Therapeutic Targeting of p300/CBP in Clear Cell Renal Cell Carcinoma
Abstract
Renal Cell Carcinoma (RCC) is a lethal disease whose incidence is on the rise. It is categorized into various subtypes, with the most aggressive clear cell RCC (ccRCC), representing about 85% of all RCC tumors. Alterations in the VHL gene -- encoding the von Hippel Lindau tumor suppressor protein, pVHL -- have been strongly linked to sporadic ccRCC and considered to be a leading cause of ccRCC development. VHL inactivation results in aberrant accumulation of Hypoxia Inducible Factors (HIFs) and activates hypoxia-induced cancer-promoting genes. The two proteins p300 and CBP are required for functioning of HIFs and thereby are also involved in activation of cancer-promoting genes. In addition, both p300 and CBP serve as coactivators of LDH-A, a central enzyme that regulates metabolism in ccRCC cancer cells. Furthermore, increased activity of LDH-A is associated with tumor metastasis and resistance to anticancer therapy. Studies evaluating the prognostic role of p300/CBP in ccRCC outcomes have yielded conflicting results, with one study reporting that p300 activity directly correlates with ccRCC aggressiveness, while the other study reporting no association. Our studies will be focused on evaluation of the therapeutic efficacy of novel p300/CBP inhibitor CCS1477 using clinically relevant cell and animal models of human ccRCC. CCS1477 is the first drug to be used in patients that specifically targets p300/CBP. This novel drug is currently under phase I/II clinical trials for the treatment of solid tumors and haematological cancers. Current targeted molecular strategies, including multi-targeted tyrosine kinase inhibitors (TKIs), have resulted in a doubling of progression-free survival and significant gains in overall survival (median 18-30 months), however, complete and durable responses to TKI treatment have been noted in only a few cases, necessitating chronic therapy for the majority of RCC patients, which is often associated with significant toxicity. In an attempt to improve efficacy and overcome drug resistance a combinatorial strategy of using agents targeting different cancer driving intracellular signals. Therefore, we also plan to evaluate the potential synergistic effect of combined treatment; the cells will be treated with CCS1477 in the presence or absence of clinically relevant TKIs. Additionally, we plan to determine the link between p300/CBP activity, clinical outcomes, and response to TKIs in ccRCC patients. This will allow us to determine if p300/CBP might provide useful biomarkers for prognostic and therapeutic purposes in ccRCC. The successful completion of the proposed studies will provide preclinical support and justification for transitioning CCS1477 to a clinical trial for the treatment of ccRCC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110252
Entities
People
- Petr Makhov
Organizations
- United States Army