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Myeloid Syk promotes tumor immunosuppression and inhibits anti-tumor adaptive immunity

Award Number: K22CA229594
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Myeloid Syk promotes tumor immunosuppression and inhibits anti-tumor adaptive immunity - Abstract: The activation of the immune response to yield durable antitumor immunity and anti-cancer activity has become a reality. However, an unmet medical need exists in that not all cancer patients respond to anti-PD1 or other checkpoint inhibitors currently in clinical use. This has led to a push to identify other negative regulators of the innate and adaptive immune response for anti-cancer therapeutics. Myeloid cells including macrophages and myeloid derived suppressor cells, play important roles in mediating tumor growth and immunosuppression. The long-term goal is to better understand the signaling mechanisms in myeloid cells which mediate tumor immunosuppression and anti-tumor immunity observed in the tumor microenvironment (TME). The objective in this particular application is to determine the role of myeloid Syk kinase in mediating macrophage mediated immunosuppression and to test Syk or novel dual Syk/PI3K inhibitors in combination with αPD1 mAb for maximal adaptive immune response against the tumor. The central hypothesis motivating this research is that Syk kinase programs Mos to immunosuppressive phenotype in the TME and its inhibition along with PI3K and/or a check point inhibitors will activate anti-tumor immune responses. This hypothesis has been formulated on the basis of genetic evidence generated in our laboratory utilizing PI3Kγ -/- and Syk-/- murine models for immuno-oncology. The rationale for the proposed research is that understanding molecular mechanisms by which myeloid Syk promote immunosuppression has the potential to translate Syk and dual Syk/ PI3K inhibitors to treat cancers driven by the Mo-dependent immunosuppressive TME. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: Aim 1, we will determine the role of Syk kinase in tumor growth and immunosuppression. Aim 2 we will determine the mechanism by which the Syk kinase regulates immunosuppressive transcriptional programming in macrophages including changes in the Mo transcriptome. Aim 3 we will determine the effect of either Syk inhibitor or dual Syk/PI3K inhibitor in combination with immunotherapy modulators to augment anti-tumor immune response. The approach is innovative because it utilizes a novel small-molecule inhibitory chemotype, SRX3207 which hits both targets, Syk and PI3K in kinase and cell based assays and that both inhibition activate antitumor immunity. The significance of our proposal lies in our capacity to provide an optimizable promising single anticancer agent which will potently activate the immune response via multiple orthogonal mechanisms and result in a durable antitumor immune response. The candidate is firmly committed to a career in cancer research and is strongly supported by the institution for her pathway to independence. She is an Assistant Project Scientist in Division of Pediatrics at University of California, San Diego. The outlined proposal builds on the candidate’s previous research experience in the field of myeloid cell signaling and a career development plan that includes focused coursework, and collaborations from a multi-disciplinary group of established researchers that will help to complete the proposed studies.


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 = $0 )
2024	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Research Manpower	000	3	4/10/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $161,230 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Research Manpower	000	3	12/1/2021	NON-COMPETING CONTINUATION	$161,230
														Subtotal = $161,230

Issue Date FY: 2021 ( Subtotal = $161,230 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Research Manpower	000	2	11/6/2020	NON-COMPETING CONTINUATION	$161,230
														Subtotal = $161,230

Issue Date FY: 2020 ( Subtotal = $161,230 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Research Manpower	000	1	11/19/2019	NEW	$161,230
														Subtotal = $161,230

Grand Total All Awards = $483,690

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Myeloid Syk promotes tumor immunosuppression and inhibits anti-tumor adaptive immunity

Award Number: K22CA229594

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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