shaohui He
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wei Xu
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jianru Xiao
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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Mansfield C, Srinivas S, Chen C, Hauber AB, Hariharan S, Matczak E, Sandin R. The effect of information on preferences for treatments of metastatic renal cell carcinoma. Curr Med Res Opin 2016; 32:1827-1838. [PMID: 27404275 DOI: 10.1080/03007995.2016.1211521] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
OBJECTIVE Limited information exists regarding the effect of uncertainty in outcomes on patient preferences for metastatic renal cell carcinoma (mRCC) treatments. This study tested the effect on patients' preferences and willingness to tolerate toxicities when patients were provided with information about possible correlations between treatment-related toxicities and efficacy. RESEARCH DESIGN AND METHODS Patients with self-reported RCC diagnosis completed an online survey. Respondents were randomly assigned to the information treatment (i.e. information about the possible correlation). Medicines were defined by progression-free survival (PFS), three toxicities potentially correlated with PFS, and one toxicity uncorrelated with PFS. Direct-elicitation questions measured willingness to tolerate the toxicities, preferences for medicines with higher toxicity but a higher chance of longer PFS, and preferences for medicines with higher toxicity during treatment and a 2 week dosing schedule break. A discrete-choice experiment (DCE) tested the effect of information on relative preferences for medication attributes. RESULTS A total of 378 RCC patients completed the survey. Respondents who received the information reported greater willingness to accept more severe toxicities and preferred treatment with a higher chance of longer PFS but more severe toxicities. The DCE results were consistent with the hypothesis that the information increased willingness to tolerate toxicities; however, the results were only statistically significant for changes in fatigue (none to severe; p < 0.05) and hypertension (none to manageable; p < 0.05). LIMITATIONS Online recruitment through patient support groups may limit generalizability to the population of patients with mRCC who would be candidates for the targeted therapies. CONCLUSIONS The findings suggest that RCC patients have diverse preferences but may be willing to continue targeted therapies, even in the presence of severe toxicities, if there is a chance of improved clinical benefit. Physicians should provide patients with comprehensive information about medication features, including toxicities and efficacy (and their potential correlation), to improve compliance and optimize outcomes.
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Affiliation(s)
| | - Sandy Srinivas
- b Stanford University Medical Center , Stanford , CA , USA
| | | | - A Brett Hauber
- a RTI Health Solutions , Research Triangle Park , NC , USA
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Bourlon MT, Gao D, Trigero S, Clemons JE, Breaker K, Lam ET, Flaig TW. Clinical significance of sunitinib-associated macrocytosis in metastatic renal cell carcinoma. Cancer Med 2016; 5:3386-3393. [PMID: 27758076 PMCID: PMC5224865 DOI: 10.1002/cam4.919] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 08/11/2016] [Accepted: 08/18/2016] [Indexed: 12/12/2022] Open
Abstract
Increases in the mean corpuscular volume (MCV) have been observed in patients with metastatic renal cell carcinoma (mRCC) on tyrosine kinase inhibitor (TKI) treatment; however, its association with progression‐free‐survival (PFS) is unknown. We aimed to characterize TKI‐associated macrocytosis in mRCC and its relationship with PFS. Retrospective review of data on macrocytosis and thyroid dysfunction on mRCC patients treated with sunitinib and/or sorafenib. These results are evaluated in the context of our previous report on the association of hypothyroidism in this setting. We assessed PFS as clinically defined by the treating physician. Seventy‐four patients, 29 of whom received both drugs, were included. A treatment period was defined as time from initiation to discontinuation of either sunitinib or sorafenib; 103 treatment periods [sorafenib (47), sunitinib (56)] were analyzed. Macrocytosis was found in 55 and 8% of sunitinib‐ and sorafenib‐treated patients, respectively, P < 0.001. The median time to developing macrocytosis was 3 months (m, range 1–7). Median PFS in sunitinib‐treated patients was 11 m (95% CI: 6–19). Median PFS was higher among those with macrocytosis compared to normocytosis (21 m [95% CI: 11–25] vs. 4 m [95% CI: 3–8] P = 0.0001). Macrocytosis and hypothyroidism were two significant predictors of PFS. The greatest difference in PFS among all patients was observed in patients with both macrocytosis and hypothyroidism (25 m), compared to the normocytic and euthyroid patients (5 m) (P < 0.0001). Sunitinib‐related macrocytosis was associated with prolonged PFS, and concurrent development of hypothyroidism and macrocytosis further prolonged PFS. Increased MCV may have a role as a predictive biomarker for sunitinib. Prospective studies accounting for other known prognostic factors are needed to confirm this finding.
