Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer specific mortality, and is currently incurable. Defining new mechanisms that can predict progression and drive lethal CRPC is critical. Notch1 receptor, a cell surface-signaling molecule dysregulated in many cancers, is highly expressed in CRPC. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of poorly differentiated prostate carcinoma. Consistent with its activation in clinical CRPC, tumors driven by NICD1 in combination with alternative pathways altered in prostate cancer are metastatic and resistant to androgen deprivation.
Genetic and pharmacological inhibition of Notch1 activity decreases cell proliferation and colony formation of 22RV1 prostate cancer cells in vitro. 22RV1 subcutaneous xenograft growth was significantly impaired by treatment with pharmacological inhibitors of Notch1 activation over the course of 20-day treatment. Further, Notch1 inhibition in combination with other standard prostate cancer treatments compounded efficacy of individual treatments to attenuate colony formation potential of prostate cancer cells in vitro.
The Notch1 signaling axis, confirmed to synergize with multiple pathways to promote metastatic CRPC already provides a novel pathway for diagnostic stratification of prostate cancer patients. Our studies additionally implicate Notch1 as a therapeutically relevant target for aggressive prostate cancer.
Citation Format: Meghan A. Rice, En-Chi Hsu, Tanya Stoyanova. Therapeutic inhibition of Notch1 in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4917. doi:10.1158/1538-7445.AM2017-4917