Posted March 24, 2017

Bhavani Krishnan, Ph.D., Lineberger Comprehensive Cancer Center
University of North Carolina Chapel Hill

Bhavani Krishnan, Ph.D., Lineberger Comprehensive Cancer Center - University of North Carolina Chapel Hill

According to the American Cancer Society approximately 64,000 new kidney cancer diagnoses are expected in the US this year. Among the standard of care options to treat the most common type of kidney cancer, also known as Clear Cell Renal Cell Carcinoma (ccRCC), are inhibitors that target the mammalian target of rapamycin (mTOR). mTOR is a type of protein called a kinase and, as is typical for a kinase, mTOR regulates a wide variety of cellular functions such as cell growth and survival. Although mTOR inhibitors arrest tumor growth and help prolong patient survival, less than 5% of patient tumors respond with significant tumor shrinkage. Thus, there is a strong need for improved treatment options.

Dr. Bhavani Krishnan received a Visionary Postdoctoral Award in fiscal year 2012 to study novel therapeutic strategies that address the need for improved ccRCC treatment. Published literature describes vast interactions between different kinase pathways, and that inhibition of mTOR leads to a feedback mechanism that activates other kinases. Dr. Krishnan proposed to identify the kinases activated in response to mTOR inhibition, and then test any clinically available inhibitors to those kinases in combination with the mTOR inhibitor, Everolimus. Her overall hypothesis was that combining Everolimus with a second inhibitor that targets the deregulated kinase would improve ccRCC therapeutic outcomes.

Dr. Krishnan exploited an innovative technique developed by collaborators (Dr. Gary Johnson PhD, Department of Pharmacology UNC Chapel Hill) to assess the kinase(s) activity in cells and/or tissues. This technique allowed Dr. Krishnan to identify four kinases/kinase families that were activated in RCC cells treated with Everolimus. The promising target candidates chosen for further investigation were: 1) a family of kinases known as SRC kinases, 2) tyrosine kinase 2 (TYK2), 3) ribosomal protein S6 kinase family (RSK family), and 4) cyclin dependent kinase 5 (CDK5).

The SRC family of kinases made a particularly intriguing target because the SRC inhibitor, Dasatinib, is FDA-approved. Dr. Krishnan focused her efforts investigating the effects of Everolimus and Dasatinib, alone and in combination, in mouse models of RCC derived from patient tumors. The mice treated with both inhibitors exhibited significant tumor shrinkage and prolonged survival compared to the mice treated with either inhibitor alone. Based on this early success, Dr. Krishnan’s mentor (Dr. William Kim MD, Department of Medicine UNC Chapel Hill) obtained additional funding to further explore therapeutic strategies for treating ccRCC that target the identified kinases. The hope is that with further validation, clinical trials in humans could be initiated with relative ease since compounds to the identified target kinases are already FDA-approved and/or in pre-clinical development for other indications.

Dr. Krishnan’s project has already provided key preliminary data into the role of kinases, and kinase inhibitors, in the treatment of ccRCC. She continues to explore the promise of using inhibitors of the other identified kinase targets in combination with Everolimus. Given the availability and current clinical development of multiple kinase inhibitors, Dr. Krishnan is hopeful that these findings will ultimately translate into the clinical setting and improve ccRCC patient outcomes.

Schematic demonstrates two independent mechanisms that drive kidney tumor growth—growth factors leading to mTOR activation, and increased activity of key kinases (TYK2, SRC family of kinases, RSK, and CDK5). Dr. Krishnan’s work tested the hypothesis that the combination of select kinase inhibitors and mTOR inhibitors will result in increased tumor shrinkage, as compared to either treatment option alone.