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Affiliation(s)
- Maria T Bourlon
- Division of Medical Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Dexiang Gao
- Department of Biostatistics and Informatics, University of Colorado, Denver, Colorado
| | - Sara Trigero
- School of Medicine, University of Colorado Denver, Aurora, Colorado
| | - Julia E Clemons
- School of Medicine, University of Colorado Denver, Aurora, Colorado
| | - Kathryn Breaker
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado.,University of Colorado Cancer Center, Aurora, Colorado
| | - Elaine T Lam
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado.,University of Colorado Cancer Center, Aurora, Colorado
| | - Thomas W Flaig
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado.,University of Colorado Cancer Center, Aurora, Colorado
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Molecular Markers and Targeted Therapeutics in Metastatic Tumors of the Spine: Changing the Treatment Paradigms. Spine (Phila Pa 1976) 2016; 41 Suppl 20:S218-S223. [PMID: 27488299 DOI: 10.1097/brs.0000000000001833] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY TYPE A review of the literature. OBJECTIVE The aim of this study was to discuss the evolution of molecular signatures and the history and development of targeted therapeutics in metastatic tumor types affecting the spinal column. SUMMARY OF BACKGROUND DATA Molecular characterization of metastatic spine tumors is expected to usher in a revolution in diagnostic and treatment paradigms. Molecular characterization will provide critical information that can be used for initial diagnosis, prognosticating the ideal treatment strategy, assessment of treatment efficacy, surveillance and monitoring recurrence, and predicting complications, clinical outcome, and overall survival in patients diagnosed with metastatic cancers to the spinal column. METHODS A review of the literature was performed focusing on illustrative examples of the role that molecular-based therapeutics have played in clinical outcomes for patients diagnosed with metastatic tumor types affecting the spinal column. RESULTS The impact of molecular therapeutics including receptor tyrosine kinases and immune checkpoint inhibitors and the ability of molecular signatures to provide prognostic information are discussed in metastatic breast cancer, lung cancer, prostate cancer, melanoma, and renal cell cancer affecting the spinal column. CONCLUSION For the providers who will ultimately counsel patients diagnosed with metastases to the spinal column, molecular advancements will radically alter the management/surgical paradigms utilized. Ultimately, the translation of these molecular advancements into routine clinical care will greatly improve the quality and quantity of life for patients diagnosed with spinal malignancies and provide better overall outcomes and counseling for treating physicians. LEVEL OF EVIDENCE N/A.
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Creel PA. Optimizing patient adherence to targeted therapies in renal cell carcinoma. Clin J Oncol Nurs 2016; 18:694-700. [PMID: 25427704 DOI: 10.1188/14.cjon.694-700] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The current standard of care for treating metastatic renal cell carcinoma is sequential therapy with vascular endothelial growth factor-targeted agents (i.e., axitinib, bevacizumab, pazopanib, sorafenib, and sunitinib) and mammalian target of rapamycin inhibitors (i.e., everolimus and temsirolimus). To maximize adherence to and persistence with targeted therapy, which should help improve clinical benefit, a clear understanding of the tolerability profiles of these agents and implementation of early, appropriately aggressive adverse event (AE) prevention and management strategies are key. Active and aggressive AE management should improve the quality of life of patients during the course of their treatment. Nurses are in a unique position to educate patients on the potential AEs they may experience and their prevention and management. This article reviews the safety and tolerability of currently available targeted therapies recommended for use in the second-line treatment setting, as well as their management in the context of maximizing clinical outcomes and patient quality of life.
