Steven Corsello, MD | Old Drugs, New Uses: Surprising Opportunities for Cancer Therapy

Why It Matters

Repurposing existing molecules with a molecular‑glue mechanism offers a faster, cost‑effective route to treat pancreatic cancer, a disease with limited effective therapies.

Key Takeaways

• Phenotype screening uncovers repurposed drugs with cancer activity.
• PRISM barcoding enables pooled testing of hundreds of tumor lines.
• TRIM21 identified as biomarker and functional target for pancreatic therapy.
• Molecular glue compounds bind TRIM21, degrade nuclear pore complex.
• Optimized oral agents show tumor regression in preclinical pancreatic models.

Summary

Dr. Steven Corsello presented a Stanford‑based program that systematically repurposes existing drugs for oncology by combining a curated drug library, high‑content cellular readouts, and a pipeline to uncover mechanisms of action. The centerpiece is the PRISM platform, which tags thousands of cancer cell lines with DNA barcodes, allowing pooled viability screens against hundreds of compounds in a single assay.

Using PRISM, the team screened a “drug repurposing hub” and identified a former tool compound, code‑named PRLX, that selectively inhibited pancreatic and head‑and‑neck cancer lines. Sensitivity correlated strongly with high expression of the E3 ligase TRIM21, suggesting a predictive biomarker. Functional genomics—CRISPR knockout and activation—validated TRIM21 as both a required gene for drug response and a driver of sensitivity.

Structural studies revealed PRLX binds directly to TRIM21, acting as a molecular glue that recruits nuclear pore complex proteins for ubiquitination and proteasomal degradation. This targeted protein‑degradation mechanism mirrors thalidomide‑based strategies but exploits a novel ligase. Optimized, orally bioavailable derivatives induced rapid tumor regression in multiple pancreatic xenograft models, demonstrating preclinical efficacy.

The work illustrates how large‑scale phenotype screens can expose unexpected drug‑target relationships, accelerate repurposing timelines, and generate new therapeutic modalities for hard‑to‑treat cancers such as pancreatic adenocarcinoma. Ongoing studies will assess therapeutic windows, immunomodulatory effects, and path toward clinical development.

Original Description

Steven Corsello, MD

Assistant Professor of Medicine–Oncology

Josephine Q. Berry Faculty Scholar in Cancer Research

To outsmart cancer, we need to identify new vulnerabilities in its form. Learn how Dr. Corsello and his team are systematically testing existing drugs against cancer models, finding new ways to kill cancer cells through entirely unexpected mechanisms. Dr. Corsello will discuss how drug repurposing reveals novel targets and therapeutic strategies, charting a path forward for a new class of cancer therapeutics born from reimagining existing drugs with next-generation biology.

Part of Stanford Medicine Alumni Day 2026