Friday, December 26, 2025 12/26/2025

Pro-Drug Enolase Inhibitors in Precision Oncology

Award Number: R01CA231509
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/08/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Pro-Drug Enolase Inhibitors in Precision Oncology - ABSTRACT. Genomic deletions of major tumor suppressor genes are frequent events in cancer yet presently remain therapeutically unactionable for the purpose of precision oncology. Our lab has pioneered an innovative therapeutic paradigm known as collateral lethality, whereby genes neighboring a TSG locus encoding a key housekeeping enzyme are coincidentally deleted. We discovered that the metabolic vulnerabilities arising from such collateral deletions may be therapeutically exploited through inhibition of the enzyme’s redundant isoform. Emblematic of this framework are cancers harboring homozygous deletion of the glycolytic enzyme Enolase 1 (ENO1). As glycolysis is an essential bioenergetic process, ENO1-homozygous deleted cancers are entirely reliant on the ENO2 to perform glycolysis and ensure the cellular viability. Inhibition of ENO2 selectively kills ENO1-homozygous deleted the cancers while leaving normal tissues unperturbed. To pharmacologically act on this vulnerability, our lab has developed an ENO2-preferred inhibitor, HEX. As testament to the strong therapeutic viability of collateral lethality, we have shown that HEX is capable of completely eradicating ENO1- homzoygous deleted intracranial orthotopic models of glioblastoma in mice at concentrations well-tolerated in non-human primates. Such robust anti-neoplastic effects are unprecedented in the context of glioblastoma and speak to the power of the collateral lethality approach. One critique of the focus of collateral lethality is its scope: in the case of ENO1-deletions, only a small percentage of patients would be able to benefit. To broaden the therapeutic reach of collateral lethality, this proposal will focus on targeting ENO1-heterozygous deleted cancers, which comprise ~20% of all human cancers. This will be accomplished by adding tumor subtype-specific pro- drug moieties onto HEX to improve its delivery. While ENO1-heterozygous deleted cancers are deficient in total Enolase, they are not nearly as depleted as ENO1-homozygous deleted cancers are. As HEX is a negatively charged molecule, tumor-subtype specific pro-drug attachment onto HEX will not only enhance its cell permeability but will also improve its tumor specificity. Together, these two traits will enable drug dosing at lower concentrations to afford a therapeutic window sufficiently large to treat ENO1-heterozygous deleted cancers without the perturbing normal tissues. Overall, this proposal leverages the concept of rational pro-drug design to improve the specific of our core ENO2 inhibitor so that we may widen the therapeutic reach of collateral lethality.


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 = $0 )
2026	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	5	12/17/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $329,668 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	5	6/3/2025	NON-COMPETING CONTINUATION	$32,966
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	5	1/17/2025	NON-COMPETING CONTINUATION	$296,702
														Subtotal = $329,668

Issue Date FY: 2024 ( Subtotal = $313,186 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$16,484
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	4	1/12/2024	NON-COMPETING CONTINUATION	$296,702
														Subtotal = $313,186

Issue Date FY: 2023 ( Subtotal = $323,076 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	1/27/2023	NON-COMPETING CONTINUATION	$323,076
														Subtotal = $323,076

Issue Date FY: 2022 ( Subtotal = $323,076 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	2/1/2022	NON-COMPETING CONTINUATION	$296,702
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	2	5/24/2022	NON-COMPETING CONTINUATION	$26,374
														Subtotal = $323,076

Issue Date FY: 2021 ( Subtotal = $329,668 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	2/8/2021	NEW	$329,668
														Subtotal = $329,668

Grand Total All Awards = $1,618,674

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Pro-Drug Enolase Inhibitors in Precision Oncology

Award Number: R01CA231509

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/08/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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