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9
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Volume-based predictive biomarkers of sequential FDG-PET/CT for sunitinib in cancer of unknown primary: identification of the best benefited patients. Eur J Nucl Med Mol Imaging 2016; 44:199-205. [DOI: 10.1007/s00259-016-3504-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 08/25/2016] [Indexed: 01/17/2023]
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Dornbusch J, Walter M, Gottschalk A, Obaje A, Junker K, Ohlmann CH, Meinhardt M, Zacharis A, Zastrow S, Schoffer O, Grimm MO, Klug SJ, Wirth MP, Fuessel S. Evaluation of polymorphisms in angiogenesis-related genes as predictive and prognostic markers for sunitinib-treated metastatic renal cell carcinoma patients. J Cancer Res Clin Oncol 2016; 142:1171-82. [PMID: 26935927 DOI: 10.1007/s00432-016-2137-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 02/18/2016] [Indexed: 12/31/2022]
Abstract
PURPOSE Single nucleotide polymorphisms (SNPs) in angiogenesis-associated genes might play an important role in activity of the tyrosine kinase inhibitor sunitinib and could affect survival of cancer patients treated with this drug. The aim of this retrospective study was to elucidate the role of 10 known SNPs in VEGFA, VEGFR1, VEGFR2 and VEGFR3 as potential prognostic and predictive markers in an independent cohort of patients with metastatic renal cell carcinoma (mRCC). METHODS DNA from 121 mRCC patients treated with sunitinib was used to analyze SNPs by TaqMan genotyping assays. Disease control rate was evaluated according to RECIST. Adverse effects of sunitinib were registered from medical records. The results of Cox and logistic regression were verified by correction for multiple testing. RESULTS Kaplan-Meier analysis revealed a reduced progression-free survival in patients with the wild-type (WT) allele of the VEGFA SNP rs699947 compared to variant alleles. Patients with the AA/AC-alleles of the VEGFR1 SNP rs9582036 had an improved median overall survival compared to those with the CC-WT allele what could be confirmed by multivariable Cox proportional hazard regression analyses. No statistically significant associations between the analyzed SNPs and higher risk for adverse effects were observed. CONCLUSIONS The results of this study suggest that most of the selected SNPs in angiogenesis-related genes are not associated with survival of mRCC patients after sunitinib therapy or with adverse effects. Only the VEGFR1 SNP rs9582036 showed a statistically significant association with overall survival. The potential of SNPs as prognostic and predictive markers for sunitinib-treated mRCC patients should be finally assessed by prospective studies.
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Affiliation(s)
- Juana Dornbusch
- Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Martina Walter
- Department of Urology, University Hospital of Jena, Lessingstr. 1, 07743, Jena, Germany
| | - Andrea Gottschalk
- Institute for Medical Informatics and Biometry, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Alice Obaje
- Department of Urology, University Hospital of Jena, Lessingstr. 1, 07743, Jena, Germany
| | - Kerstin Junker
- Department of Urology, Saarland University Medical Center, Kirrberger Str. 1, 66424, Homburg, Germany
| | - Carsten-Henning Ohlmann
- Department of Urology, Saarland University Medical Center, Kirrberger Str. 1, 66424, Homburg, Germany
| | - Matthias Meinhardt
- Institute of Pathology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Aristeidis Zacharis
- Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Stefan Zastrow
- Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Olaf Schoffer
- Cancer Epidemiology, University Cancer Center Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Marc-Oliver Grimm
- Department of Urology, University Hospital of Jena, Lessingstr. 1, 07743, Jena, Germany
| | - Stefanie J Klug
- Cancer Epidemiology, University Cancer Center Dresden, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Manfred P Wirth
- Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany
| | - Susanne Fuessel
- Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
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Bono P, Oudard S, Bodrogi I, Hutson TE, Escudier B, Machiels JP, Thompson JA, Figlin RA, Ravaud A, Basaran M, Porta C, Bracarda S, Brechenmacher T, Lin C, Voi M, Grunwald V, Motzer RJ. Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia: Combined Subgroup Analyses of the RECORD-1 and REACT Trials. Clin Genitourin Cancer 2016; 14:406-414. [PMID: 27287020 PMCID: PMC5063024 DOI: 10.1016/j.clgc.2016.04.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Accepted: 04/18/2016] [Indexed: 02/05/2023]
Abstract
Background Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. Patients and Methods Adults with vascular endothelial growth factor–refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. Results In RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. Conclusion Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies.
