Phase I Study Successfully Targets Metastatic Kidney Cancer

MedicalResearch.com Interview with:

Kevin D. Courtney, M.D., Ph.D.  Assistant Professor UT Southwestern Medical Cente

Dr. Courtney

Kevin D. Courtney, M.D., Ph.D. 
Assistant Professor
UT Southwestern Medical Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer. Metastatic ccRCC does not respond to traditional chemotherapy.

Current standard treatments for metastatic ccRCC include drugs called vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) that block the growth of new blood vessels that feed the cancer, as well as drugs that inhibit an enzyme called mTOR that is involved in ccRCC growth and immune therapies that rev up the body’s immune response to try to fight the cancer. Each of these treatments can have significant side effects for patients that can make them difficult to tolerate.

Metastatic ccRCC is largely incurable, and we need novel and better-tolerated treatments. A central driver of ccRCC is a protein called hypoxia inducible factor 2alpha (HIF-2alpha). This protein has been very difficult to try to target with a drug. This study is the first to test a drug that targets HIF-2alpha in patients with metastatic ccRCC. The study results showed that the HIF-2alpha inhibitor, PT2385 (Peloton Therapeutics) was active in fighting metastatic ccRCC and was well-tolerated.

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Four Management Options For Small Kidney Masses

MedicalResearch.com Interview with:

Hiten D. Patel, MD, MPH Resident, Urological Surgery James Buchanan Brady Urological Institute The Johns Hopkins Medical Institutions Baltimore, Maryland 21287

Dr. Hiten Patel

Hiten D. Patel, MD, MPH
Resident, Urological Surgery
James Buchanan Brady Urological Institute
The Johns Hopkins Medical Institutions
Baltimore, Maryland 21287 

MedicalResearch.com: What is the background for this study?

Dr. Patel: The study reports results of a systematic review contracted by the Agency for Healthcare Research and Quality based on input from stakeholders. Part of the motivation was due to the American Urological Association’s desire to use the results as a basis to update relevant clinical guidelines.

There are four major management options for clinically localized small renal masses diagnosed on imaging including active surveillance, thermal ablation, partial nephrectomy, and radical nephrectomy. The body of research evaluating these management options is broad, but many of the studies performing comparative analyses have limitations. Therefore, the systematic review aimed to evaluate a number of outcomes (e.g. overall survival, cancer specific survival, local recurrence, metastasis, renal function, complications, and perioperative outcomes) based on available comparative studies in the literature.

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Study Targets Obesity Genes That May Raise Risk of Kidney Cancer

MedicalResearch.com Interview with:

Dr. Xifeng Wu, MD PhD Department Chair, Department of Epidemiology, Division of OVP, Cancer Prevention and Population Sciences Director, Center for Translational and Public Health Genomics Professor, Department of Epidemiology Division of Cancer Prevention and Population Sciences The University of Texas MD Anderson Cancer Center, Houston, Texas

Dr. Xifeng Wu

Dr. Xifeng Wu, MD PhD
Department Chair, Department of Epidemiology, Division of OVP, Cancer Prevention and Population Sciences
Director, Center for Translational and Public Health Genomics
Professor, Department of Epidemiology
Division of Cancer Prevention and Population Sciences
The University of Texas MD Anderson Cancer Center, Houston, Texas

Medical Research: What is the background for this study? What are the main findings?

Dr. Wu: Obesity is a well-established risk factor for renal cell carcinoma (RCC), the most common form of kidney cancer. It has been estimated that more than 40% of RCC incident cases in the US may be attributed to excessive body weight. Growing body of evidence suggests that obesity may also influence clinical outcome of RCC; however, the findings are sometimes conflicting. So far, the molecular mechanism linking obesity to RCC risk or prognosis is not well understood. In this study, we evaluated the promoter CpG site methylation of 20 candidate obesity-related genes and their association with RCC risk and recurrence in a two-phase study of 240 newly diagnosed, previously untreated RCC patients. Pyrosequencing was conducted on paired RCC tumor and normal adjacent tissues to measure promoter methylation. Among the 20 markers, we found NPY, LEP and LEPR showed significant differential methylation levels between tumors and normal adjacent tissues, and methylation was significantly higher in tumors in both discovery and validation groups. Consistent with our findings, we also found lower expression of LEPR in tumor tissues compared to normal adjacent tissues in data obtained from The Cancer Genome Atlas. Additionally, high LEPR methylation in tumors was associated with more advanced tumor features, such as high pathologic stage, high grade and clear cell RCC histology, and increased risk of recurrence compared to the low methylation group. These results suggest that tissue changes in promoter methylation in obesity-related genes may provide some biological basis for the association between obesity and RCC outcome, and that LEPR may be an independent prognostic indicator of recurrence in RCC patients. Further research in larger study population and functional studies are warranted to validate our findings and to elucidate the underlying causal mechanisms.

