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Targeting the Unfolded Protein Response Master Regulator BiP to Induce CellDeath in Multiple Myeloma

Award Number: K08CA297136
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/19/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Targeting the Unfolded Protein Response Master Regulator BiP to Induce CellDeath in Multiple Myeloma - PROJECT ABSTRACT This application describes my research on a plasma cell (PC) survival pathway in Multiple Myeloma (MM) to be performed within the context of a 5-year mentored career development plan. My ultimate goal is to become an independent physician-scientist in the area of MM as a laboratory-based Hematology/Oncology academic and to develop potential therapeutics for use in trials. Under the guidance of my primary mentors, Dr. David Allman and Dr. Alfred Garfall, at the University of Pennsylvania, I have developed a structured training plan consisting of intensive laboratory research, didactics, and oversight by an experienced faculty advisory committee. The proposed research will center on mechanisms of cell survival in MM mediated by the unfolded protein response (UPR) pathway by focusing on a key negative regulator of the pathway, BiP, and its potential as a therapeutic target. MM is an incurable plasma cell cancer that despite treatments is universally fatal. One key reason for lack of durable therapies is a limited understanding of survival pathways, such as the UPR. Professional protein secreting cells such as PCs are uniquely dependent on the UPR for survival. PCs produce 2-10,000 antibodies per second, and this extreme protein load actively engages the UPR to adapt to the stresses of high output protein production. If stress is unable to be resolved, the UPR transitions from pro-survival to pro-death. It is known that this transition occurs through gene transcription programs, but the specific programs and their time courses are unclear. I require further training in bioinformatic analysis of transcriptional datasets to tease apart this transition. The activation of these gene programs by the UPR is controlled by the negative regulator BiP. Its removal leads to UPR activation, making it both a good target to study the pro-survival to pro-death transition but also as a therapeutic target to force prolonged UPR activation and death. By using a novel BiP-targeting agent and novel MM model systems, this proposal will characterize changes in gene expression during the UPR- mediated pro-survival to pro-death transition and determine what death pathways are responsible for this transition (Aim1). It will also test the efficacy of novel BiP-targeting approaches in untreated and relapsed MM in a patient derived xenograft mouse model (Aim2). These findings will provide insight into the biology of MM survival mechanisms, provide the rationale for BiP-targeting as a therapeutic approach and provide data for larger grant applications. In undertaking the proposed studies and training plan, I will develop the skills and expertise necessary to establish an independent career in translational research.


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 = $0 )
2026	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Research Manpower	000	1	12/12/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $280,638 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Research Manpower	000	1	9/19/2025	NEW	$280,638
														Subtotal = $280,638

Grand Total All Awards = $280,638

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Targeting the Unfolded Protein Response Master Regulator BiP to Induce CellDeath in Multiple Myeloma

Award Number: K08CA297136

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/19/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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