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Affiliation(s)
- Petri Bono
- Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Finland.
| | - Stephane Oudard
- Department of Oncology, Georges Pompidou Hospital, Paris, France
| | | | - Thomas E Hutson
- Medical Oncology, US Oncology/Baylor-Sammons Cancer Center, Dallas, TX
| | | | - Jean-Pascal Machiels
- Institut Roi Albert II, Service d'Oncologie Médicale, Cliniques universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université catholique de Louvain, Brussels, Belgium
| | | | - Robert A Figlin
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Alain Ravaud
- Medical Oncology Hôpital, Saint André CHU, Bordeaux, France
| | - Mert Basaran
- Institute of Oncology, Istanbul University, Istanbul, Turkey
| | - Camillo Porta
- Medical Oncology, IRCCS San Matteo University Hospital Foundation, Pavia, Italy
| | - Sergio Bracarda
- Medical Oncology, San Donato Hospital, Istituto Toscano Tumori (ITT), Arezzo, Italy
| | | | | | | | - Viktor Grunwald
- Clinic for Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Medical School Hannover, Hannover, Germany
| | - Robert J Motzer
- Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY
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Chapman DW, Jans HS, Ma I, Mercer JR, Wiebe LI, Wuest M, Moore RB. Detecting functional changes with [(18)F]FAZA in a renal cell carcinoma mouse model following sunitinib therapy. EJNMMI Res 2014; 4:27. [PMID: 26116107 PMCID: PMC4451188 DOI: 10.1186/s13550-014-0027-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 05/05/2014] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND The multitargeting tyrosine kinase inhibitor (TKI) sunitinib is currently the first-line drug therapy for metastasizing renal cell carcinoma (RCC). TKIs have profound effects on tumor angiogenesis, leading to modifications of the tumor microenvironment. The goal of this study was to determine whether these treatment-induced changes can be detected with [(18)F]FAZA. METHODS The present study utilized positron emission tomography (PET) to analyze tumor oxygenation status during and after sunitinib therapy in the murine Caki-1 RCC tumor model. Dynamic and static scans were performed, as well as ex vivo biodistributions at 3 h post injection (p.i.). Immunohistochemical analysis of tumor tissue was carried out for the quantification of pimonidazole binding and the hypoxia-associated factors CD-31, Ki-67, and Von Willebrand factor (VWF). In addition, in vitro cellular uptake studies were done to analyze the direct effects of sunitinib on the Caki-1 cells. RESULTS During therapy with sunitinib (40 mg/kg/day), uptake of [(18)F]FAZA into Caki-1 mice decreased by 46 ± 5% (n = 4; 5 days) at 3 h post injection (p.i.) during the first study and 22 ± 5% (n = 8; 9 days) during the long-term study, indicating a decrease in the tumor's hypoxia level. However, when drug therapy was stopped, this effect was reversed completely, and the tumor [(18)F]FAZA uptake increased to 126 ± 6% (n = 6) of the control tumor uptake, indicative of an even higher level of tumor hypoxia compared to the therapy starting point. Sunitinib had no direct effect on [(18)F]FAZA uptake into Caki-1 cells in vitro. CONCLUSION [(18)F]FAZA PET could be used to monitor drug response during sunitinib therapy in RCC and may guide combination therapies based on the tumor's hypoxia status.
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Affiliation(s)
- David W Chapman
- />Department of Oncology Cross Cancer Institute, University of Alberta, 11560 University Ave, Edmonton, Alberta Canada T6G 1Z2 Canada
- />Department of Surgery, Walter C Mackenzie Health Sciences Centre, University of Alberta, 8440 112 Street, Edmonton, AB T6G 2B7 Canada
| | - Hans-Sonke Jans
- />Department of Oncology Cross Cancer Institute, University of Alberta, 11560 University Ave, Edmonton, Alberta Canada T6G 1Z2 Canada
| | - Ivy Ma
- />Department of Surgery, Walter C Mackenzie Health Sciences Centre, University of Alberta, 8440 112 Street, Edmonton, AB T6G 2B7 Canada
| | - John R Mercer
- />Department of Oncology Cross Cancer Institute, University of Alberta, 11560 University Ave, Edmonton, Alberta Canada T6G 1Z2 Canada
| | - Leonard I Wiebe
- />Department of Oncology Cross Cancer Institute, University of Alberta, 11560 University Ave, Edmonton, Alberta Canada T6G 1Z2 Canada
| | - Melinda Wuest
- />Department of Oncology Cross Cancer Institute, University of Alberta, 11560 University Ave, Edmonton, Alberta Canada T6G 1Z2 Canada
| | - Ronald B Moore
- />Department of Oncology Cross Cancer Institute, University of Alberta, 11560 University Ave, Edmonton, Alberta Canada T6G 1Z2 Canada
- />Department of Surgery, Walter C Mackenzie Health Sciences Centre, University of Alberta, 8440 112 Street, Edmonton, AB T6G 2B7 Canada
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13
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Révision de l’index thérapeutique des thérapies ciblées dans le cancer du rein : le mieux peut-il être l’ennemi du bien ? La toxicité peut-elle prédire l’efficacité ? Bull Cancer 2014; 101:608-18. [DOI: 10.1684/bdc.2014.1935] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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del Puerto-Nevado L, Rojo F, Zazo S, Caramés C, Rubio G, Vega R, Chamizo C, Casado V, Martínez-Useros J, Rincón R, Rodríguez-Remírez M, Borrero-Palacios A, Cristóbal I, Madoz-Gúrpide J, Aguilera O, García-Foncillas J. Active angiogenesis in metastatic renal cell carcinoma predicts clinical benefit to sunitinib-based therapy. Br J Cancer 2014; 110:2700-7. [PMID: 24786599 PMCID: PMC4037833 DOI: 10.1038/bjc.2014.225] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 02/27/2014] [Accepted: 04/04/2014] [Indexed: 01/15/2023] Open
