About

Steven M. Corsello is a physician scientist and medical oncologist at Stanford University, serving as an Assistant Professor of Medicine (Oncology) and, by courtesy, of Chemical and Systems Biology. His laboratory operates at the intersection of functional genomics and chemical biology, with the goal of advancing novel molecular mechanisms of cancer inhibition to clinical use. His research aims to leverage phenotypic screening and functional genomics to determine new anti-cancer mechanisms of small molecules, develop targeted therapy approaches against solid tumors, and build a community resource for drug repurposing discovery. Corsello is actively involved in clinical trials and research related to cancer therapeutics, with a focus on molecular mechanisms and drug discovery.

Research topics

• Biology
• Biochemistry
• Chemistry
• Biophysics
• Cell biology

Selected publications

• Insights on Future Directions in Cancer Research from the 2026 AACR NextGen Stars

  Cancer Discovery · 2026-04-01

  article
  PublisherDOI

• Abstract NG07: Discovery of TRIM21 molecular glues that drive potent anti-tumor efficacy via nuclear pore complex degradation

  Cancer Research · 2026-04-17

  article1st authorCorresponding

  Abstract Cancer cells are acutely dependent on nuclear transport due to elevated transcriptional activity, suggesting a therapeutic opportunity for inhibition of the nuclear pore complex (NPC). Through a combination of large-scale phenotypic profiling, genome-scale functional genomics, and mass spectrometry-based proteomics, we discovered that the clinical drug PRLX-93936 (PRLX) is a molecular glue that binds and reprograms the TRIM21 E3 ubiquitin ligase to degrade the NPC, resulting in potent inhibition of pancreatic ductal adenocarcinoma (PDAC) cells.PRLX, an optimized derivative of erastin, was previously tested in phase 1 trials with modest activity. Importantly, unlike erastin, PRLX induced apoptosis rather than ferroptosis via an unknown molecular target. To identify sensitive cancer models, we profiled PRLX against ∼900 cell lines using the PRISM barcoded screening approach, which demonstrated lineage-specific activity against PDAC and head and neck cancers. This activity strongly correlated with high mRNA expression of the TRIM21 E3 ligase. Next, we conducted genome-scale CRISPR/Cas9 knockout and activation screens, which revealed TRIM21 as the top functional mediator of PRLX response across the entire genome. TRIM21 knockout conferred complete resistance to PRLX, while TRIM21 overexpression was sufficient to sensitize cells to the drug. Given the strong functional evidence, we hypothesized that TRIM21 is the direct molecular target of PRLX. TRIM21 is a cytosolic antibody receptor known for its role in degrading intracellular pathogens. We first performed a tiled mutagenesis screen of the TRIM21 gene, which identified multiple mutations clustering at a putative binding pocket in the PRYSPRY substrate recognition domain. We then confirmed direct compound binding to the recombinant TRIM21 PRYSPRY domain via surface plasmon resonance (SPR). Since TRIM21 is a ubiquitin ligase, we sought to identify its potential neo-substrates upon compound treatment. We performed extensive proteomic profiling to evaluate changes in protein abundance, ubiquitination, and TRIM21 proximity labeling. All three methods unexpectedly identified nuclear pore complex proteins as the top hits. Re-analysis of our CRISPR knockout screen data revealed that a single guide RNA (out of four) against NUP98 conferred strong resistance. This active guide uniquely targeted the NUP98 autoproteolytic domain (APD) and yielded complete resistance to PRLX. Using multiple orthogonal assays (NanoBiT, TR-FRET, and SPR), we demonstrated that the compound acts as a molecular glue to induce physical proximity between TRIM21 and NUP98. This molecular glue mechanism is highly effective against cancer because, as prior work shows, cancer cells undergo apoptosis upon NPC disruption while normal cells can recover. We confirmed this selective vulnerability. Compound treatment led to a loss of short-lived pro-survival mRNAs in cancer cells (by qPCR and RNAscope), and live-cell imaging showed that while the proliferation of non-malignant cells was slowed, PDAC cells underwent rapid and irreversible cell death. These findings support a model where temporary, TRIM21-mediated NPC degradation creates a therapeutic window by preferentially inducing cancer cell death. Using PRLX as a starting point, phenotype-guided medicinal chemistry optimization yielded novel compounds with >10-fold greater potency, improved drug-like properties, and robust oral bioavailability. An improved derivative, JWZ-8-103, was successfully co-crystallized with the TRIM21 PRYSPRY domain, structurally confirming the binding mode and enabling further optimization. To establish translational potential, we employed patient-derived PDAC organoids and in vivo models. Prospectively selecting organoids based on TRIM21 expression confirmed its potential as a predictive biomarker of compound efficacy. Furthermore, optimized compounds demonstrated robust anti-PDAC efficacy in vivo against multiple KRAS-mutant xenograft models. In summary, our work demonstrates the power of unbiased phenotypic screening to uncover novel cancer biology and develop targeted therapeutics. We have discovered potent, orally bioavailable TRIM21 molecular glues that degrade the NPC, validated a predictive biomarker, and established a strong therapeutic rationale and preclinical efficacy for their use in solid tumors. Ongoing work is focused on developing compounds with enhanced potency, evaluating drug combinations, and performing preclinical toxicology studies. The discovery of TRIM21-mediated NPC degraders presents an unexpected and promising new strategy for the treatment of PDAC and other challenging solid tumors. Citation Format: Steven M. Corsello. Discovery of TRIM21 molecular glues that drive potent anti-tumor efficacy via nuclear pore complex degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr NG07.

