Sunday, October 27, 2024
10/27/2024
Inactivation of the VHL tumor suppressor protein (pVHL) is frequently observed in clear cell Renal Cell Carcinoma (RCC). The mutated pVHL does not bind and degrade the regulatory α-subunits of the hypoxia- inducible factor (HIF-1/2/3α) under normoxia causing overexpression of HIF-dependent pro-angiogenic factors such as VEGF, EPO, PDGF, etc. As a result, RCCs are highly vascular in nature. Extensive studies have established that the inhibition of the HIF pathway is sufficient to suppress tumor growth by the VHL‒/‒ RCC cells, offering an attractive target to treat this disease. We have shown that pure honokiol inhibits the HIF pathway and hypoxia-mediated expression of pro-angiogenic genes in a number of cancer cell lines. Honokiol also inhibits constitutively active HIF pathway and expression of pro-angiogenic genes in VHL‒/‒ RCC4 cells under normoxia. Further, we have determined the mechanism of action of honokiol using chromatin immunoprecipitation experiments. These finding have allowed us to synthesize a new class of boron based HIF inhibitors with improved efficacy and anti-angiogenic properties under in vitro conditions. In this project we propose two specific aims: (i) determine the structure-activity-relationship (SAR) of honokiol analogs on the inhibition of the HIF pathway and (ii) determine the efficacy of selected honokiol analogs in a xenograft RCC mouse model. At the completion of this project, our expectation is that we will have evaluated the potential therapeutic efficacy of honokiol analogs as a treatment strategy for RCC. In addition to primary positive impact of our findings, potential outcomes may benefit treatment of other systemic problems associated with VHL mutations, e.g. hemangioblastomas of retina and CNS. Finally, activation of the HIF pathway plays critical roles in the development of many different cancer types at multiple stages. Evaluation of honokiol analogs as inhibitors of the HIF pathway is expected to provide an important tool to further define the contribution of this pathway in cancer development and resistance. Relevance to Public Health: RCC is an important disease with ≈60,000 new cases predicted each year with >13,000 deaths. The clear cell carcinoma are the most common form of RCC and making up nearly 70% of cases. Unfortunately, cure for RCC is only available to those with limited stage disease which can be surgically resected, as to date systemic therapies cannot eradicate the cancer if it has spread distantly. In advanced stages, systemic therapies are given to stabilize the disease. No conventional cytotoxic chemotherapy agents have demonstrated significant activity in this disease as monotherapy or combinations. Anti-VEGF therapies have been largely ineffective, possibly due to contribution of other pro-angiogenic factors, such as EPO, PDGF, etc. in RCC. Thus, there remains an unmet medical need to develop more effective treatments for RCC. The proposed research will evaluate honokiol and its analogs as inhibitors of the HIF pathway and more effective therapeutic agent for the treatment of RCC.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
