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Cis-aconitate decarboxylase (ACOD1) in PMN-MDSC and prostate cancer progression

Award Number: R01CA276235
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/18/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Cis-aconitate decarboxylase (ACOD1) in PMN-MDSC and prostate cancer progression - PROJECT SUMMARY/ABSTRACT Immune checkpoint therapy (ICT) has revolutionized the care of several malignancies, resulting in durable response and even cure in a small subset of cancer patients. However, unlike tumors that are highly responsive to ICT (e.g., melanoma), the majority of patients with advanced prostate cancer respond poorly to ICT and no survival benefits have been observed in non-selective patients. Although recent preclinical and clinical studies have shed some light on the mechanisms of immunoresistance in prostate cancer, the cellular and molecular basis of immunoresistance in prostate cancer remains poorly characterized. Myeloid-derived suppressor cells (MDSCs), a group of pathologically activated monocytes and neutrophils with potent immunosuppressive activities, have been implicated as one of the key mechanisms in driving tumor progression, metastasis, and therapeutic resistance, including resistance to ICT, in various cancers. MDSCs can be classified as polymorphonuclear or granulocytic MDSCs (PMN-MDSCs or G-MDSCs) or monocytic MDSCs (M-MDSCs), with PMN-MDSCs as the predominant population in most cancer types. We and others have demonstrated that PMN-MDSCs are the major MDSC subset in mouse and human prostate cancers, playing an important role in prostate cancer progression and resistance to anti-androgen therapy and ICT. Correspondingly, therapeutically targeting MDSCs delays prostate cancer progression and improves responses to anti-androgen therapy and ICT in preclinical models. Importantly, PMN-MDSCs may be clinically relevant to prostate cancer, as they are abundantly present in both primary and metastatic tumors. Emerging evidence suggests that metabolic reprogramming of PMN-MDSCs plays an important role in their immunosuppressive activities, yet the underlying molecular mechanisms are still poorly defined. Through transcriptome analyses (single-cell RNA-seq, microarray, and bulk RNA-seq) of multiple datasets, we identified Acod1, which encodes cis-aconitate decarboxylase (ACOD1), as one of the most highly expressed metabolic genes in immunosuppressive PMN-MDSCs. ACOD1, which catalyzes the synthesis of itaconate from cis- aconitate in the tricarboxylic acid (TCA) cycle, is a novel immunomodulator with potent anti-inflammatory and antimicrobial effects in mammalian cells, especially in macrophages. Our results unexpectedly showed that ACOD1 may also be a potential regulator of PMN-MDSCs. We hypothesize that ACOD1 promotes tumor progression and resistance to ICT in prostate cancer through metabolic reprogramming of PMN-MDSCs. We will test our hypothesis in the following aims: Aim 1). Determine the role of ACOD1 in regulating the immunosuppressive activities of PMN-MDSCs. Aim 2). Determine the role of ACOD1 in PMN-MDSCs in driving prostate cancer progression. Aim 3). Determine whether Acod1 KO improves the response of prostate cancer to ICT.


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 = $370,575 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	12/15/2025	NON-COMPETING CONTINUATION	$333,518
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	4	4/16/2026	NON-COMPETING CONTINUATION	$37,057
														Subtotal = $370,575

Issue Date FY: 2025 ( Subtotal = $370,575 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	12/13/2024	NON-COMPETING CONTINUATION	$333,518
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	3	6/2/2025	NON-COMPETING CONTINUATION	$37,057
														Subtotal = $370,575

Issue Date FY: 2024 ( Subtotal = $352,047 )
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 Biology Research	001	2	4/16/2024	NON-COMPETING CONTINUATION	$18,529
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 Biology Research	000	2	12/12/2023	NON-COMPETING CONTINUATION	$333,518
														Subtotal = $352,047

Issue Date FY: 2023 ( Subtotal = $370,575 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	1/18/2023	NEW	$370,575
														Subtotal = $370,575

Grand Total All Awards = $1,463,772

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Cis-aconitate decarboxylase (ACOD1) in PMN-MDSC and prostate cancer progression

Award Number: R01CA276235

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/18/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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