Abstract
Background: Sunitinib represents a widely used therapy for metastatic renal cell carcinoma patients. Even so, there is a group of patients who show toxicity without clinical benefit. In this work, we have analysed pivotal molecular targets involved in angiogenesis (vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (KDR), phosphorylated (p)KDR and microvascular density (MVD)) to test their potential value as predictive biomarkers of clinical benefit in sunitinib-treated renal cell carcinoma patients. Methods: Vascular endothelial growth factor-A, KDR and pKDR-Y1775 expression as well as CD31, for MVD visualisation, were determined by immunohistochemistry in 48 renal cell carcinoma patients, including 23 metastatic cases treated with sunitinib. Threshold was defined for each biomarker, and univariate and multivariate analyses for progression-free survival (PFS) and overall survival (OS) were carried out. Results: The HistoScore mean value obtained for VEGF-A was 121.6 (range, 10–300); for KDR 258.5 (range, 150–300); for pKDR-Y1775 10.8 (range, 0–65) and the mean value of CD31-positive structures for MVD visualisation was 49 (range, 10–126). Statistical differences for PFS (P=0.01) and OS (P=0.007) were observed for pKDR-Y1775 in sunitinib-treated patients. Importantly, pKDR-Y1775 expression remained significant after multivariate Cox analysis for PFS (P=0.01; HR: 5.35, 95% CI, 1.49–19.13) and for OS (P=0.02; HR: 5.13, 95% CI, 1.25–21.05). Conclusions: Our results suggest that the expression of phosphorylated (i.e., activated) KDR in tumour stroma might be used as predictive biomarker for the clinical outcome in renal cell carcinoma first-line sunitinib-treated patients.
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Affiliation(s)
- L del Puerto-Nevado
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - F Rojo
- Department of Pathology, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - S Zazo
- Department of Pathology, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - C Caramés
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - G Rubio
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - R Vega
- Department of Pathology, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - C Chamizo
- Department of Pathology, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - V Casado
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - J Martínez-Useros
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - R Rincón
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - M Rodríguez-Remírez
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - A Borrero-Palacios
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - I Cristóbal
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - J Madoz-Gúrpide
- Department of Pathology, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - O Aguilera
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
| | - J García-Foncillas
- Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain
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The effect of sunitinib on the plasma exposure of intravenous paracetamol and its major metabolite: paracetamol glucuronide. Eur J Drug Metab Pharmacokinet 2014; 40:163-70. [PMID: 24676873 PMCID: PMC4426134 DOI: 10.1007/s13318-014-0191-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 03/08/2014] [Indexed: 12/04/2022]
Abstract
The study aimed to examine the effect of sunitinib on the plasma exposure of intravenous paracetamol and its major metabolite, paracetamol glucuronide. Both drugs share metabolic pathways in the liver, and the drug interactions between sunitinib and paracetamol administered in higher doses were reported. These interactions resulted in hepatotoxicity. The adult New Zealand male rabbits were divided into three groups (6 animals each): rabbits receiving sunitinib and paracetamol (SUN + PC), rabbits receiving sunitinib (SUN), and a control group receiving paracetamol (PC). Sunitinib was administered orally (25 mg) and paracetamol was administrated intravenously (35 mg/kg). Blood samples for sunitinib and SU12662 assays were collected up to 96 h after drug administration and for paracetamol and paracetamol glucuronide up to 300 min after drug administration. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin were analysed before and after drug administration. A number of pharmacokinetic parameters were analysed. There were no differences in the levels of AST, ALT, and bilirubin among the groups at either time point. Significantly higher values of AUC0–t, AUC0–∞, and Cmax and lower clearance and volume of distribution of paracetamol were observed in group PC vs. group SUN + PC (p < 0.01). The maximum plasma concentration of paracetamol glucuronide tended to be higher in group PC 213.27 μg/mL (90 % CI 1.06, 1.25; p = 0.0267). Statistically significant differences were revealed for paracetamol glucuronide mean residence time (MRT); MRT was higher in group SUN + PC than in group PC (p = 0.0375). The mean tmax of paracetamol glucuronide was similar in both groups: SUN + PC and group PC (15 and 20 min, respectively). The mean tmax of sunitinib was different in groups SUN + PC and SUN (10.0 and 7.0, respectively; p = 0.0134). At the studied doses, neither of the drugs, whether administered alone or together, had hepatotoxic effects. The present study was not able to confirm that sunitinib, administered at low doses in conjunction with paracetamol, displays a hepatoprotective effect. Significant differences were observed in some pharmacokinetic parameters of paracetamol.
