Bridge Funding Award Program

Sigma1 Targeted Modification of Nuclear Envelope Architecture in Prostate Cancer

Prostate cancer progression is governed by master regulatory proteins known as transcription factors, specifically the androgen receptor (AR), Myc, and E2Fs. While AR has served as the standard therapeutic target for decades, patients frequently develop resistance, leading to the emergence of lethal metastatic castration-resistant prostate cancer (mCRPC). In these advanced stages, the disease typically shifts its dependency to Myc and E2Fs; Myc acts as a metabolic accelerator that integrates growth and survival signals, while E2Fs orchestrate the cellular infrastructure required for rapid division.

This pathological growth requires a massive expansion of the nucleus and its protective barrier, the nuclear envelope (NE). Because the building blocks for the NE are supplied by the endoplasmic reticulum (ER) – the cell’s manufacturing hub – this interface represents a critical vulnerability in the cancer’s operational structure.

The Kim Lab has identified Sigma1 (gene name SIGMAR1), a unique scaffolding protein located within the ER membrane, as a primary "gatekeeper" regulating these vital NE-ER connections and the localization of oncogenic drivers. Building on this discovery, the lab has developed a first-in-class small molecule compound that targets Sigma1 to disrupt the structural integrity of the cancer cell’s command center.

This innovative approach is dual-action: it selectively suppresses the activity of Myc and E2F by starving the nucleus of structural support, while simultaneously acting as an immunomodulatory agent to stimulate a systemic anti-tumor immune response.

This research aims to define these novel dynamics to establish a new therapeutic paradigm for patients whose cancer no longer responds to treatment. Dr. Kim and his collaborators will use this award to complete this project and publish it in multiple manuscripts.

The project is supported by a robust intellectual property portfolio, including two composition-of-matter and four method-of-use patents, and the current objectives focus on generating high-impact data to de-risk the technology for clinical transition through a newly established start-up company.