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From biology to therapy: mechanism-informed targeting in translocation renal cell carcinoma

Award Number: R01CA302918
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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From biology to therapy: mechanism-informed targeting in translocation renal cell carcinoma - PROJECT SUMMARY Renal cell carcinoma (RCC) is one of the top ten most common cancers worldwide. RCCs are highly heterogeneous, with multiple distinct histological subtypes. One aggressive subtype, translocation renal cell carcinoma (tRCC), is driven by a gene fusion involving a transcription factor in the MiT/TFE gene family, most commonly TFE3. Currently, there are no approved therapies specifically targeting tRCC, and existing RCC treatments show only modest response rates in tRCC. Discovery of new molecular targets in tRCC is therefore a pressing and unmet medical need. Our prior work has identified CDH17, a cell surface cadherin protein activated by the TFE3 translocation, as being highly and selectively expressed in tRCC. Cell-surface proteins overexpressed in a cancer-selective fashion are attractive therapeutic targets, and T cell redirection therapy towards these antigens has proven effective in several cancer types. In preliminary studies, we have generated a diverse panel of fully human monoclonal binders targeting multiple extracellular epitopes of CDH17. In this project, we will explore the hypothesis that CDH17, as a downstream effector of the driver fusion in tRCC, can be effectively targeted with T cell redirected therapy in this recalcitrant cancer. In Aim 1, we will investigate how TFE3 fusions regulate CDH17 biology and validate CDH17 as an immunotherapy target in tRCC. We will determine if CDH17 is a direct transcriptional target of TFE3 fusions, characterize which extracellular epitopes of CDH17 are most exposed in tRCC, and will examine the effects of targeting different CDH17 domains on integrin interaction and β-catenin signaling. In Aim 2, we will test the therapeutic potential of our monoclonal antibodies in tRCC in the format of CDH17-targeting T cell engagers (TCEs). CDH17-targeting TCEs targeting various epitopes in the extracellular region of CDH17 will be tested for activity in tRCC xenograft models. The tumor-intrinsic and T cell-intrinsic molecular features of response and resistance to CDH17-TCEs will also be elucidated. Finally, we will comprehensively characterize the immune microenvironment in tRCC via multiplex immunofluorescence and spatial transcriptomics, which may guide strategy for future CDH17-targeting immunotherapies. Overall, this project will credential CDH17 as a therapeutic target in tRCC and provide insights into its regulation by TFE3 fusions. This work has the potential to lead to the first therapy specifically targeted to the biology of tRCC and to improve clinical outcomes for patients with this aggressive cancer, which currently has no established standard of care. Although this project minimizes animal use by leveraging extensive in vitro studies, in vivo mouse models are required to evaluate tumor response, T-cell expansion/trafficking, and therapeutic efficacy in a physiologic context and in preparation for clinical translation. Mice are the most appropriate model because well-established xenograft and tRCC systems are available, and all studies will use the minimum number needed for statistical rigor.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $737,086 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	1	6/30/2026	NEW	$737,086
														Subtotal = $737,086

Grand Total All Awards = $737,086

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From biology to therapy: mechanism-informed targeting in translocation renal cell carcinoma

Award Number: R01CA302918

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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