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Microglia facilitate glioma progression through the Pyk2 and FAK signaling - hurricane funded extention

Award Number: SC1GM122691
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2021

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Microglia facilitate glioma progression through the Pyk2 and FAK signaling - hurricane funded extention - Glioblastoma tumors carry an exceptionally poor prognosis with median survival of approximately one year following diagnosis. Treatment resistance and invasive nature of glioma tumors negates the effectiveness of current medical approaches. Microglia infiltrate most gliomas and release factors which influence tumor growth and invasion. It was shown that soluble factors, released by microglia activate migration, proliferation, and resistance to applied chemotherapy in cultured glioma cell lines. Previously we demonstrated that microglia promote dispersal of glioma cells through the Pyk2 signaling pathway. Our preliminary data show that pharmacological inhibition of Pyk2/FAK in glioma cells reduce proliferation and increase cytotoxic effect of temozolomide in the presence of microglia. We hypothesize that microglia release factors to promote migration, proliferation, chemotherapy resistance, and tumor recurrence through the Pyk2/FAK pathways. The use of Pyk2/FAK blockers will reduce the microglial effect on tumor growth, dispersal, recurrence, and resistance to therapy. Combinatorial therapies utilizing Pyk2/FAK inhibitors together with chemotherapeutic compounds have the potential to provide significant treatment benefits. In the present study, we will utilize resected human glioblastoma tissues and cell biology approaches to investigate the intracellular mechanisms exploited to promote microglia-activated glioma invasiveness and proliferation. We will also examine, in a murine model, the effectiveness of supplementing traditional chemotherapeutic glioblastoma treatment with a Pyk2/FAK blocker on tumor growth and recurrence. To test our hypothesis we propose the following specific aims: Specific Aim #1: To test the hypothesis that microglia activate migration, invasion and proliferation of glioma cells through Pyk2 and FAK intracellular pathways. Specific Aim #2: To investigate combined effect of temozolomide (TMZ) and the Pyk2/FAK blocker PF- 562271 on tumor growth and animal mortality. Specific aim #3: To investigate the effectiveness of combined treatment with TMZ and PF-562271 on glioma recurrence after tumor resection. Validation of our hypothesis will provide a platform for developing therapeutic strategies aimed at elimination of the microglial component on glioma growth and recurrence and, thereby, increasing treatment efficacy.


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 = -$75,984 )
2026	2019	UNIVERSIDAD CENTRAL DEL CARIBE, INC	100 AVE LAUREL	BAYAMON	PR	00956	BAYAMON	USA	Extramural Research Restoration Program: Hurricanes Harvey, Maria, and Irma – non-construction	000	2	10/1/2025	SUPPLEMENT FOR EXPANSION	-$75,984
														Subtotal = -$75,984

Issue Date FY: 2024 ( Subtotal = -$20,625 )
2024	2021	UNIVERSIDAD CENTRAL DEL CARIBE, INC	100 AVE LAUREL	BAYAMON	PR	00956	BAYAMON	USA	Biomedical Research and Research Training	000	4	5/15/2024	NON-COMPETING CONTINUATION	-$20,625
														Subtotal = -$20,625

Issue Date FY: 2021 ( Subtotal = $330,781 )
2021	2021	UNIVERSIDAD CENTRAL DEL CARIBE INC	AVE LAUREL URB SANTA JUANITA	BAYAMON	PR	00956	BAYAMON	USA	Biomedical Research and Research Training	000	4	8/10/2021	NON-COMPETING CONTINUATION	$330,781
2021	2019	UNIVERSIDAD CENTRAL DEL CARIBE, INC.	100 AVE LAUREL LOMAS VERDES	BAYAMON	PR	00956	BAYAMON	USA	Extramural Research Restoration Program: Hurricanes Harvey, Maria, and Irma – non-construction	001	2	9/5/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $330,781

Issue Date FY: 2019 ( Subtotal = $661,562 )
2019	2019	UNIVERSIDAD CENTRAL DEL CARIBE INC	AVE LAUREL URB SANTA JUANITA	BAYAMON	PR	00956	BAYAMON	USA	Biomedical Research and Research Training	001	3	8/20/2019	NON-COMPETING CONTINUATION	$330,781
2019	2019	UNIVERSIDAD CENTRAL DEL CARIBE INC	AVE LAUREL URB SANTA JUANITA	BAYAMON	PR	00956	BAYAMON	USA	Extramural Research Restoration Program: Hurricanes Harvey, Maria, and Irma – non-construction	000	2	4/26/2019	SUPPLEMENT FOR EXPANSION	$330,781
														Subtotal = $661,562

Issue Date FY: 2018 ( Subtotal = $330,781 )
2018	2018	UNIVERSIDAD CENTRAL DEL CARIBE INC	AVE LAUREL URB SANTA JUANITA	BAYAMON	PR	00956	BAYAMON	USA	Biomedical Research and Research Training	000	2	8/20/2018	NON-COMPETING CONTINUATION	$330,781
														Subtotal = $330,781

Issue Date FY: 2017 ( Subtotal = $330,781 )
2017	2017	UNIVERSIDAD CENTRAL DEL CARIBE INC	AVE LAUREL URB SANTA JUANITA	BAYAMON	PR	00956	BAYAMON	USA	Biomedical Research and Research Training	000	1	8/7/2017	NEW	$330,781
														Subtotal = $330,781

Grand Total All Awards = $1,557,296

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Microglia facilitate glioma progression through the Pyk2 and FAK signaling - hurricane funded extention

Award Number: SC1GM122691

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2021

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