Abstract PR020: Targeting cadherin-17 in translocation renal cell carcinoma

Abstract Background Translocation renal cell carcinoma (tRCC) is a rare and aggressive variant of kidney cancer (RCC) defined by an oncogenic gene fusion of a transcription factor in the MiT/TFE gene family, most commonly TFE3. tRCC lacks a biologically-directed treatment strategy and patients have poor clinical outcomes, representing an unmet need amongst kidney cancers. Cadherin-17 (CDH17) has been previously shown to be a promising cell surface target in neuroendocrine and gastrointestinal cancers. Methods We analyzed differentially expressed genes between tRCCs (n=17) vs ccRCCs (n=526) or normal kidneys (n=129) from the TCGA bulk RNA-seq cohort to identify tRCC-enriched genes. Upregulated genes from both comparisons were intersected and filtered for those encoding proteins localized to the plasma membrane or cell junctions to identify potential cell surface targets. Cadherin-17 (CDH17) emerged from these analyses as a tRCC-specific transcript. We validated CDH17 transcriptomic expression in tRCC in bulk RNA-seq from the PCAWG, Wang1, and IMMotion2 cohorts. We generated a tissue microarray (TMA) of 23 tRCC tumors (primary and metastatic) from 21 patients and performed immunohistochemistry staining for CDH17. Staining was independently reviewed by two pathologists. Thereafter, we generated a panel of fully human heavy-chain only (VH) antibodies against extracellular domains of CDH17 using a humanized mouse platform and expressed them in a second-generation chimeric antigen receptor (CAR) – T cell format. We tested the anti-CDH17 CAR-T panel against tRCC cell lines in in vitro functional assays and validated the top performers in murine models. Results CDH17 is highly expressed in tRCC (regardless of TFE fusion partner) compared to normal kidney and other RCC subtypes in bulk RNA-seq data from TCGA, PCAWG, Wang1 and IMMotion2 cohorts and has limited expression in normal tissues. TMA of tRCC tumors showed high membranous CDH17 staining (Median H-score 268, n = 23). A panel of 17 anti-CDH17 VH antibody binders was subjected to epitope mapping and identified binders were shown to target various extracellular domains of CDH17. Anti-CDH17 CAR-T cells demonstrated high cytotoxicity against tRCC in co-culture assays. Top performing CAR-T candidates were tested in two tRCC cell derived xenograft and one tRCC patient derived xenograft murine models and showed complete and durable tumor responses. Conclusions CDH17 is a novel cell surface target in tRCC. CAR-T therapy targeting CDH17 is a promising treatment strategy in tRCC. References: 1. Wang et al. Malignant melanotic Xp11 neoplasms exhibit a clinicopathologic spectrum and gene expression profiling akin to alveolar soft part sarcoma: a proposal for reclassification. J Pathol. 2020. Aug;251(4):365-377. PMID: 32418203. 2. Motzer et al. Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade. Cancer Cell. 2020 Dec 14;38(6):803-817.e4. PMID: 33157048. Citation Format: Prateek Khanna, Jiao Li, Shahryar Khoshtinat. Nikkhoi, Prathyusha Konda, Cary N. Weiss, Shanivi Srikonda, Yasmin Nabil. Laimon, Berkay Simsek, Sayed Matar, Martina De. Vizio, Sabina Signoretti, Anusuya M. Ramasubramanian, Eric L. Smith, Srinivas R. Viswanathan. Targeting cadherin-17 in translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr PR020.