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Daste A, Grellety T, Gross-Goupil M, Ravaud A. Protein kinase inhibitors in renal cell carcinoma. Expert Opin Pharmacother 2013; 15:337-51. [PMID: 24328606 DOI: 10.1517/14656566.2014.869210] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Metastatic Renal Cell Carcinoma (mRCC) was historically treated with cytokine therapy with a poor outcome. In the last decade, new therapies targeting vascular endothelial growth factor (VEGF) or the mammalian target of rapamycin (m-TOR) pathways demonstrated efficacy in mRCC. Protein kinase inhibitors as well as monoclonal antibodies targeting these pathways have become the standard treatment of renal cell carcinoma (RCC) in the first-line setting and beyond. AREAS COVERED This review describes the various Phase III trials concerning protein kinase inhibitors including anti-angiogenic tyrosine kinase inhibitors (TKIs) and m-TOR serine/threonine kinase inhibitors, which have demonstrated a benefit in the treatment of mRCC. It focuses on efficacy, safety and management. EXPERT OPINION VEGF TKI and m-TOR inhibitors have significantly improved the outcome of mRCC and offer a gain in survival by sequential treatments for the majority of patients. But they induce a particular toxicity profile. An adequate management of each drug and its sequence in treatment is essential to optimise the outcome and preserve the quality of life (QoL) of patients with mRCC. In forthcoming years, pending results should indicate whether VEGF TKI are of interest in an adjuvant setting and if new drugs targeting will challenge the current standard guidelines in the metastatic setting.
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Affiliation(s)
- Amaury Daste
- Hôpital Saint-André, Bordeaux University Hospital-CHU Bordeaux, Department of Medical Oncology , 1 Rue Jean Burguet, 33075 Bordeaux , France +33 5 56 79 58 96 ;
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Noh GT, Kim MH, Suh JY, Song Y, Lee CK, Baek JH, Lee YS, Cho G, Kim E, Kim YR, Cho HJ, Lim D, Kim JK. Sunitinib--CLIO conjugate: a VEGFR/PDGFR-targeting active MR probe. Mol Imaging Biol 2013; 16:340-9. [PMID: 24185817 DOI: 10.1007/s11307-013-0697-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Revised: 09/10/2013] [Accepted: 10/02/2013] [Indexed: 12/11/2022]
Abstract
PURPOSE This study was conducted to evaluate feasibility of sunitinib-CLIO conjugate as a vascular endothelial growth factor receptor/platelet-derived growth factor receptor (VEGFR/PDGFR)-specific magnetic resonance (MR) probe. PROCEDURE VEGFR/PDGFR-targeting MR probe was synthesized by conjugating cross-linked iron-oxide (CLIO) with tyrosine-kinase inhibitor (sunitinib). In VEGFR/PDGFR-positive (U118MG) and VEGFR/PDGFR-negative (HT29) cells and tumor models, conjugate-driven ΔR 2 was estimated, while CLIO was used as control. Prussian-blue staining was performed for quantifying the amount of tumor-binding conjugates. RESULTS ΔR 2 between sunitinib-CLIO-treated and non-treated cells was greater in U118MG (mean, 2.1/s) than in HT29 cells (1.0/s). In in vivo study, conjugate induced a greater ΔR 2 in U118MG (11.2/s) than HT29 tumors (5.9/s). Conjugate-induced R 2 changes were not correlated with degree of Gd-DTPA enhancement, demonstrating that tumor binding of sunitinib-CLIO was independent of enhanced permeability and retention effect. % area of Prussian-blue staining was greater in U118MG (8.5 %) than in HT29 (1.4 %). CONCLUSIONS Sunitinib-CLIO conjugate can be used as an active MR probe for quantifying VEGFR/PDGFR.
