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

  • Cell Rep Med. 2025 Oct 30:102423. doi: 10.1016/j.xcrm.2025.102423.
Pavlos Msaouel  1 ,  Nizar M Tannir  2 ,  Funda Meric-Bernstam  3 ,  Jennifer M King  4 ,  Martin H Voss  5 ,  Jessica P Cheng  2 ,  Susan S Thomas  2 ,  Zita D Lim  2 ,  Menuka Karki  6 ,  Rong He  6 ,  Giannicola Genovese  7 ,  Rahul A Sheth  8 ,  Davis R Ingram  9 ,  Diana Shamsutdinova  9 ,  Khalida M Wani  9 ,  Wei-Lien Wang  10 ,  Alexander J Lazar  11 ,  Dominique Knipper-Davis  12 ,  Amber Berlinski  12 ,  Tayla Soares  12 ,  Danil Stupichev  12 ,  Kirill Kryukov  12 ,  Suren Davitavyan  12 ,  Anna Novokreshchenova  12 ,  Dmitry Lebedev  12 ,  Stanislav Kurpe  12 ,  Andrey Kravets  12 ,  Dmitrii Belousov  12 ,  Michael Hensley  12 ,  Alexander Bagaev  12 ,  Francesca Paradiso  12 ,  Vladimir Kushnarev  12
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: [email protected].
  • 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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