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Individualized Sunitinib Dosing Improved Response Rate in Renal Cell Cancer

MedicalResearch.com Interview with:
Georg A. Bjarnason, MD, FRCP(C)
The Anna-Liisa Farquharson Chair in Renal Cell Cancer Research
Associate Professor, Faculty of Medicine, University of Toronto
Division of Medical Oncology, Sunnybrook Odette Cancer Centre
Toronto, ONT, Canada

Medical Research: What is the background for this study?

Dr. Bjarnason: Higher sunitinib drug exposure is associated with better response (RR), progression free (PFS) and overall survival (OS). Retrospective data show poorer PFS and OS in patients with minimum toxicity on the 28 day (d)/14 d schedule vs patients needing dose/schedule changes. We hypothesized that toxicity-driven dose/schedule changes would optimize drug exposure.

Medical Research: What are the main findings?

Dr. Bjarnason: The main findings of this report include:

  1. Individualized Sunitinib therapy is safe and feasible in a multicenter setting (13 study canters).
  2. Response rates (CR+PR+ SD rate of 89.2%) are among the best for any tyrosine-kinase inhibitor (TKI) in renal cell cancer with implications for dosing of sunitinib in other indications and for the dosing of other TKI’s. Only 10% of patients were refractory to Sunitinib. This has been around 20% in other studies.3. Dose intensity was improved in 65% of patients vs. the standard dosing schema for Sunitinib. 20% of patients were dose escalated, and much fewer patients needed dose reductions or stopped due to toxicity.
  3. The primary endpoint is PFS and the data are too early for this but: 37/102 (36.3%) patients have been on therapy longer than the 8.5 Mo PFS in the EFFECT comparator trial and 25/83 (30.1%) of these patients are still on therapy.  For 49 patients with CR+PR the median time on therapy is 14.3 months (29 patients (59%) still on treatment). For 42 patients with standard treatment the median time in therapy is 6.8 months (15 patients (34%) still on treatment).

Medical Research: What should clinicians and patients take away from your report?

Dr. Bjarnason: Many oncologists are already using alternate schedules for sunitinib because of the toxicity associated with the standard 4/2 schedule. These data provide them with an algorithm for individualized sunitinib therapy that is safe and associated with a very good response rate and time on therapy.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Bjarnason: The safety and activity of other targeted drugs might be optimized by individualizing therapy based on toxicity.

Citation:

Presented at 2015 ASCO Meeting:

Phase II study of individualized sunitinib as first-line therapy for metastatic renal cell cancer

J Clin Oncol 33, 2015 (suppl; abstr 4555)

Author(s):

Georg A. Bjarnason, Jennifer J. Knox, Christian K. Kollmannsberger, Denis Soulieres, D. Scott Ernst, Christina M. Canil, Eric Winquist, Pawel Zalewski, Sebastien J. Hotte, Scott A. North, Daniel Yick Chin Heng, Robyn Jane Macfarlane, Peter M. Venner, Ian Tannock, Anil Kapoor, Bernhard J. Eigl, Aaron Richard Hansen, Piotr Czaykowski, Ben Boyd, Naveen S. Basappa; Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada; BC Cancer Agency, Vancouver Cancer Centre, Vancouver, BC, Canada; Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada; London Regional Cancer Centre, London, ON, Canada; Ottawa Reg Cancer Centre, Manotick, ON, Canada; London Health Sciences Centre, London, ON, Canada; Lakeridge Health, Oshawa, ON, Canada; Juravinski Cancer Centre, Hamilton, ON, Canada; Cross Cancer Institute, Edmonton, AB, Canada; Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada; Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada; Cross Cancer Inst, Edmonton, AB, Canada; Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada; BC Cancer Agency, Vancouver, BC, Canada; Princess Margaret Hospital, Toronto, ON, Canada; CancerCare Manitoba, Winnipeg, MB, Canada; Ozmosis Research Inc, Toronto, ON, Canada

