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Developing a Translation Pipeline for VHL Mutant Malignancies

Award Number: U01CA236489
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Developing a Translation Pipeline for VHL Mutant Malignancies - Abstract Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is the initiating or “truncal” event in both the sporadic as well as hereditary type of clear cell renal cell carcinomas (ccRCCs) and VHL – associated tumors. pVHL forms an ubiquitin ligase complex that targets the HIF (Hypoxia-inducible Factor) transcription factor for proteasomal degradation when oxygen is available. Deregulation of HIF, and particularly HIF2α, drives pVHL-defective tumor formation in vivo. Drugs against the HIF-responsive gene product, VEGF, have been approved for the treatment of ccRCC, but are not curative and have only modest activity against VHL–associated tumors. Earlier work by DF/HCC and NCI investigators credentialed HIF2α as a driver in ccRCC and VHL disease and we have sought to bring HIF2α inhibitors to the clinic. Our collaboration on the UO1 grant entitled “Developing a translational pipeline for patients with VHL mutated malignancies” has served to enhance the understanding of this crucial transcription factor and facilitate clinical development of HIF2α inhibitors. Over the last four years, DF/HCC and NCI investigators co-led two studies of a first-in-class inhibitor belzutifan that established proof of concept that HIF2α can be drugged. In ccRCC, Dr. Choueiri led the trial that showed that belzutifan was well tolerated and clinically active in a subset of heavily pre-treated patients. Building on this work, Dr. Choueiri's leading the pivotal belzutifan trial in ccRCC patients who have failed standard therapy (NCT04195750). The UO1 supported work of the Kaelin Lab has led to belzutifan combination trials with approved drugs (e.g., NCT05468697). In a parallel effort, Drs. Linehan and Srinivasan led, and DF/HCC investigators participated in, the phase 1/2 clinical trial that led to the FDA approval of belzutifan in patients with VHL disease (NCT03401788). This rapid regulatory approval was made possible by an NCI comparison of the historical experience of patients in the NCI VHL Family Database to those treated with belzutifan at the NIH Clinical Research Center. This work elucidated the impact of targeting HIF2α in VHL mutation driven tumors. All of these projects were facilitated by close collaborations with patient advocates and industry colleagues at monthly UO1 meetings. In our current grant period, we have established a collection of precious, belzutifan-treated VHL and ccRCC patient tumor samples; obtained from clinical trials co-led by UO1 investigators; that will enhance our ability to execute our aims. Working in parallel with industry colleagues, our UO1 team will continue to pursue the identification of predictive and pharmacodynamic (PD) biomarkers that will enable the rational application of HIF2α inhibitors. Novel combination regimens will be studied in parallel clinical trials and pre-clinical models to facilitate translational research. The long-term significance and ultimate clinical impact of this work will be to identify new therapeutic strategies for patients with VHL–associated tumors.


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: 2025 ( Subtotal = $606,369 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	003	6	5/22/2025	NON-COMPETING CONTINUATION	$60,769
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	002	6	4/4/2025	NON-COMPETING CONTINUATION	$545,600
2025	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	001	5	2/25/2025	COMPETING CONTINUATION	$18,060
2025	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	4	2/25/2025	NON-COMPETING CONTINUATION	-$18,060
														Subtotal = $606,369

Issue Date FY: 2024 ( Subtotal = $669,180 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	5	2/19/2024	COMPETING CONTINUATION	$669,180
														Subtotal = $669,180

Issue Date FY: 2022 ( Subtotal = $400,168 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	4	7/15/2022	NON-COMPETING CONTINUATION	$400,168
														Subtotal = $400,168

Issue Date FY: 2021 ( Subtotal = $408,334 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	002	3	8/24/2021	NON-COMPETING CONTINUATION	$0
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	001	3	3/31/2021	NON-COMPETING CONTINUATION	$408,334
2021	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	2	2/4/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $408,334

Issue Date FY: 2020 ( Subtotal = $410,974 )
2020	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	001	2	3/26/2020	NON-COMPETING CONTINUATION	$410,974
2020	2019	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	1	12/24/2019	NEW	$0
														Subtotal = $410,974

Issue Date FY: 2019 ( Subtotal = $649,803 )
2019	2019	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	1	3/21/2019	NEW	$649,803
														Subtotal = $649,803

Grand Total All Awards = $3,144,828

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Developing a Translation Pipeline for VHL Mutant Malignancies

Award Number: U01CA236489

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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