Project Details
Description
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
Status | Finished |
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Effective start/end date | 7/1/21 → 12/31/22 |
Funding
- VITRAC Therapeutics, LLC (AGMT 07-02-2021)
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