TICaRT Team Presentation: Utilizing Chimeras to Reverse Therapy-Induced Cachexia

Jeremy Ducharme, Ph.D.
Postdoctoral fellow, UF College of Public Health & Health Professions, Department of Physical Therapy; UF Health Cancer Center 

Madison Carelock 
Predoctoral fellow and Ph.D. candidate, UF College of Medicine, Department of Pathology; UF Health Cancer Center 

The involuntary loss of body weight that occurs in many cancer patients is a condition called cachexia. This loss of body weight is due to the loss of skeletal muscle mass, which negatively impacts physical function, quality of life, treatment tolerance, and survival. Our research team has shown that skeletal muscles from people and mice with pancreatic tumors exhibit skeletal muscle damage, persistent immune cell infiltration, and impaired regeneration. These phenotypes may be influenced by the accumulation of senescent cells, which are cells that no longer divide but secrete inflammatory cytokines, chemokines, proteases, and growth factors known to negatively impact skeletal muscle. However, there is currently no comprehensive research investigating the accumulation of senescent cells in the skeletal muscle of tumor-bearing hosts, and thus no study that tests whether selectively targeting and eliminating senescent cells (senolytics) can prevent their accumulation and delay or inhibit cancer-induced muscle wasting. To address this gap, we collected muscles from mice with pancreatic tumors treated with and without chemotherapy. We observed an increase in several hallmark indicators of senescence at a time point that corresponds with the onset of cancer-induced skeletal muscle wasting, and this accumulation was further exacerbated by chemotherapy. These findings identify senescent cells in skeletal muscle as potential therapeutic targets for the treatment of cancer-induced muscle wasting. Our next series of experiments will build from this foundation, and we will administer a senolytic proteolysis targeting chimera against a protein that regulates cell division to test whether this treatment can prevent senescent cell accumulation and combat skeletal muscle wasting in the context of pancreatic cancer.

Ducharme is a postdoctoral fellow in the Judge Laboratory at UF studying the regulation of muscle mass and cancer-associated muscle pathology. His individual research project is testing a novel compound for its ability to prevent cancer-induced muscle atrophy.

Carelock is a predoctoral fellow and fourth-year Ph.D. candidate in the laboratory of Weizhou Zhang, Ph.D., studying cancer biology, immunology and drug development. Her thesis project involves using targeted protein degradation in the context of metastatic breast cancer to target cancer cells and suppressive immune cells within the tumor microenvironment for disease attenuation.  

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