Reprogramming Chromatin Modifiers in Kidney Cancer

Project: Research project

Project Details

Description

Kidney cancer is the seventh most common malignancy in the United States, and the rising incidence, particularly of small (less than 4 cm) tumors, can be partially attributed to incidental detection due to the widespread use of radiological imaging. Despite strict adherence to national surveillance guidelines, the mortality for kidney cancer is unchanged over two decades, and one-third of kidney cancer recurrences are still missed, indicating a need to identify patients with a higher risk for recurrence. Even patients with small tumors can unexpectedly die from kidney cancer, and once patients develop metastatic disease, they generally die of their disease within 3 years. One dire, unmet clinical need is to develop an assay compatible with routine tissue processing that would identify patients with small tumors that will go on to die of metastatic disease. This is directly relevant to the military's focus on gaps in cancer prevention and treatment.

Large-scale studies analyzing cancers of the kidney, brain, or bone marrow have identified recurrent key biochemical changes, called epigenomic changes, to the environment of DNA, which can alter how the molecular blueprints of a cell are interpreted. A second unmet clinical need is that although these biochemical changes occur in upwards of 50% of kidney cancer, we lack an understanding of how drugs would target these changes.

Our preliminary data indicate that the alterations of the DNA environment make kidney cancer cell lines uniquely more susceptible to chemotherapy regimens commonly employed in bone marrow cancers. As a proof of concept, we treated patients affected by refractory kidney cancer with a bone marrow cancer drug, with one patient having a complete response to therapy. Furthermore, these biochemical changes to the DNA environment in small kidney cancers are associated with a higher risk of disease recurrence and add prognostic value to existing treatment algorithms. Based on our preliminary data, we hypothesize that the biochemical changes in DNA represent reversible changes and that kidney cancer cells can be 'reprogrammed' by drugs that target these changes.

Our project focuses on (1) identifying pathways that regulate the biochemical changes in the DNA that drive the growth of metastatic kidney cancer, (2) testing approved drugs to reverse the biochemical changes in the DNA, and (3) validating molecular signatures linked to unexpected early recurrences in archived small kidney tumors at Mayo Clinic. As a practicing Mayo Clinic oncologist with clinical expertise in renal cell carcinoma, 75% protected research time, a track record of significant publications in renal cell carcinoma, a track record of being awarded extramural grants, molecular biology training in a National Institutes of Health-funded combined M.D./Ph.D. program, and a dedicated 600-foot lab, these factors make me an ideal candidate to rapidly translate our research findings into clinical practice. My mentorship team has dedicated expertise in kidney cancer epidemiology and epigenetics with experience in developing prognostic assays compatible with existing clinical specimens. If funded for a Career Development Award, our team science efforts combined with the clinical resources available at Mayo Clinic will support my career goal to become an independently funded investigator with a focus in the epigenomic changes in kidney cancer, a Department of Defense topic area for fiscal year 2016. In the current funding environment, the scarcity of funds disproportionally affects junior investigators, as well as research in less common malignancies such as kidney cancer. Kidney cancer disproportionately affects military professionals and families, with patients averaging 12 years of lost life. Completion of this proposal would potentially identify patients with small kidney tumors that have a higher risk of succumbing to their disease, which is relevant to the military patients and to the military's focus on cancer prevention and treatment.

Ultimately, the intended outcome of these studies will be both an improved understanding, at the molecular level, of the functions of DNA biochemical modifications and, at the translational level, a unique opportunity to accelerate the drug development process, which traditionally takes ~14 years, by repurposing drugs with existing clinical data. More importantly, completion of these studies may identify drugs that target metastases in a broad range of human cancers with similar alterations, while minimizing risk to future clinical trial patients by using drugs with a known safety profile.

StatusActive
Effective start/end date1/1/16 → …

Funding

  • Congressionally Directed Medical Research Programs: $577,661.00

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