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Affiliation(s)
- Gwang Tae Noh
- Department of Chemistry, Sejong University, Seoul, 143-747, South Korea
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Bianchi L, Rossi L, Tomao F, Papa A, Zoratto F, Tomao S. Thyroid dysfunction and tyrosine kinase inhibitors in renal cell carcinoma. Endocr Relat Cancer 2013; 20:R233-45. [PMID: 23833016 DOI: 10.1530/erc-13-0201] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The most recent World Health Organization classification of renal neoplasms encompassed nearly 50 distinctive renal neoplasms. Different histological subtypes have different clinical outcomes and show different responses to therapy. Overall, the incidence of kidney cancer has increased worldwide in the last years. Although the most common type of kidney cancer is localized renal cell carcinoma (RCC), with a 5-year survival rate of 85%, about one third of patients present advanced or metastatic disease at diagnosis, with a 5-year survival rate of only 10%. Multi-targeted receptor tyrosine kinase inhibitors (TKIs, sunitinib and sorafenib), the anti-VEGF MAB bevacizumab in association with interferon-α, and the mTOR inhibitors are now approved for the treatment of mRCC. Recently, the novel agents pazopanib and axitinib have also demonstrated efficacy in mRCC patients. Several recent retrospective and prospective trials have suggested that some of their adverse events, such as hypertension, hypothyroidism, and hand foot syndrome (HFS) may act as potential biomarkers of response and efficacy of treatment. In this review, we analyzed the studies that have suggested a relationship between hypothyroidism onset and a better outcome of mRCC patients treated with TKIs. The biological mechanisms suggesting and explaining this correlation are not well known and different speculative theories have been considered in order to investigate the clinical link between hypothyroidism occurrence and the prolonged therapy with TKIs in solid tumors. Furthermore, the management of this unexplained side effect is very important to maximize the efficacy of therapy in mRCC patients because there is a clear and consistent relationship between drug dose and efficacy of treatment. Certainly, other studies are needed to clarify whether a better outcome is associated with hypothyroidism induced to TKIs in patients with mRCC.
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Affiliation(s)
- Loredana Bianchi
- Oncology Unit - ICOT, Department of Medico-Surgical Sciences and Biotechnologies, University of Rome 'Sapienza', Latina, Italy
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O'Rourke CJ, Knabben V, Bolton E, Moran D, Lynch T, Hollywood D, Perry AS. Manipulating the epigenome for the treatment of urological malignancies. Pharmacol Ther 2013; 138:185-96. [PMID: 23353098 DOI: 10.1016/j.pharmthera.2013.01.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Accepted: 01/10/2013] [Indexed: 12/26/2022]
Abstract
Urological malignancies (cancers of the prostate, bladder, kidney and testes) account for 15% of all human cancers and more than 500,000 deaths worldwide each year. This group of malignancies is spread across multiple generations, affecting the young (testicular) through middle and old-age (kidney, prostate and bladder). Like most human cancers, urological cancers are characterized by widespread epigenetic insult, causing changes in DNA hypermethylation and histone modifications leading to silencing of tumor suppressor genes and genomic instability. The inherent stability yet dynamic plasticity of the epigenome lends itself well to therapeutic manipulation. Epigenetic changes are amongst the earliest lesions to occur during carcinogenesis and are essentially reversible (unlike mutations). For this reason, much attention has been placed over the past two decades on deriving pharmacological compounds that can specifically target and reverse such epi-mutations, either halting cancer on its developmental trajectory or reverting fully formed cancers to a more clinically manageable state. This review discusses DNA methyltransferase and histone deacetylase inhibitors that have been extensively studied in preclinical models and clinical trials for advanced and metastatic urological cancers.
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Affiliation(s)
- Colm J O'Rourke
- Prostate Molecular Oncology, Institute of Molecular Medicine, Trinity College, Dublin, Ireland
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