Kidney Cancer Program
Program Mission: The Kidney Cancer Program seeks to conduct innovative basic research into the molecular basis of cancers of the kidney with the goal of identifying meaningful biomarkers for prognosis and early detection, novel therapeutic targets and potentially effective therapies used either alone or in combination. In addition, the Kidney Cancer Program hopes to conduct cutting edge clinical trials across all disease strata in the hopes of identifying more effective treatments and better ways of predicting who should receive each therapy. Finally, the Kidney Cancer Program seeks to better educate its members, the DF/HCC community and the physicians across New England as to the opportunities for progress in kidney cancer investigation.
Program researchers were awarded a prestigious “Specialized Program of Research Excellence” (SPORE) grant from the National Cancer Institute in 2003. This grant was successfully renewed in 2009 and remains the only SPORE ever awarded for the study of kidney cancer. This research funding carries with it both the means and the responsibility to play a leadership role in translating basic science advances into improved treatment approaches for patients with kidney cancer.
Specific Program Goals:
1. Identify and validate novel targets in kidney cancer
2. Identify biomarker(s) for renal cancer
3. Leverage program and SPORE infrastructure to facilitate drug development
4. Identify molecular and biologic predictors of response to various therapies
5. Establish an educational program for DF/HCC and the region
Value Added/Future Priorities
The past 4 years have seen unprecedented advances in the treatment of patients with advanced RCC with the approval or impending approval of 5 new agents. These advances have greatly changed the critical questions and priorities for research in this field. The DF/HCC Kidney Cancer Program has positioned itself to play a leading role in addressing these critical questions and these issues will become increasingly emphasized over the next year and beyond.
- Expand efforts to identify new targets for RCC, including those that cooperative with VHL loss-synthetic lethal-and those that are independent of VHL.
- Expand validation of novel therapeutic targets in preclinical models and in patients with RCC including those focused on PI3K/Akt/MTor pathway, c-met pathway and HIF2alpha. The preclinical work will be aided by existing xenograft models including those involving minimally passaged tumors obtained from RCC patients, MTAs from pharmaceutical companies for drugs that hit these pathways and in several cases support from the SPORE grant. We anticipate that clinical trials testing these novel targeted agents will follow, with DF/HCC investigators being uniquely positioned to perform related correlative studies.
- Expand biomarker/tumor marker work by performing analyses of candidate markers in pre and post-nephrectomy specimens and serial blood samples in patients on therapy as well as establishing and validating an animal model for tumor associated biomarker discovery. With the identification of candidate markers and the serial collection of blood, urine and tissue from patients with different stages of RCC we are uniquely situated to make inroads in this important research objective.
- Complete IL-2 Select and RAD001 Biomarker trials and further expand efforts to develop predictors of response to targeted therapeutics. With several effective treatments now available for patients with advanced RCC, continuing/completing our efforts to identify tumor related factors that can help treatment selection have become increasingly important. The DF/HCC has been leaders in this line of research and is poised to continue in that capacity including investigations of predictors of response to novel therapies such as those mentioned in item 2 above.
- Use multiple RCC xenograft models including short term cultures and orthotopically transplanted agents to further evaluate for treatment scheduling opportunities and mechanisms of angiogenic escape for sorafenib and sunitinib. With the extensive use of sorafenib and sunitinib first-line understanding mechanisms of resistance and developing strategies for delaying or overcoming it have become a major priority for the field. The DF/HCC Kidney Cancer Program has played a leading role in these investigations that have included tissue, imaging, and blood studies as well preclinical and clinical trials. With the support of the SPORE grant and pharmaceutical industry we are poised to lead this important research into the future.
- Evaluate the role of continued VEGFR pathway blockade in the VEGFR TKI resistance setting. With the impending approval of RAD001 for treatment of sorafenib or sunitinib refractory RCC, it has become a priority to determine whether maintaining blockade of the VEGF pathway can improve upon the results seen with a mTOR inhibitor. The DF/HCC Clinical investigative group views this as a priority and is prepare to test this through a variety of clinical trials including studies of temsirolimus and bevacizumab (currently be reviewed within DF/HCC IRB) and RAD 001 +/-bevacizumab (proposed within the Intergroup mechanism) in sunitinib refractory patients.
- Continue to expand the role of imaging in RCC diagnosis and as predictive and surrogate biomarkers. Perfusion imaging has been shown to be most useful in kidney cancer and we are poised to further explore a DF/HCC developed novel and accurate perfusion imaging technique (ASL perfusion MRI) in preclinical and patients with RCC. In addition, we have initiated studies looking at the role of FDG-PET scanning in predicting response to Tor inhibitors and CAIX-PET imaging in identifying high CAIX expressing tumors, an approach that might aid in treatment selection.
- Evaluate opportunities for coordinating immunotherapy with targeted therapy as well as novel immunotherapy combinations in patients with advanced RCC. The DC:tumor vaccine strategy developed within DF/HCC has shown its most promising results in patients with advanced RCC. Furthermore the discovery of potential immuno-augmentative effects on sunitinib and the availability of agents that block the PD1-PD1ab pathway (known to be an important poor prognostic factor in RCC) create opportunities to improve the vaccination approach. With the support of the SPORE and collaborations with the DF/HCC Immunology Program we are also poised to lead this important investigative field.
- Continue to expand the role of urologists, radiation oncologists, population scientists and radiologists in KCP activities including translational clinical trials. We have recruited several young urologists to DF/HCC institutions and have worked hard to encourage their research careers and provide them opportunities to collaborate in translational research studies. Furthermore, urologists such as Drew Wagner and Aria Olumi, radiation oncologists such as Irving Kaplan, radiologists such as Ivan Pedrosa and David Alsop and population scientists such as Eunyoung Cho, have been supported through DF/HCC funds and in several instances this support has led to their receiving independent outside support. We anticipate that these efforts will continue and expand over the next few years.
- Continue and expand effort to explore the biology and treatment opportunities for non-clear cell RCC and other tumors of the kidney. We initiated clinical trials of a c-met inhibitor in papillary RCC that has shown encouraging efficacy in patients with c-met mutations within their tumors. It is likely that these agents will change the treatment of this subset of RCC patients. In addition, KCP investigators have been leaders in exploring the biology of Wilms Tumor (Haber and Rivera), Tuberosclerosis (Dabora) and HLRCC (Seth, Sukhatme and Henske) and we anticipate within the next several years that these investigations will translate into novel therapeutic opportunities for patients with these diseases.
- Continue educational conferences that focus on providing information about ongoing and future research and clinical trials to DF/HCC community, national Kidney Cancer research community and the lay public. Our efforts to date have established a variety of modes, means and venues for communication which we intend to continue with the hope of these becoming institutional activities for the kidney cancer community.