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Preventing Therapeutic Resistance in RAS-mutated Pediatric Cancers

Award Number: R21CA267515
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Preventing Therapeutic Resistance in RAS-mutated Pediatric Cancers - Project Summary/Abstract For pediatric patients with RAS-mutated tumors, clinical trials testing targeted therapies are limited due to the paucity of preclinical data. This is unfortunate, as targeted therapies have the potential to make a significant impact on morbidity for pediatric patients. Cytotoxic agents significantly delay normal childhood development leading to lifelong sequalae. In contrast, targeted therapies that preferentially attack RAS-mutated tumor cells while sparing normal developing tissue can limit unwanted sequalae and enhance overall outcomes for pediatric cancer patients. Unfortunately, single-agent targeting of RAS-mutated cancer cells using either MEK inhibitors or mutant RAS inhibitors is largely ineffective; resistance rapidly develops due to upregulation of multiple RTKs and subsequent hyperactivation of WT RAS signaling. Thus, alternative therapeutic approaches are needed to treat RAS-mutated pediatric cancers. Toward this end, we take two complementary approaches at inhibiting WT RAS signaling designed to enhance the effectiveness of targeted therapies in RAS-mutated pediatric cancers. While each approach seems obvious in hindsight, neither has been tested in pre-clinical models of RAS-mutated pediatric cancers. We first examine the extent to which broad inhibition of proximal RTK signaling using inhibitors to the common proximal RTK signaling intermediates SHP2 or SOS1 enhances the efficacy of and delays therapeutic resistance to MEK or mutant RAS inhibitors in RAS-mutated non-CNS pediatric cancer cells. Since MEK inhibition induces compensatory RTK-dependent signaling cascades, co-targeting RTK signaling with MEK is an attractive approach to treat RAS-mutated pediatric cancers. However, studies in multiple RAS-mutated cancers revealed that the specific RTK that is reactivated can vary between cell lines or studies, even within the same cancer type. Thus, rather than using specific RTK inhibitors that may differ for each patient, we inhibit the common proximal RTK signaling intermediates SHP2 or SOS1, and use both pharmacologic and drug resistance assays to determine which drug-drug combinations are the most potent at enhancing drug killing and inhibiting therapeutic resistance. We then test the most promising therapeutic combinations in patient-derived xenograft models. As a second approach, we determine the extent to which combined inhibition of mutant RAS and WT RAS effector signaling enhances the efficacy of and delays therapeutic resistance to mutant RAS inhibitors in RAS- mutated non-CNS pediatric cancer cells. RAS proteins show differential activation of RAF and PI3K pathways: HRAS potently activates PI3K but poorly activates RAF, whereas KRAS potently activates RAF but poorly activates PI3K. Since both MEK and PI3K pathways must be inhibited for effective killing of RAS-mutated pediatric cancers, we use this fundamental understanding of signaling differences between mutant RAS family members to examine rational therapeutic approaches in RAS-mutated non-CNS pediatric cancer cells. We then test the most promising therapeutic combinations in patient-derived xenograft models.


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: 2024 ( Subtotal = $164,671 )
2024	2024	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Cancer Treatment Research	000	3	1/16/2024	NON-COMPETING CONTINUATION	$164,671
														Subtotal = $164,671

Issue Date FY: 2023 ( Subtotal = $9,993 )
2023	2023	HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC., THE	6720-A ROCKLEDGE DR STE 100	BETHESDA	MD	20817	MONTGOMERY	USA	Cancer Treatment Research	000	2	2/7/2023	NON-COMPETING CONTINUATION	$9,993
														Subtotal = $9,993

Issue Date FY: 2022 ( Subtotal = $213,876 )
2022	2022	HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC., THE	6720-A ROCKLEDGE DR STE 100	BETHESDA	MD	20817	MONTGOMERY	USA	Cancer Treatment Research	000	1	1/31/2022	NEW	$213,876
2022	2022	HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC., THE	6720-A ROCKLEDGE DR STE 100	BETHESDA	MD	20817	MONTGOMERY	USA	Cancer Treatment Research	001	1	9/22/2022	NEW	$0
														Subtotal = $213,876

Grand Total All Awards = $388,540

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Preventing Therapeutic Resistance in RAS-mutated Pediatric Cancers

Award Number: R21CA267515

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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