# Project 2 NF-#B regulation in muscle wasting and pancreatic cancer-induced cachexia

> **NIH NIH P01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $496,381

## Abstract

PROJECT SUMMARY: PROJECT 2
Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of skeletal
muscle and adipose tissues. This syndrome occurs in a majority of cancers and contributes to approximately a
third of all cancer deaths. Currently, no effective therapy exists to combat this malignant disorder. For pancreatic
ductal adenocarcinoma (PDAC), the most aggressive formof pancreatic cancer, the potential benefit for effective
cachexia therapies may be even greater than for other cachexia-associated malignancies, since 85% of these
patients lose on average 14% of their pre-illness weight, and cachexia dramatically limits their ability to tolerate
surgery, chemo- or radiotherapy. New therapies will likely evolve from an enhanced understanding of the
mechanisms leading to muscle wasting and tumor development (the primary driver of cachexia). This program
project brings together expert investigators in skeletal muscle, oncology, immunology, and cachexia, to explore
the role an NF-B/IL-6/STAT3 signaling axis within the macroenvironment of cancer cachexia – considering both
mechanisms of muscle loss and the development of PDAC. In Project 2 of this program, focus will be placed on
the NF-B portion of this signaling axis. Recent efforts have centered on two new concepts. The first is that
cancer cachexia associates with the activation of muscle stem cells initiating a repair pr ocess on the muscle
fiber. NF-B is activated in stem cells, and functions to block repair and promote muscle wasting through the
regulation of a local muscle inflammatory condition. The second discovery provides insight in how NF-B
functions within the tumor cell during development of PDAC. Using a mouse model of pancreatic cancer, we
showed that NF-B plays a critical role in protecting tumor cells from the surveillance property of anti-tumor
macrophages and cytotoxic T cells. NF-B is able to suppress both innate and adaptive immunity through the
regulation of the immunosuppressive cytokine, GDF15. The goal of this project is to explore the hypothesis that
NF-B functions in the macroenvironment of cancer cachexia by acting in muscle stem cells to block muscle
repair, as well as promoting PDAC through the production of immunosuppressive genes such as GDF-15.
Towards this goal we seek to perform the following two specific aims: 1) Determine the relevance of NF-B
regulation of muscle inflammation in cancer cachexia; and 2) Determine how NF-B regulation of GDF-15 and
immune modulation promotes PDAC. Achieving this goal will enhance our understanding of the relevance of NF-
B and how this signaling component intersects with IL-6 and STAT3 to regulate muscle wasting and tumor
development within the macroenvironment of cancer cachexia.

## Key facts

- **NIH application ID:** 10898567
- **Project number:** 5P01CA236778-04
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Denis C Guttridge
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $496,381
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898567

## Citation

> US National Institutes of Health, RePORTER application 10898567, Project 2 NF-#B regulation in muscle wasting and pancreatic cancer-induced cachexia (5P01CA236778-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10898567. Licensed CC0.

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