MUSC Hollings Cancer Center researchers Denis Guttridge, Ph.D., Michael Ostrowski, Ph.D., and colleagues at Indiana University were recently awarded a $9.7 million program project grant by the National Cancer Institute (NCI).
Over the five-year grant period, the team aims to uncover the biology behind cachexia, a syndrome of cancer characterized by involuntary and excessive weight loss caused by the depletion of skeletal muscle and adipose tissue. This is the first time that the NCI has awarded a program project grant to study cancer cachexia, which affects approximately 50% of all cancer patients.
Guttridge, a specialist in cachexia, said this is an important area of research, as cachexia depletes patients’ quality of life and affects cancer treatment by decreasing treatment tolerance and making patients excessively weak. It is estimated that nearly one-third of all cancer deaths can be attributed to this wasting syndrome, which is devastating for not only the patient but their families as well.
The project explores the role of the macroenvironment in pancreatic cancer-induced cachexia to address a debilitating condition that, from an oncology standpoint, was historically not considered a disease condition. The oncology field now recognizes that tackling cachexia should be a top priority for improving a patient’s quality of life. Funders have also come to a similar realization. Understanding and reversing cachexia is one of the current Cancer Grand Challenges, a research funding partnership between the NCI and Cancer Research UK designed to fund the most cutting-edge cancer research.
“The program project grant is aligned with Hollings’ focus on patient quality of life. Therapies to treat cancer-induced cachexia will improve patients’ quality of life and increase the chance of successful cancer treatment.”
— Dr. Denis Guttridge
“Cachexia is very prominent in patients with pancreatic ductal adenocarcinoma (PDAC). Approximately 70% of PDAC patients have cachexia. Studying cachexia in PDAC is useful because it allows us to look at the biological cause early on. In other cancers, cachexia appears when the cancer is very advanced,” said Guttridge.
Combined expertise and over six years of collaboration led to the successful funding of this program project. In what is a dream team that has been assembled to address the issue, Guttridge is working with Teresa Zimmers, Ph.D., who brings additional expertise in cachexia, and Hollings colleague Ostrowski, who adds in-depth knowledge of the tumor microenvironment, fibroblasts and signaling pathway interactions to the project. He also has prior experience leading a breast cancer-focused program project.
Ostrowski said program projects allow experts to come together in order to tackle challenging problems. “The sum is synergistic and greater than the individual parts. Both Zimmers and Guttridge have experience in researching cachexia, and I am bringing understanding of tumor microenvironments and fibroblasts to the team,” said Ostrowski, a professor in the Department of Biochemistry and Molecular Biology at MUSC.
Zimmers, the H.H. Gregg Professor of Cancer Research at Indiana University and a longtime advocate of cachexia research with the NCI, is hopeful since this team brings together complementary expertise that is missing from single projects, such as R01 grants. “We are the right people to make headway to address this problem,” she said.
Guttridge studies one of the key inflammatory signaling pathways, NF-κB, in skeletal muscles. Prior studies indicated that the NF-κB signaling pathway and other inflammatory molecules are very active in cachexia. However, it is not known how the inflammation, cancer and excessive weight loss are biologically regulated. Using a mix of animal models and clinical samples from pancreatic cancer patients, the team will look at the cancer macroenvironment in order to understand the complex biology.
“While the vast majority of cancer studies look at the tumor microenvironment, this work looks at the signaling pathways that communicate between the different tumors and surrounding microenvironments.”
— Dr. Michael Ostrowski
Examining the macroenviroment is an exciting approach for the team to take, said Ostrowski. “While the vast majority of cancer studies look at the tumor microenvironment, this work looks at the signaling pathways that communicate between the different tumors and surrounding microenvironments,” he said.
For example, connective tissue cells called fibroblasts are found both in skeletal muscle and tumor microenvironments; however, it is not known if fibroblasts in the different microenvironments respond similarly to the inflammatory molecules. The team’s goal is to provide new biological insight, which will be coordinated by four cores within the program project grant: administration, human biospecimens, immunophenotyping and biostatistics.
Each collaborator brings different strengths and resources to the team, said Zimmers. “Indiana University has the busiest surgical unit for PDAC in the country. We will be providing the patient biospecimens, and MUSC will be performing single-cell RNA sequencing and multispectral imaging of the tumor, skeletal muscle and fat from PDAC patients with cachexia.”
Guttridge said new biological insight will lead to new therapeutic targets, which is exciting. “The program project grant is aligned with Hollings’ focus on patient quality of life. Therapies to treat cancer-induced cachexia will improve patients’ quality of life and increase the chance of successful cancer treatment,” he said. “Future drugs developed for cancer-related cachexia may also be relevant for patients suffering from other disease-induced cachexia, such as COPD, chronic kidney disease and congestive heart failure.”