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2025 Rob & Cindy Citrone – PCF Young Investigator Award

Targeted Delivery of NSD2 Inhibitors Reverse Epigenetic Resistance and Improve Prostate Cancer Immunotherapy

Blaise Kimmel, PhD      
The Ohio State University

Mentors: Steven Clinton

Description:

  • Castration-resistant prostate cancer (CRPC) is an advanced state of prostate cancer that remains incurable and a significant cause of mortality. Current therapies are limited by various resistance and immune evasion mechanisms, underscoring the need for innovative strategies to restore anti-tumor immune responses and overcome treatment resistance.
  • Epigenetic therapies target proteins that regulate gene expression, and have promise for overcoming therapy resistance in prostate cancer and enhancing immune responses.  NSD2 is an epigenetic regulator that promotes oncogenic gene expression in prostate cancer and is associated with CRPC progression and poor outcomes, and also may have a role in immune regulation.
  • Dr. Blaise Kimmel is investigating whether NSD2 inhibition can reprogram tumor gene expression, enhance anti-tumor immune responses and sensitize tumors to immunotherapy.
  • This project will develop a new NSD2 inhibitor that can specifically be targeted to prostate cancer cells by also binding to the prostate cancer protein PSMA, and validate preclinical drug specificity, efficacy, pharmacokinetics, and toxicity. The impact of the NSD2 inhibitor on immune reprogramming and anti-tumor immunity will then be determined in prostate cancer models, as well as its efficacy in combination with immunotherapy.
  • If successful, this project will establish the role of NSD2 in prostate cancer and anti-tumor immune biology, and produce a promising new NSD2 inhibitor therapy for treatment-resistant prostate cancer, which may have therapeutic synergy with immunotherapy, and is ready for testing in the clinic.

What this means to patients: Despite multiple therapeutic options, CRPC remains almost universally lethal, necessitating research and development of new therapies. Dr. Kimmel’s project will develop and preclinically validate a first-in-class NSD2-targeted therapy that not only inhibits prostate cancer progression but also enhances anti-tumor immunity, offering a transformative strategy for advanced prostate cancer treatment ready for translation into clinical trials.