The AACR Grant for Innovative Bladder Cancer Research is a new grant mechanism that seeks to encourage the development of novel approaches to address bladder cancer.

2025 Grantees

Scientific Statement of Research

Enfortumab vedotin (EV), an antibody–drug conjugate targeting Nectin-4, is an FDA-approved treatment for metastatic urothelial carcinoma (mUC). Resistance to EV frequently arises through downregulation of Nectin-4. A genome-wide CRISPR screen implicated the retinol transporter STRA6 and downstream retinoic acid signaling as regulators of Nectin-4 expression. The investigators hypothesize that activation of the retinoic acid pathway with all-trans retinoic acid (ATRA) will sustain Nectin-4 levels and improve EV efficacy. In this proposal, Dr, Chu and her team will test whether ATRA upregulates Nectin-4 and enhances EV responsiveness, and examine ATRA’s effects on luminal versus basal differentiation and ATRA’s capacity to prevent emergence of Nectin-4–low, EV-resistant cells. The study is expected to reveal how retinoid signaling regulates tumor differentiation and inform novel therapeutic strategies to extend EV benefit in mUC.

Biography

Dr. Chu earned her medical degree and completed a urology residency at University of California, San Francisco (UCSF), followed by fellowship training in urologic oncology at Memorial Sloan Kettering Cancer Center. As a surgeon-scientist, her research focuses on understanding mechanisms of resistance to targeted therapies in urologic cancers. Currently an Assistant Professor of Urologic Oncology at UCSF, she leads multiple neoadjuvant clinical trials investigating targeted therapies.

Acknowledgement of Support

“Receiving the 2025 AACR-Grant for Innovative Bladder Cancer Research will accelerate my translational studies on retinoid signaling and Nectin-4 regulation, enabling development of novel strategies to overcome EV resistance. This support will advance my trajectory as an independent surgeon-scientist and leader in bladder cancer therapeutics.”

Scientific Statement of Research

CDADC1 is a newly identified (d)CTP/CTP deaminase that converts dCTP, CTP, and dCMP into dUTP, UTP, and dUMP. While its enzymatic properties are known, its role in cancer remains undefined. Metabolomic profiling of bladder cancer cells overexpressing CDADC1 revealed disrupted nucleotide balance and increased γH2AX, consistent with replication-associated DNA damage. Analysis of TCGA data revealed that approximately 37% of bladder cancers harbor co-deletion of CDADC1 and RB1. Dr. Faltas hypothesizes that co-deletion of CDADC1 and RB1 causes dTTP depletion and checkpoint defects, generating a synthetic vulnerability. He aims to determine how CDADC1-RB1 co-deletion alters nucleotide pools and genome integrity, and to test therapeutic strategies such as dUTPase and ATR inhibitors and TOP1-targeting antibody-drug conjugates. This work will explore a potential metabolic-checkpoint synthetic lethal interaction and whether it could inform treatment strategies for a subset of bladder cancers.

Biography

Dr. Faltas is an associate professor of medicine and cell & developmental biology at Weill Cornell Medicine and Chief Research Officer of the Englander Institute for Precision Medicine. He is a practicing genitourinary medical oncologist and physician-scientist whose research explores APOBEC3 cytidine deaminases as evolutionary drivers of mutagenesis and therapeutic resistance in bladder cancer.

Acknowledgement of Support

“This AACR-Grant for Innovative Bladder Cancer Research will accelerate my investigation of CDADC1 as a therapeutic target and support development of novel strategies for bladder cancer.”