Identification of therapeutic targets for renal medullary carcinoma via integrated genomic and transcriptomic profiling

Pavlos Msaouel¹, Nizar M Tannir², Funda Meric-Bernstam³, Jennifer M King⁴, Martin H Voss⁵, Jessica P Cheng², Susan S Thomas², Zita D Lim², Menuka Karki⁶, Rong He⁶, Giannicola Genovese⁷, Rahul A Sheth⁸, Davis R Ingram⁹, Diana Shamsutdinova⁹, Khalida M Wani⁹, Wei-Lien Wang¹⁰, Alexander J Lazar¹¹, Dominique Knipper-Davis¹², Amber Berlinski¹², Tayla Soares¹², Danil Stupichev¹², Kirill Kryukov¹², Suren Davitavyan¹², Anna Novokreshchenova¹², Dmitry Lebedev¹², Stanislav Kurpe¹², Andrey Kravets¹², Dmitrii Belousov¹², Michael Hensley¹², Alexander Bagaev¹², Francesca Paradiso¹², Vladimir Kushnarev¹²

Affiliations

¹ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (GSBS), Houston, TX, USA. Electronic address: pmsaouel@mdanderson.org.
² Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Division of Hematology-Oncology, Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA.
⁵ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁶ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Interventional Radiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹² BostonGene Corporation, Waltham, MA 02453, USA.

PMID: 41172996
DOI: 10.1016/j.xcrm.2025.102423

Free article

Identification of therapeutic targets for renal medullary carcinoma via integrated genomic and transcriptomic profiling

Pavlos Msaouel et al. Cell Rep Med. 2025.

Free article

. 2025 Nov 18;6(11):102423.

doi: 10.1016/j.xcrm.2025.102423. Epub 2025 Oct 30.

Authors

Affiliations

¹ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences (GSBS), Houston, TX, USA. Electronic address: pmsaouel@mdanderson.org.
² Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Division of Hematology-Oncology, Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA.
⁵ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁶ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Interventional Radiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹² BostonGene Corporation, Waltham, MA 02453, USA.

PMID: 41172996
DOI: 10.1016/j.xcrm.2025.102423

Abstract

Renal medullary carcinoma (RMC) is a rare but highly aggressive kidney cancer that resists conventional therapies. To identify therapeutic targets, this study employs histopathologic, genomic, and transcriptomic profiling of 25 RMC samples. TROP2, EPCAM, CLDN6, and CDH6 are significantly overexpressed compared with other renal and solid tumors. Pathway analyses indicate Hippo pathway upregulation and a tumor microenvironment rich in fibroblasts and neutrophils. We subsequently explore treatment of four heavily pretreated patients, all with high TROP2 expression, using sacituzumab govitecan, a TROP2-targeted antibody-drug conjugate. Of these four patients, one patient achieves a partial response with symptom improvement, two patients maintain stable disease, and the median progression-free survival reaches 2.9 months. This study represents the most extensive molecular characterization of RMC to date, identifying TROP2 and other potential therapeutic targets. Sacituzumab govitecan demonstrates potential clinical benefit, warranting further evaluation in prospective trials to confirm its efficacy and explore additional targets identified herein.

Keywords: CDH6; CLDN6; EPCAM; Hippo pathway; SMARCB1; TROP2; renal medullary carcinoma; sacituzumab govitecan.

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Conflict of interest statement

Declaration of interests P.M. has received honoraria for service on a Scientific Advisory Board for Mirati Therapeutics, Bristol Myers Squibb, and Exelixis; consulting for Axiom Healthcare Strategies; non-branded educational programs supported by DAVA Oncology, Exelixis, and Pfizer; and research funding for clinical trials from Regeneron Pharmaceuticals, Takeda, Bristol Myers Squibb, Mirati Therapeutics, Gateway for Cancer Research, and the University of Texas MD Anderson Cancer Center. N.M.T. reported receiving and personal fees (honoraria) from Calithera Biosciences during the conduct of the study; grants (sponsored trial) from Calithera Biosciences Inc., Bristol Myers Squibb (BMS), Nektar Therapeutics, Arrowhead Pharmaceuticals, and Novartis, as well as personal fees (honoraria) from Calithera Biosciences, BMS, Eisai Medical Research, Merck Sharp & Dohme (MSD), Deka Biosciences, Neoleukin Therapeutics, Exelixis, and Ono Pharmaceutical outside the submitted work. F.M.-B. reported receiving consulting fees from AstraZeneca Pharmaceuticals, Becton Dickinson, Calibr (a division of Scripps Research), Daiichi Sankyo, Dava Oncology, Debiopharm, EcoR1 Capital, eFFECTOR Therapeutics, Elevation Oncology, Exelixis, GT Aperion, Incyte, Jazz Pharmaceuticals, LegoChem Biosciences, Lengo Therapeutics, Menarini Group, Molecular Templates, Protai Bio, Ribometrix, Tallac Therapeutics, Tempus, and Zymeworks; honoraria for service on a Scientific Advisory Board for Cybrexa, FogPharma, Guardant Health, Harbinger Health, Karyopharm Therapeutics, LOXO-Oncology, Mersana Therapeutics, OnCusp Therapeutics, Sanofi Pharmaceuticals, Seagen, Theratechnologies, and Zentalis Pharmaceuticals; honoraria for non-branded educational programs supported by DAVA Oncology; travel support by the European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO), Cholangiocarcinoma Foundation, and Dava Oncology; as well as research funding for clinical trials from Jazz Pharmaceuticals, Zymeworks, Aileron Therapeutics Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., and Taiho Pharmaceutical Co. D.K.-D., A.B., T.S., D.S., K.K., S.D., A.N., D.L., S.K., A.K., D.B., M.H., A.B., F.P., and V.K. are employees of BostonGene Corporation.

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Identification of therapeutic targets for renal medullary carcinoma via integrated genomic and transcriptomic profiling

Affiliations

Identification of therapeutic targets for renal medullary carcinoma via integrated genomic and transcriptomic profiling

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous