Therapeutic Targeting of Aurora Kinase A in Lethal Prostate Cancer Using a Novel Inhibitor
Abstract
Scientific Rationale, Objectives, and Aims. Prostate cancer (PCa) is the most frequently diagnosed non-skin cancer in American men, and advanced PCa remains a leading cause of cancer-related death. Despite recent advances, median survival for patients with metastatic castration-resistant PCa (mCRPC) remains only 4-6 years. Novel treatment strategies are critical to extend survival and improve outcomes for patients diagnosed with metastatic disease. Recently, a class of drugs called PARP inhibitors was found effective in advanced PCa, and the U.S. Food and Drug Administration (FDA) approved the use of two of them, Olaparib and Rucaparib, for the treatment of mCRPC. However, the efficacy of RAPR inhibitors is limited to the <20% of patients with mutations in genes responsible for DNA damage repair (DDR). Further, tumors harboring mutations in some DDR genes, such as BRCA1 and BRCA2, showed a superior response and outcome to others. Expanding the relevance of PARP inhibitors to a more general population would add another effective treatment regimen for thousands of patients every year. Thus, we have worked to identify a treatment strategy that will improve and expand the utility of PARP inhibitors to the vast majority of PCa patients that do not have DDR gene mutations. Aurora kinase A (AURKA) is a protein essential for cell division and other functions necessary for PCa cell survival and growth. When cells have a significant burden of gene mutations, as is seen in cells with dysfunctional DDR, AURKA activity is augmented to allow ongoing cell division and survival of the tumor. Thus, combinatorial use of AURKA inhibitors might further improve DDR-mutant patients response to PARP inhibitors. Additionally, through a separate mechanism, inhibition of AURKA activity results in loss of DNA damage repair, creating a state similar to that seen in patients with mutations in this pathway. Thus, we hypothesize that treatment with an AURKA inhibitor will expand the pool of patients likely to respond to treatment with PARP inhibitors in a combination therapy strategy. Finally, AURKA activity is involved in upregulating the androgen receptor (AR) and its variants. Inhibition of AURKA activity has the potential to improve response to the AR pathway inhibitors and bypass treatment resistance. Therapeutic targeting of AURKA has been hindered by the lack of a selective and safe inhibitor. Our collaborator, VITRAC Therapeutics, has recently developed VIC-1911, a highly selective AURKA inhibitor that showed excellent tolerability and few side effects in a phase I trial of solid tumors. Our preliminary data showed that VIC-1911 inhibits AURKA activity in PCa with high selectivity and sensitivity, suppressing DDR and leading to PCa cell death. This may occur in part through the inhibition of Myc proteins, which are known to regulate DDR gene expression. Thus, we have assembled the proposed studies to investigate the downstream genes/pathways altered by VIC-1911 (Aim 1.1.-1.2), develop selection biomarkers for patients that are most likely to respond to VIC-1911 (Aim 1.3), and test potential combination therapies with PARP and/or AR pathway inhibitors such as Olaparib and Enzalutamide, respectively, in preclinical models of PCa (Aim 2). Ultimate Applicability of the Research: The proposed research is highly responsive to the PCRP Overarching Challenges seeking to (1) Develop treatments that improve outcomes for men with lethal prostate cancer, and (2) Define the biology of prostate cancer progression to lethal prostate cancer to reduce death. Our preliminary analyses of public data have shown that AURKA is upregulated in PCa and further in mCRPC. Its level strongly correlates with BRCA1/2 expression, indicating that its inhibition might lead to dysfunctional DDR, sensitizing the tumors to PARP inhibitors. This correlation is likely mediated by Myc proteins, which (c-Myc or N-Myc) are also abundantly expressed in all st
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310525
Entities
People
- Jindan Yu
Organizations
- Emory University
- United States Army