In honor of our 30th anniversary, we’re catching up with former grant recipients to hear how their work has impacted kidney cancer care and research.
Dr. Martin Voss is a medical oncologist and the Clinical Director of Genitourinary Medical Oncology Service at Memorial Sloan Kettering Cancer Center. He received a 2012 ASCO Young Investigator Award supported by the KCA. We spoke with Dr. Voss about his project – Predictive Tissue Biomarkers for mTOR Inhibitors in Advanced Renal Cell Carcinoma (RCC) – and what he has been working on recently.
I started working as a clinical research fellow in the Kidney Cancer Research Group at the beginning of my 2nd year of Medical Oncology fellowship training. At that point I had just completed a full year rotating through the various oncology subspecialty clinics my home institution Memorial Sloan Kettering Cancer Center (MSKCC). This was before the era of IO therapy, and management of metastatic RCC was almost entirely built on targeted therapies, the two MOAs exploited being VEGF and mTOR signaling. It occurred to me then that despite the fact that this disease the prototype entity for successful development of molecularly targeted agents, little emphasis had been placed on the development of predictive biomarkers in the context of the pivotal trials that established the agents already on the market. In part, this was due to technical limitations of developing such markers.
Our group had treated many patients since these trials, providing ample opportunity to study candidate markers retrospectively. NGS testing was now arriving in the clinical space, and one of the first assays for panel testing from paraffin-embedded specimens was being developed at my institutions. Its developer had newly established his lab at MSKCC and was eager to find clinical collaborators. There also was a new PI at MSKCC’s Human Oncology and Pathogenesis Program who was setting up a kidney cancer lab and eager to get translational projects off the ground to generate preliminary data. I met with both of them and proposed my idea to look at outlier cases with unusual responses to mTOR inhibitor therapy. We set this project up and got started within a few weeks.
We found that indeed, patients with unusually deep or lasting responses to mTOR directed agents, were likely to harbor oncogenomic correlates of such effect in their tumors – namely loss-of-function or activating mutations in key regulators of this pathway. Others reported similar findings in separate cohorts. This raised the question whether these biomarkers were only relevant (retrospectively) in the context of outlier responses. In subsequent years our group saw several patients in real-world practice whose tumors harbored the same alterations but did not benefit. A few years later I was able to address this question more comprehensively when had the opportunity to collaborate with the biomarkers team of a pharmaceutical company analyzing archival tissue from a large cohort of patients treated on a clinical trial studying mTOR and VEGF targeted agents in RCC. We learned then that our previously proposed paradigms could not be broadly applied.
It helped raise one of the most relevant biomarkers questions for mTOR directed therapies, then standards of care in this disease.
The prospect of detecting a signal for a potentially predictive marker was tremendously exciting to me at the time. It brought the hope to individualize care and provide opportunity to do what many patients are still asking for in my clinic now: leverage all information we can for individual patients to optimize choice of therapy.
It did, absolutely. With this project our group started profiling tumor tissue for our patients using archival specimen (e.g. from their nephrectomy). Although we did not establish a biomarker then we have continued to build our database, ask questions and maximize the amount of information we can gain from a patient‘s history and stored tissue.
My clinical and research focus is still kidney cancer. In my research I focus on drug and biomarker development in common and rare variants of kidney cancer.
I am appreciative of the support I have received through the Kca. Receiving the YIA was an important milestone early in my academic development; it motivated and enabled me to build an independent career in kidney cancer research. I have been fortunate having found my way into the field of RCC in such an opportune time and am so excited for our patients to have witnessed so many successes and the tremendous progress the field has seen in recent years. Undoubtedly, there are more to come.