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A Chemical Genetic Approach to Exploring Novel Therapeutic Space for Colorectal Cancer

Award Number: R01CA258736
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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A Chemical Genetic Approach to Exploring Novel Therapeutic Space for Colorectal Cancer - Project Summary Metastatic colorectal cancer (mCRC) is the second leading cause of cancer-related mortality in the United States, and annually accounts for nearly 500,000 deaths worldwide. Currently, the small molecule kinase inhibitor (KI) regorafenib is the primary second line therapy for metastatic CRC that is not treatable with immunotherapy or anti-EGFR therapies. However, regorafenib generally provides only modest improvements in survival— typically months—and often at the cost of significant side effects. Proposed targets for regorafenib include kinases that act within tumor cells as well as non-autonomously; however, with over 500 possible targets in the human kinome, the exact mechanism by which this compound operates remains controversial and not fully known. This presents a daunting challenge; without a verifiable target or mechanism, no clear path exists to guide the development of improved therapies for mCRC. Here, we propose an alternative approach to drug development that focuses on kinase networks in the context of the whole animal. Specifically, we will take a multidisciplinary approach to define kinases that are beneficial to inhibit (‘pro-targets’) or avoid (‘anti-targets’) in the context of KRAS-variant CRC. Using Drosophila and mammalian models, we will identify kinases that—when reduced—alter the efficacy of regorafenib and similar compounds. We will also conduct extensive structure-activity relationship analyses, evaluating how modifications in already identified lead compounds impact changes in efficacy and therapeutic index. Finally, we will use computational structural biology to convert our chemical genetic insights into highly optimized and precise polypharmacological leads. In this final step, we generate new analogs to selectively eliminate putative anti-target activity while maintaining or increasing inhibitory activity against other beneficial targets. We have used our chemical genetic platform to identify a promising lead compound, APS5-86-2, that demonstrates significant activity relative to regorafenib in several mCRC models, including human patient derived xenografts (PDX). Comparative analysis suggests that the improved activity of APS5-86-2 relative to regorafenib derives from distinct polypharmacology on several RTKs and critical cancer drivers, including CDK9, AURKA, EGFR, BRAF, and RAF1. In this proposal, we examine the mechanism and importance of these and other putative pro- and anti-target kinases using genetic analysis and in vivo target engagement. The objective is to identify the kinase networks that mediate KRAS-variant mCRC by combining chemical biology with genetics, and to then derive inhibitors that best attack these networks through structure-based drug design. We have been successful previously with a similar approach, but in less complex tumor models (Dar et al., Nature, 2012; Sonoshita et al., Nature Chem. Bio., 2018); here we seek to extend our platform to a more prevalent disease with the goal of directly impacting mCRC by creating new, highly differentiated, and improved drugs.


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 = $589,867 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Treatment Research	003	6	2/12/2025	NON-COMPETING CONTINUATION	$589,867
2025	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Treatment Research	002	4	1/22/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$228,237
2025	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	001	3	1/22/2025	NON-COMPETING CONTINUATION	-$138,561
2025	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	000	2	1/22/2025	NON-COMPETING CONTINUATION	-$89,676
														Subtotal = $589,867

Issue Date FY: 2024 ( Subtotal = $622,641 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Treatment Research	000	5	1/31/2024	NON-COMPETING CONTINUATION	$589,870
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Treatment Research	001	5	4/17/2024	NON-COMPETING CONTINUATION	$32,771
														Subtotal = $622,641

Issue Date FY: 2023 ( Subtotal = $642,774 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	000	3	2/25/2023	NON-COMPETING CONTINUATION	$606,974
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Treatment Research	002	4	8/23/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$504,213
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	001	3	8/22/2023	NON-COMPETING CONTINUATION	-$468,413
														Subtotal = $642,774

Issue Date FY: 2022 ( Subtotal = $604,219 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	000	2	4/1/2022	NON-COMPETING CONTINUATION	$604,219
														Subtotal = $604,219

Issue Date FY: 2021 ( Subtotal = $635,077 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Treatment Research	000	1	2/25/2021	NEW	$635,077
														Subtotal = $635,077

Grand Total All Awards = $3,094,578

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A Chemical Genetic Approach to Exploring Novel Therapeutic Space for Colorectal Cancer

Award Number: R01CA258736

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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