  PublisherDOI

• Defining the Antitumor Mechanism of Action of a Clinical-stage Compound as a Selective Degrader of the Nuclear Pore Complex

  Cancer Discovery · 2025-09-02 · 4 citations

  articleOpen accessSenior author

  Cancer cells are acutely dependent on nuclear transport due to elevated transcriptional activity, suggesting an unrealized opportunity for selective therapeutic inhibition of the nuclear pore complex (NPC). Through large-scale phenotypic profiling of cancer cell lines, genome-scale functional genomic modifier screens, and mass spectrometry-based proteomics, we discovered that the clinical drug PRLX-93936 is a molecular glue that binds and reprograms the TRIM21 ubiquitin ligase to degrade the NPC. Upon compound-induced TRIM21 recruitment, the nuclear pore is ubiquitylated and degraded, resulting in the loss of short-lived cytoplasmic mRNA transcripts and the induction of cancer cell apoptosis. Direct compound binding to TRIM21 was confirmed via surface plasmon resonance and X-ray crystallography, whereas compound-induced TRIM21-nucleoporin complex formation was demonstrated through multiple orthogonal approaches in cells and in vitro. Phenotype-guided optimization yielded compounds with 10-fold greater potency and drug-like properties, along with robust pharmacokinetics and efficacy against pancreatic cancer xenografts and patient-derived organoids. SIGNIFICANCE: This study establishes the cancer therapeutic potential of optimized TRIM21 molecular glues to degrade the NPC and underscores the value of reexamining drugs with previously unknown mechanisms using current technologies.

  PublisherOA PDFDOI

• Figure S5 from Defining the Antitumor Mechanism of Action of a Clinical-stage Compound as a Selective Degrader of the Nuclear Pore Complex

  2025-12-02

  articleOpen accessSenior author

  <p>Presents a CRISPR/Cas9 base editor mutagenesis screen of TRIM21 using ABE and CBE and shows population doublings, guide z-scores, and comparative analyses for PRLX and JWZ-8-103.</p>

  PublisherOA PDFDOI

• A clinical-stage oncology compound selectively targets drug-resistant cancers

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-30

  preprintOpen access

  Re-evaluating existing clinical compounds can uncover previously unrecognized mechanisms that reshape a drug's therapeutic potential. The small molecule Procaspase-Activating Compound 1 (PAC-1) entered oncology testing as a proposed activator of caspase-driven apoptosis. Here, we show that PAC-1-driven cytotoxicity occurs in the absence of executioner caspase expression, demonstrating that its anti-cancer activity occurs via an alternative mechanism. We provide genetic, biochemical, and biophysical evidence demonstrating that PAC-1 functions as a highly selective iron chelator that eliminates cancer cells by disrupting iron homeostasis. Unexpectedly, we discovered that expression of the key chemotherapy-resistance pump MDR1 confers marked hypersensitivity to PAC-1 treatment. While PAC-1 is only weakly effluxed by MDR1 under basal conditions, this process is potentiated when PAC-1 is bound to iron. Consequently, PAC-1 induces progressive iron depletion and selective cytotoxicity in otherwise drug-resistant MDR1-expressing cancer cells. Together, these findings redefine PAC-1's mechanism-of-action and establish a framework for exploiting multidrug resistance as a therapeutic vulnerability through targeted iron starvation.

