Targeted Therapies and Associated Biomarkers in Human Cancers
- Author(s): Nelson, Luke
- Advisor(s): Razorenova, Olga V
- et al.
Targeted therapy represents a class of cancer treatments that interferes with specific cancer-associated molecules and aims to specifically attack reprogrammed cancer cells, leaving normal cells unaffected. In this dissertation, we investigate novel approaches for targeted therapy in Clear Cell-Renal Cell Carcinoma (CC-RCC) and Triple Negative Breast Cancer (TNBC).
In CC-RCC, we uncovered an interaction of the tumor suppressor gene VHL with the Rho/ROCK signaling pathway, identifying this pathway as a potential therapeutic target. We found that ROCK inhibition preferentially induces massive mitotic errors in VHL-deficient cells and suggest that the induction of mitotic catastrophe represents a novel therapeutic strategy for VHL-deficient cancers. We further demonstrate that Cyclin-dependent kinase (CDK) inhibitors show significant cytotoxic activity in VHL-deficient CC-RCC in vitro and in a patient-derived xenograft (PDX) orthotopic mouse model. Importantly, we show that these inhibitors do not induce apoptosis in non-transformed cells, or CC-RCC cells engineered to re-express VHL. In TNBC, we obtained clinical evidence that the oncogene CUB Domain Containing Protein 1 (CDCP1) is co-activated with the oncogenic kinase c-Src and its downstream target Protein Kinase C δ (PKC-δ) in a subset of patient specimens, and that this class of patients may benefit from the emerging therapeutics targeting this pathway.
Together, these studies contribute to expansion of the targeted therapy library in CC-RCC and TNBC and help to set the stage for more focused preclinical studies to evaluate the efficacy of targeting these pathways.