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Exploiting A Critical Vulnerability To Glutamine Antimetabolite Therapy in Fibrolamellar Hepatocellular Carcinoma (FLC)

Award Number: R01CA289041
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Exploiting A Critical Vulnerability To Glutamine Antimetabolite Therapy in Fibrolamellar Hepatocellular Carcinoma (FLC) - Project Abstract Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal form of liver cancer that primarily affects children and young adults without cirrhosis. There are no approved systemic therapies for FLC, and it is usually refractory to treatment approaches developed for other forms of liver cancer. A chimeric transcript between DNAJB1 and PRKACA was identified as a signature genomic event in FLC and leads to activation of PKAc. However, pharmacological inhibition of PKAc for FLC with traditional small molecule inhibitors has been infeasible due to on-target toxicity. Our preliminary data derived from preclinical models of FLC and human FLC tumors show that the DNAJB1-PRKACA fusion results in a metabolic rewiring of the tumor cell, leading to glutamine dependence. Induction of the DNAJB1-PRKACA fusion in preclinical cell lines is associated with sensitivity to glutamine antimetabolite therapy. Glutamine dependency in FLC results in a nutrient-depleted tumor immune microenvironment (TiME) that is enriched in immunosuppressive metabolites (e.g., ammonia, acidosis), impairing antitumor immunity. In an in vivo model of FLC, the combination of glutamine antimetabolite therapy plus an immune checkpoint inhibitor (ICI) reverses T cell dysfunction within the tumor immune microenvironment (TiME) and induces antitumor immunity resulting in robust tumor control. We are translating these preclinical findings into a clinical trial of a glutamine antagonist (sirpiglenastat) in combination with a PDL1 inhibitor (durvalumab). In Aim 1, we will conduct a clinical trial to test the safety and clinical activity of sirpiglenastat in combination with durvalumab, in children or adults with advanced FLC. In Aim 2, we will determine whether treatment with sirpiglenastat combined with durvalumab suppresses glutamine-dependent processes and increase the number of activated FLC-specific T cells within the tumor microenvironment. In Aim 3, we will identify the molecular mechanism and specific metabolic perturbations through which the DNAJB1-PRKACA fusion induces glutamine addiction and immune suppression. This work will advance a promising new treatment approach for advanced FLC, a tumor type that currently confers a median survival of only one year. Uncovering the activity of specific pathways that make FLC glutamine dependent will establish a more complete understanding of metabolic biomarkers of glutamine addiction, and will reveal synergistic vulnerabilities, which may be targetable for even more effective treatment approaches. We anticipate that these avenues of inquiry will likely be generalizable to other classes of glutamine addicted tumors.


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 = $578,793 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	2	2/28/2025	NON-COMPETING CONTINUATION	$578,793
														Subtotal = $578,793

Issue Date FY: 2024 ( Subtotal = $650,089 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	1	2/28/2024	NEW	$650,089
														Subtotal = $650,089

Grand Total All Awards = $1,228,882

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Exploiting A Critical Vulnerability To Glutamine Antimetabolite Therapy in Fibrolamellar Hepatocellular Carcinoma (FLC)

Award Number: R01CA289041

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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