  PublisherDOI

• Figure S6 from Defining the Antitumor Mechanism of Action of a Clinical-stage Compound as a Selective Degrader of the Nuclear Pore Complex

  2025-12-02

  articleOpen accessSenior author

  <p>Shows SPR binding analyses of PRLX and analogues to TRIM21 PRYSPRY, and immunoblot verification of TRIM21 expression in knockout cells reconstituted with TRIM21 cDNAs.</p>

  PublisherOA PDFDOI

• Figure S2 from Defining the Antitumor Mechanism of Action of a Clinical-stage Compound as a Selective Degrader of the Nuclear Pore Complex

  2025-12-02

  articleOpen accessSenior author

  <p>Evaluates CRISPR/Cas9 knockout hits affecting PRLX response, including effects on TRIM21 expression and restoration by TRIM21 reintroduction.</p>

  PublisherOA PDFDOI

• Figure S1 from Defining the Antitumor Mechanism of Action of a Clinical-stage Compound as a Selective Degrader of the Nuclear Pore Complex

  2025-12-02

  articleOpen accessSenior author

  <p>Depicts PRLX sensitivity across cancer cell lines, TRIM21 expression and functional perturbation, CRISPR/Cas9 screen results, and rescue experiments.</p>

  PublisherOA PDFDOI

• Figure S11 from Defining the Antitumor Mechanism of Action of a Clinical-stage Compound as a Selective Degrader of the Nuclear Pore Complex

  2025-12-02

  articleOpen accessSenior author

  <p>Depicts live-cell imaging, lethal fraction analyses, and protein interaction/immunoblot assays demonstrating TRIM21-dependent PRLX-induced nucleoporin destabilization and rapid cancer cell death.</p>

  PublisherOA PDFDOI

• Data from Defining the Antitumor Mechanism of Action of a Clinical-stage Compound as a Selective Degrader of the Nuclear Pore Complex

  2025-12-02

  articleOpen accessSenior author

  <div>Abstract<p>Cancer cells are acutely dependent on nuclear transport due to elevated transcriptional activity, suggesting an unrealized opportunity for selective therapeutic inhibition of the nuclear pore complex (NPC). Through large-scale phenotypic profiling of cancer cell lines, genome-scale functional genomic modifier screens, and mass spectrometry–based proteomics, we discovered that the clinical drug PRLX-93936 is a molecular glue that binds and reprograms the TRIM21 ubiquitin ligase to degrade the NPC. Upon compound-induced TRIM21 recruitment, the nuclear pore is ubiquitylated and degraded, resulting in the loss of short-lived cytoplasmic mRNA transcripts and the induction of cancer cell apoptosis. Direct compound binding to TRIM21 was confirmed via surface plasmon resonance and X-ray crystallography, whereas compound-induced TRIM21–nucleoporin complex formation was demonstrated through multiple orthogonal approaches in cells and <i>in vitro</i>. Phenotype-guided optimization yielded compounds with 10-fold greater potency and drug-like properties, along with robust pharmacokinetics and efficacy against pancreatic cancer xenografts and patient-derived organoids.</p>Significance:<p>This study establishes the cancer therapeutic potential of optimized TRIM21 molecular glues to degrade the NPC and underscores the value of reexamining drugs with previously unknown mechanisms using current technologies.</p></div>

  PublisherDOI

Recent grants

• Targeting casein kinase 1-alpha for cancer therapy

  NIH · $1.0M · 2018–2024

Frequent coauthors

• Todd R. Golub

  Broad Institute

  109 shared

• Marios Giannakis

  Dana-Farber Cancer Institute

  50 shared

• Kimmie Ng

  Harvard University

  43 shared

• Matthew Meyerson

  Dana-Farber Cancer Institute

  43 shared

• Lauren K. Brais

  39 shared

• Kimberly Stegmaier

  Harvard University

  34 shared

• Kenneth N. Ross

  34 shared

• Eliezer M. Van Allen

  Broad Institute

  30 shared

Labs

• Corsello LabPI

Education

• M.D.

  Stanford University

• B.S.

  University of California, San Diego

Awards & honors

• Drug Discovery Award, The Mark Foundation for Cancer Researc…
• NextGen Star, American Association for Cancer Research (2026…
• Clinical Investigator Award, Damon Runyon Cancer Research Fo…
• Shmunis Family Innovation Award in Cancer Therapeutics, Stan…
• The 20 under 40 in BioPharma, Endpoints News (2020)