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Development of a clinically relevant mouse model of lung cancer cachexia to study pathoetiology and therapeutic strategies

Award Number: R21CA283492
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/04/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Development of a clinically relevant mouse model of lung cancer cachexia to study pathoetiology and therapeutic strategies - PROJECT SUMMARY Cancer cachexia (CC) is characterized by unintentional weight loss secondary to adipose and skeletal muscle tissue wasting. It results from a complex interaction between the tumor and host, where tumor released factors reprogram peripheral organ and tissue metabolism to cause wasting. CC affects a majority of patients with lung, pancreatic, and gastrointestinal cancer, in addition to patients with other advanced stage cancers, and is associated with increased treatment-related toxicity, poor response to chemo- and immunotherapy and is estimated to cause ~20% of all cancer-related deaths. Lung cancer is the second most common cancer worldwide and the leading cause of cancer-related deaths. A majority of lung cancer patients exhibit signs of CC at diagnosis, with up to 75% experiencing tissue wasting during treatment. Oncogenic KRAS mutations increase the risk for CC and are found in many aggressive cancers that are prone to CC, including pancreatic, gastrointestinal and lung cancer. In fact, a large majority of lung adenocarcinomas show evidence for elevated Ras pathway activation (84%). Studies have described murine lung cancer models with mutated Kras that develop CC, but these models fail to reproduce the pathophysiology and time course of CC in human patients. Thus, our goal is to develop and test mouse Kras driven lung cancer models that more accurately reproduce the clinical condition to facilitate identification of pathoetiological mechanisms and to provide an experimental system that enables testing of pharmacological and supportive care interventions over a more clinically relevant time frame. This proposal builds on our strong preliminary results from lung club cell specific KrasG12D mouse models characterizing the phenotypes and time course of CC initiation and progression. Based on our preliminary data, we hypothesize that our KrasG12D lung adenocarcinoma model more closely mimics the pathophysiology of human CC in its phenotypes and time course compared to a similar Kras driven mouse model that aligns with the rapid time course of commonly used murine lung CC models. To develop this model and test our hypotheses, we will use a combination of genetically engineered mouse models and in vitro models consisting of tumor organoids developed from these animals, along with skeletal muscle and adipose cell cultures. Results from our studies will advance the field by providing novel in vivo and in vitro models to study the pathophysiology of CC and to test therapeutic interventions. Collectively, these tools and knowledge will inform translation of basic science discoveries into more effective treatments for CC in 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: 2024 ( Subtotal = $173,208 )
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cancer Treatment Research	000	2	8/1/2024	NON-COMPETING CONTINUATION	$173,208
														Subtotal = $173,208

Issue Date FY: 2023 ( Subtotal = $218,790 )
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cancer Treatment Research	000	1	8/4/2023	NEW	$218,790
														Subtotal = $218,790

Grand Total All Awards = $391,998

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Development of a clinically relevant mouse model of lung cancer cachexia to study pathoetiology and therapeutic strategies

Award Number: R21CA283492

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/04/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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