Aim 1: Test VIC-1911 in combination with enzalutamide in CRPC models. We found that AURKA is significantly up-regulated in CRPC as compared to primary PCa and is further drastically induced in NEPC as compared to CRPC (data not shown), suggesting that AURKA might provide essential mechanisms to bypass AR-targeted therapies. Although analysis of VIC-1911 in NCI cell line panel revealed modest efficacy in multiple PCa cell lines, it is noteworthy that the CRPC cell line 22Rv1 showed the best IC50 of 0.068 uM (Table on the right). Therefore, it will be interesting to evaluate the efficacy of VIC-1911, either alone or in combination with enzalutamide in CRPC cell lines, xenograft, or PDX models. In this present proposal, we will focus on in vitro assays first. We predict that the combination of VIC-1911 will block a major escape pathway and increase the efficacy of enzalutamide in CRPC models. Aim 2: Evaluate the efficacy of VIC-1911, either alone or in combination with chemotherapy, in NEPC models. AURKA is the most strongly up-regulated in NEPC across all stages of PCa. As such, a phase II clinical trial has examined the efficacy of AURKA inhibitor alisertib in metastatic PCa with molecular features of NEPC (Beltran, Oromendia et al. 2019) . Although the study did not reach its primary endpoint, a subset of patients showed significant clinical benefit, despite toxicity issues with Alisertib. Thus, it will be important to evaluate VIC-1911, either alone or in combination with standard chemotherapy (cisplatin and etopside) in NEPC models. We predict that the combination will achieve much better effects in cell killing. Aim 3: Examine the effects of VIC-1911 in regulating DNA damage responses and test its efficacy in combination with PARP inhibitors (PARPi) in CRPC and NEPC models. A recent study in ovarian cancer cells reported a novel function of AURKA beyond its reported roles in mitosis (Do, Hirst et al. 2017). They showed that AURKA inhibition reduces BRCA1 level, leading to BRCAness and deficiency in homologous recombination repair, thereby increasing non-homologous end-joining (NHEJ). Studies have shown that, in cells with mutations in DNA damage response and repair (DDR) genes - primarily BRCA1/2, PARP1 catalytic activity is essential in regulating NHEJ and PARP inhibition disrupts NHEJ, resulting in chromosomal instability and cell death (Brenner, Ateeq et al. 2011). This is called synthetic lethality of BRCA loss and PARP inhibition. Accordingly, Do et al demonstrated strong synergy between AURKA inhibitor Alisertib and PAPR inhibitor Rucaparib in ovarian cells with or without DDR (Do, Hirst et al. 2017). Here we propose to investigate AURKA regulation of BRCAness in PCa models and test the effects of VIC-1911 in combination with PAPR inhibitors. Aim 3.1. Examine how AURKA overexpression, knockdown, or inhibition by VIC-1911 regulate the levels of BRCA1, BRCA2, DNA damage, and NHEJ in PCa cells. We predict that AURKA inhibition will decrease BRCA1/2 and increase NHEJ, leading to dependency on PARP and sensitivity to PARPi. Aim 3.2. Evaluate synergistic effects of VIC-1911 and Olaparib in CRPC cells with or without DDR. We will generate PCa cell lines with knockdown or knockout of BRCA1, BRCA2, or ATM using CRISPR-editing technology for this purpose. Since AURKA inhibition itself can lead to BRCAness, we predict synergy between VIC-1911 and Olaparib in both control and DDR cells. A recent clinical trial has shown promising clinical benefit of Olaparib in CRPC patients with DDR (de Bono, Mateo et al. 2020), supporting
|Effective start/end date||7/1/21 → 12/31/22|
- VITRAC Therapeutics, LLC (AGMT 07-02-2021)
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