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Fibroblasts Support the Growth of Brain Metastasis by Rendering Cancer Cells Resistant to Chemotherapy and Inducing Immunosuppression in Tumor Microenvironment

Award Number: R01CA276273
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: 05/31/2028

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Fibroblasts Support the Growth of Brain Metastasis by Rendering Cancer Cells Resistant to Chemotherapy and Inducing Immunosuppression in Tumor Microenvironment - PROJECT SUMMARY/ABSTRACT Brain metastasis (BrM) is the most common intracranial tumor in adults. Despite advanced therapies, BrM remains a major cause of morbidity and mortality in patients with lung cancer. The mechanisms underlying BrM progression and immune evasion remain poorly understood. Fibroblasts are abundant in the lung cancers that have metastasized to the brain, but functions of fibroblasts in BrM are still not known. In our preliminary studies, metastasis-associated fibroblasts (MAFs) promote BrM growth through a soluble form of placental growth factor (PGF). MAF-derived PGF protect cancer cells from treatment with tyrosine kinase inhibitors (TKIs) and induce immunosuppressive environment in BrM. Based on these observations, we propose that MAFs-derived PGF supports BrM growth in two ways: 1) directly by stimulating the proliferation and chemoresistance of cancer cells; 2) indirectly by inducing an immunosuppressive tumor microenvironment. This hypothesis will be tested in two specific aims: 1) determine how MAF-derived PGF directly regulates the proliferation and TKI resistance of cancer cells in BrM. 2) determine how MAF-derived PGF causes immunosuppression in BrM. Our studies will establish the importance of MAF-derived PGF in inducing TKI resistance and immunosuppression in BrM. PGF neutralizing antibodies efficiently penetrate the brain, and already show promise in treating primary brain tumors, both in preclinical studies and in ongoing clinical trials. Our studies will provide strong mechanistic rationale and pave the way for therapeutic use of PGF antibodies in treating BrM.


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 = $412,500 )
2025	2025	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	3	6/3/2025	NON-COMPETING CONTINUATION	$412,500
														Subtotal = $412,500

Issue Date FY: 2024 ( Subtotal = $391,874 )
2024	2024	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	2	5/10/2024	NON-COMPETING CONTINUATION	$391,874
														Subtotal = $391,874

Issue Date FY: 2023 ( Subtotal = $412,500 )
2023	2023	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	1	5/31/2023	NEW	$412,500
														Subtotal = $412,500

Grand Total All Awards = $1,216,874

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Fibroblasts Support the Growth of Brain Metastasis by Rendering Cancer Cells Resistant to Chemotherapy and Inducing Immunosuppression in Tumor Microenvironment

Award Number: R01CA276273

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: 05/31/2028

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