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Developing BRAF mutant and BRAF wild-type selective strategies for radiosensitization in Anaplastic Thyroid Cancer

Award Number: R01CA246553
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Developing BRAF mutant and BRAF wild-type selective strategies for radiosensitization in Anaplastic Thyroid Cancer - Anaplastic thyroid cancer (ATC) remains one of the solid tumors that is associated with the poorest prognosis. Standard therapy includes maximal safe resection, external beam radiation therapy (EBRT), and cytotoxic chemotherapy. Despite this, there are high rates of disease recurrence. Local/regional recurrence is particularly difficult for patients with ATC, resulting in airway and/or esophageal compromise which contributes to mortality and metastatic dissemination. Novel therapies are thus needed to improve disease control and lengthen survival. Recently, genomic profiling of ATC has uncovered high frequency mutations in the RAS-RAF-MEK-ERK pathway (particularly BRAF and RAS), as well as other DNA damage and cell cycle checkpoint control genes, including TP53. Our preclinical data supports that an activating BRAFV600E mutation promotes resistance to EBRT and genotoxic therapies, through the non-homologous end-joining repair (NHEJ) DNA repair pathway. In addition, targeted inhibition of BRAFV600E with a small molecule inhibitor results in sensitization to EBRT in BRAF mutant (BRAFm) ATC. Furthermore, treatment of BRAF mutant cells with a MEK-1/2 inhibitor also results in radiosensitization. Since BRAF wild-type (BRAFwt) ATC accounts for ~ 60-70% of cases, developing targeted strategies for radiosensitization in BRAFwt ATC is also critical. As such, we find that TP53 mutant ATC is effectively radiosensitized by ATR and Wee1 kinase inhibitors, highlighting the dependency of these tumors on the G2/M cell cycle checkpoint. Finally, we will explore radiation sensitization approaches for RAS mutant ATC, another common BRAFwt molecular subtype of ATC. In this proposal, we will attempt multiple strategies to advance therapy for patients with BRAFm and BRAFwt ATC. In Aim 1, we will perform a phase I trial to determine the maximally-tolerated doses of dabrafenib (BRAF inhibitor) and trametinib (MEK-1/2 inhibitor) to be used concurrently with EBRT for BRAFm ATC, and identify biomarkers of response and molecular pathways leading to resistance. In Aim 2, we will perform mechanistic studies to better understand how BRAFm leads to accelerated DNA repair, test novel therapeutic strategies targeting components of DNA repair, and develop and optimize novel strategies targeting DNA repair in combination with EBRT and other genotoxic therapies for BRAFm ATC. In Aim 3, we will attempt to develop novel strategies for treating BRAF wild-type ATC, by testing different targeted strategies for TP53 and RAS deficient or mutated ATC in vitro and in vivo to support future clinical testing of these combinations. Together, these studies will improve our understanding of how BRAF mutations impart radio-resistance, and identify new tumor-selective combinatorial approaches for treating patients with BRAF mutant and BRAF wild-type ATC.


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 = $462,998 )
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	6	3/28/2025	NON-COMPETING CONTINUATION	$416,701
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	6	5/28/2025	NON-COMPETING CONTINUATION	$46,297
														Subtotal = $462,998

Issue Date FY: 2024 ( Subtotal = $194,528 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	5	8/1/2024	NON-COMPETING CONTINUATION	$194,528
														Subtotal = $194,528

Issue Date FY: 2023 ( Subtotal = $458,906 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	4	5/23/2023	NON-COMPETING CONTINUATION	$458,906
														Subtotal = $458,906

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	3	7/14/2022	NON-COMPETING CONTINUATION	$0
2022	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	000	3	5/31/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $445,665 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	004	3	3/31/2021	NON-COMPETING CONTINUATION	$445,665
2021	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Treatment Research	000	1	2/22/2021	NEW	-$226,665
2021	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	003	2	3/30/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$39,502
2021	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Treatment Research	002	1	3/30/2021	NEW	-$39,502
2021	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	2	2/22/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$226,665
														Subtotal = $445,665

Issue Date FY: 2020 ( Subtotal = $420,445 )
2020	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Treatment Research	000	1	7/21/2020	NEW	$420,445
														Subtotal = $420,445

Grand Total All Awards = $1,982,542

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Developing BRAF mutant and BRAF wild-type selective strategies for radiosensitization in Anaplastic Thyroid Cancer

Award Number: R01CA246553

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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