Targeting NUAK2 in Neuroendocrine Prostate Cancer
Abstract
Neuroendocrine prostate cancer is an aggressive and lethal subtype of prostate cancer. While neuroendocrine can develop from the onset as the primary lesion, it is rare. More commonly, neuroendocrine prostate cancer develops as a resistance mechanism in heavily treated, late-stage, metastatic, castrate-resistant prostate cancer referred to as treatment emergent neuroendocrine prostate cancer. This is due to heavy and earlier use of Androgen Receptor-targeted therapies such as enzalutamide. It is estimated that 20-25% of late-stage prostate cancer patients will develop neuroendocrine prostate cancer. Neuroendocrine prostate cancer patients often present with high metastatic burden, and the prognosis is poor, with a 5-year survival rate of less than 20 percent. There are currently limited treatment options for neuroendocrine prostate cancer aside from platinum-based chemotherapies. Thus, new actionable molecular targets to combat neuroendocrine prostate cancer are urgently needed. Our published and new preliminary data propose that NUAK Family Kinase 2 (NUAK2) is a highly actionable protein that can be exploited as a target for neuroendocrine prostate cancer therapy. We found that NAUK2 expression progressively increases as prostate cancer becomes more and more advanced. In patient-derived preclinical models, the expression of NUAK2 was most elevated in neuroendocrine prostate cancer subtypes. Our preliminary experiments show that genetic or pharmacological targeting of NUAK2 in neuroendocrine prostate cancer cells slowed their growth rate. The objective of our proposal is to test the potential of NUAK2 as a therapeutic target for neuroendocrine prostate cancer. NUAK2 is from a class of enzymes called kinases, and the scientific community has been very good at making medicines that block the activities of these type of proteins. Indeed, we have reported use of an investigational NUAK2 inhibitor to slow the growth of prostate cancer in mice with no observable toxicities. We now aim to test this compound in the more advanced and lethal prostate cancer subtype. We have also identified compounds that are already FDA-approved and in clinical trials that bind NUAK2 very potently and slow neuroendocrine prostate cancer cell growth in preliminary studies. We propose to exploit these clinical drugs for their beneficial NUAK2 off target activity. If our studies are successful and our hypothesis is proven, progression to clinical applications should occur quickly. These studies may greatly benefit patients diagnosed with lethal neuroendocrine prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310125
Entities
People
- Everardo Macias
Organizations
- Duke University
- United States Army