 

MedicalResearch.com Interview with: Georg A. Bjarnason, MD, FRCP(C) (2015). Individualized Sunitinib Dosing Improved Response Rate in Renal Cell Cancer 

Treatment For Small Kidney Cancers Has Evolved

Wiliam C. Huang, MD FACSAssociate Professor of Urology Division of Urologic Oncology NYU Langone Medical Center/Perlmutter Cancer InstituteMedicalResearch.com Interview with:
Wiliam C. Huang, MD FACS
Associate Professor of Urology
Division of Urologic Oncology
NYU Langone Medical Center/Perlmutter Cancer Center

Medical Research: What is the background for this study? What are the main findings?

Dr. Huang: The presentation of kidney cancers has dramatically evolved over the past two decades with most kidney cancers being incidentally diagnosed at an early stage. We have begun to recognize that at this small size (< 4 cm), the tumors are frequently indolent in nature and some are completely benign. Consequently, the management options for these small cancers have expanded and evolved.  Whereas the entire removal of the kidney was the treatment of choice in the past, alternative options including removal or ablation of the tumor-bearing portion of the kidney has become increasingly utilized. Similar to other early stage cancers, watchful waiting or observation is also becoming a reasonable treatment option.

We used the most recent SEER-Medicare Data (2001 – 2009) to evaluate the management trends and outcomes of small kidney cancers in the new millennium.  We believe that this is an important study as it provides important and practical findings, which are useful to both clinical researches as well as practicing physicians.

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Kidney Cancer: Nervous System Protein May Provide New Therapeutic Target

dr_john-coplandMedicalResearch.com Interview with:
Dr. John A. Copland, PhD
Associate Professor of Biochemistry/Molecular Biology
Professor of Cancer Biology
Cancer Basic Science
Mayo Clinic, Jacksonville, Florida

MedicalResearch: What are the main findings of the study?

Dr. Copland: In our study we identified a pro-cancerous role for a novel protein- neuronal pentraxin 2 (NPTX2). This protein, normally found expressed in brain and nervous system tissues, is highly overexpressed in kidney tumors at all stages of disease. It has never previously been associated with kidney cancer, nor has it been associated with an oncogenic function in any other cancer. NPTX2 appears to play a significant role in not only tumor cell survival, but it also promotes tumor cell migration through activation of the ionotropic glutamate receptor 4 (GluR4). GluR4, also commonly associated with nervous system tissues, appears to be manipulating the flow of calcium into the tumor cell. Both NPTX2 and GluR4 are not components of normal kidney cell function. Because calcium is an important co-factor for many signaling pathways controlling cell growth, survival, and mobility, unconstrained calcium levels in a cell can promote malignancy. We show that calcium calmodulin kinase and AKT, two oncogenic signaling pathways are activated by NPTX2 via calcium influx.
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Diabetes May Have Imply Poorer Prognosis For Renal Cell Cancer

MedicalResearch.com Interview with:
Sarah P. Psutka, MD
Fellow in Urologic Oncology
Department of Urology, Mayo Clinic

MedicalResearch: What are the main findings of each study? 

Dr. Psutka: In this study we identified all diabetic patients with localized clear cell renal cell carcinomas who were surgically treated between 1990 and 2008 in our institution and matched them with nondiabetic patients.

Our main findings were that, after controlling for major confounders such as age, sex, type of surgery, renal function, smoking status, performance status, and tumor grade and stage, diabetic patients had inferior overall survival than nondiabetic patients. Furthermore, among patients with clear cell carcinoma, diabetic patients also had shorter cancer-specific survival, suggesting that diabetes is a poor prognostic factor for patients with surgically treated renal cell carcinoma.

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