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Determining how cancer cachexia influences gluconeogenesis

Award Number: K99CA300496
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/07/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Determining how cancer cachexia influences gluconeogenesis - Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating and lethal disease associated with peripheral tissue wasting that is seen in most patients. This progressive wasting condition affecting skeletal muscle as well as fat and other tissues is referred to as cancer cachexia. PDAC patients with cancer cachexia have lower median survival than patients without cancer cachexia. There are currently no approved treatments for this disorder, including nutritional interventions. The Vander Heiden lab in a previous publication identified that the autochthonous mouse model of PDAC driven by KRAS activation with p53 deletion in the acinar cells of the pancreas was sufficient to drive cancer cachexia-induced muscle atrophy. These mice exhibited pancreatic enzyme insufficiency that was identified by the abundance of amino acids and fatty acids within the stools of cachexic KPC mice, indicating a lack of nutrient absorption. One of the key questions unanswered in the cancer cachexia field is whether the process of cancer cachexia serves to supply nutrients to the tumor to help it grow or it functions to help preserve the host. It is unknown where amino acids released from protein degradation in the muscle are going and what their purpose is. One of the organs in the body that requires an abundance of amino acids is the liver, as amino acids can be used to fuel gluconeogenesis. The rate-limiting enzyme for gluconeogenesis is phosphoenolpyruvate carboxykinase (PEPCK), which is upregulated in cancer cachexia by the IL6/JAK/STAT pathway in the liver. Therefore, we hypothesize that IL6/JAK/STAT signaling induces PEPCK and gluconeogenesis in the liver to promote cancer cachexia in primary and metastatic PDAC tumors. I will test this hypothesis in aim 1 by determining the contribution of PEPCK and gluconeogenesis in the liver to cancer cachexia and vice versa. Then in aim 2, I will study the role of IL6/JAK/STAT signaling on gluconeogenesis and metabolism in the livers of cachexic mice. Then in aim 3, I will determine whether cancer metastasis accelerates cachexia through promoting gluconeogenesis. The outcomes of this study will improve our understanding of whole-body metabolism and has therapeutic potential to facilitate the development of drug targets for cancer cachexia and/or PDAC.


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 = $133,955 )
2025	2025	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Research Manpower	000	1	8/7/2025	NEW	$133,955
														Subtotal = $133,955

Grand Total All Awards = $133,955

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Determining how cancer cachexia influences gluconeogenesis

Award Number: K99CA300496

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/07/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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