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Development and Mechanistic Studies of an Engineered Human Enzyme to Abrogate Immune Suppression due to Elevated Methylthioadenosine (MTA) by MTAP null/low Tumors

Award Number: R01CA240700
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Development and Mechanistic Studies of an Engineered Human Enzyme to Abrogate Immune Suppression due to Elevated Methylthioadenosine (MTA) by MTAP null/low Tumors - Development and Mechanistic Studies of an Engineered Human Therapeutic to Abrogate Immune Suppression due to Elevated Methylthioadenosine (MTA) by MTAP null/low Tumors One of the most common lesions observed across a broad number of cancers is the homozygous genetic deletion of methylthioadenosine phosporylase (MTAP), an enzyme that normally functions in amino acid and nucleotide recycling pathways. Deletion of MTAP in tumors results in the accumulation and secretion of its substrate methylthioadenosine (MTA). It is established that MTA is a very potent immunosuppressive molecule; importantly in preliminary studies our lab obtained strong in vivo evidence from multiple murine tumor models that the production of MTA by MTAPnull/low tumors strongly attenuates anti-tumor immune responses. This proposal describes an interdisciplinary team effort at the University of Texas at Austin detailing the development of a novel biologic cancer therapeutic, to reverse the immunosuppressive effects of MTA and aid in the treatment of patients with MTAPnull/low tumors as a key biomarker. In preliminary studies we have demonstrated that administration of an engineered human MTA degrading therapeutic (based on the human MTAP) can reverse the deleterious effects of MTA on lymphocytes in vitro, drastically retards the growth or elicits complete remissions of MTAP null murine cancer allografts and restores populations of T cells in both the tumor and tumor draining lymph node (TDLN) and demonstrates additive/synergistic effects when used in combination with existing immune checkpoint inhibitors. The evidence that the consequence of MTAP deletion acts to suppress immune effector cells and promote tolerogenic stromal cell phenotypes through the buildup of MTA now suggests a clear mechanism for why this is one of the more common gene deletions observed in cancer. Overall, we hypothesize that MTAP deletions in cancers act as an immune checkpoint that can be reversed therapeutically by enzymatic degradation of MTA in the tumor microenvironment using an engineered human methylthioadenosine phosphorylase. The work proposed here will seek to: (i) elucidate the cellular immunology and the biochemical/metabolomic and signaling mechanism(s) through which elevated extracellular MTA suppresses immune function; (ii) help clarify how MTA- mediated methyltransferase inhibition and remodeling of metabolism together with (likely secondarily) activation of the purinergic receptors impact lymphocytes; (iii) examine the efficacy of combinatorial treatments using standard of care antibody immune checkpoint inhibitors and very importantly (iv) develop an optimized MTA degrading drug that has the requisite pharmacological properties for late/stage preclinical/clinical administration..


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 = -$5,070 )
2026	2023	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Treatment Research	000	5	11/21/2025	NON-COMPETING CONTINUATION	-$5,070
														Subtotal = -$5,070

Issue Date FY: 2023 ( Subtotal = $370,782 )
2023	2023	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Treatment Research	000	5	6/29/2023	NON-COMPETING CONTINUATION	$370,782
														Subtotal = $370,782

Issue Date FY: 2022 ( Subtotal = $370,782 )
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Treatment Research	000	4	7/7/2022	NON-COMPETING CONTINUATION	$370,782
														Subtotal = $370,782

Issue Date FY: 2021 ( Subtotal = $378,348 )
2021	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Treatment Research	000	3	6/24/2021	NON-COMPETING CONTINUATION	$378,348
														Subtotal = $378,348

Issue Date FY: 2020 ( Subtotal = $377,573 )
2020	2020	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Treatment Research	000	2	6/10/2020	NON-COMPETING CONTINUATION	$377,573
														Subtotal = $377,573

Issue Date FY: 2019 ( Subtotal = $373,697 )
2019	2019	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR, MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Treatment Research	000	1	6/21/2019	NEW	$373,697
														Subtotal = $373,697

Grand Total All Awards = $1,866,112

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Development and Mechanistic Studies of an Engineered Human Enzyme to Abrogate Immune Suppression due to Elevated Methylthioadenosine (MTA) by MTAP null/low Tumors

Award Number: R01CA240700

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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