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Defining the Roles of Bone Marrow Adipocytes and FABP4/5 Signaling in Multiple Myeloma Drug Resistance - Diversity Supplement

Award Number: R37CA245330
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Defining the Roles of Bone Marrow Adipocytes and FABP4/5 Signaling in Multiple Myeloma Drug Resistance - Diversity Supplement - ABSTRACT The overall goal of this Supplemental research project is to support the career development of Michelle Karam, who is a post-baccalaureate research assistant in the Reagan lab planning to go to graduate school in biomedical science. Multiple myeloma (MM) is an incurable blood cancer that results from mutations that accumulate in the plasma cell. Myeloma cells grow in the rich soil of the bone marrow (BM), first very slowly, and then more quickly and aggressively, causing degradation of the bone and development of drug resistant clones. Although therapies exist, novel approaches to myeloma therapy are needed. Our prior work suggested that myeloma cells can become drug resistant and proliferate faster through support from proteins called fatty acid-binding proteins 4 and 5 (FABP4 and FABP5). In Specific Aim 1 of our R37 parent award, we are analyzing how BM adipocytes contribute to myeloma by using novel, three-dimensional (3D), tissue engineered cancer models. In Specific Aim 2, we use mouse models to study the roles of the FABP members in MM, as well as the roles of BM adipocytes. The long-term goal of our work is to understand molecules and mechanisms driving MM growth; this Supplement and Parent project specifically will identify new mediators driving MM and propose paradigm-shifting concepts to guide the development of new anti-MM therapies. The proposed studies in this Supplement will not overlap with ongoing work on the Parent award, but will complement and add translational significance to the findings. We have submitted a Method to Extend Research in Time (MERIT) Award Extension Request that would extend the R37 grant for two years through June 2027. This is a two year supplement request with Aim 1 in year one and Aim 2 in year two, if the extension is granted. Both Supplement Aims will be used to identify translationally significant effects and mechanisms of FABP inhibitor action on tumor cells and on the tumor immune microenvironment. Our Supplement Specific Aim 1 is to Test the feasibility for orally-administered FABP inhibitors to slow tumor progression and increase mouse survival in an immunocompetent in vivo MM model. This will be used to develop drug delivery doses and oral gavage methods for effectively inhibiting MM growth, which we will use for the following Aim. Supplement Specific Aim 2 is to: Examine mechanisms of action of FABP inhibitors in the MM BM environment, including effects on tumor and surrounding tumor microenvironment cells. This Aim will use novel methodologies and data analyses methods for flow cytometric and spatial transcriptomic analysis of MM cell growth in the BM of mice, and the effects of FABP inhibitors on the tumor and non-tumor microenvironment cells. This work should thus illuminate the actions of FABP inhibition not only on tumor cells, but also on surrounding cells, which will be essential for moving towards the clinic and thoroughly understanding the potential roles of the FABPs in MM patients.


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 = $0 )
2025	2024	MAINEHEALTH	110 FREE ST	PORTLAND	ME	04101	CUMBERLAND	USA	Cancer Treatment Research	000	5	3/27/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $452,855 )
2024	2024	MAINEHEALTH	110 FREE ST	PORTLAND	ME	04101	CUMBERLAND	USA	Cancer Treatment Research	001	5	8/1/2024	SUPPLEMENT FOR EXPANSION	$79,077
2024	2024	MAINEHEALTH	110 FREE ST	PORTLAND	ME	04101	CUMBERLAND	USA	Cancer Treatment Research	000	5	6/20/2024	NON-COMPETING CONTINUATION	$373,778
														Subtotal = $452,855

Issue Date FY: 2023 ( Subtotal = $385,581 )
2023	2023	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Cancer Treatment Research	000	4	6/30/2023	NON-COMPETING CONTINUATION	$385,581
														Subtotal = $385,581

Issue Date FY: 2022 ( Subtotal = $393,450 )
2022	2022	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Cancer Treatment Research	000	3	6/6/2022	NON-COMPETING CONTINUATION	$393,450
														Subtotal = $393,450

Issue Date FY: 2021 ( Subtotal = $393,450 )
2021	2021	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Cancer Treatment Research	000	2	6/4/2021	NON-COMPETING CONTINUATION	$393,450
														Subtotal = $393,450

Issue Date FY: 2020 ( Subtotal = $393,450 )
2020	2020	MAINEHEALTH	22 BRAMHALL ST	PORTLAND	ME	04102	CUMBERLAND	USA	Cancer Treatment Research	000	1	5/15/2020	NEW	$393,450
														Subtotal = $393,450

Grand Total All Awards = $2,018,786

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Defining the Roles of Bone Marrow Adipocytes and FABP4/5 Signaling in Multiple Myeloma Drug Resistance - Diversity Supplement

Award Number: R37CA245330

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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