Cell therapy for muscle atrophy following irradiation in Rhabdomyosarcoma
Description: There are more than 80 types of sarcomas, including Rhabdomyosarcoma, that develop within connective tissues or skeletal muscle, which if left untreated are lethal. Radiation therapy combined with surgery is the standard-of-care for sarcoma treatment; however, radiation causes severe, permanent damage to the surrounding tissues including depletion of the skeletal muscle stem cells required for maintenance and repair. Because sarcomas disproportionally affect young people (11% of all adolescent cancers), patients that survive radiation will experience muscle atrophy and reduced mobility over their lifetime. We have a strategy to generate skeletal muscle from human pluripotent stem cells (hPSCs) with the ability to build new muscles following transplantation. Since hPSCs can be readily obtained from patients from any genetic background and expanded indefinitely, we have an opportunity to provide a robust cell therapy to reconstruct tissues for sarcoma survivors. We hypothesize that transplanted hPSC derived skeletal muscle will prevent muscle atrophy and loss of muscle function after surgery and irradiation in Rhabdomyosarcomas. Aim 1. Generate a Rhabdomyosarcoma mouse model to evaluate the effects on muscle stem cell repair and function. We will perform allogenic transplant of bioluminescent-expressing human sarcoma cells into quadriceps of mice to induce tumor formation. Tumors will be subject to surgical removal and/or radiation therapy at multiple time points. We will evaluate endogenous muscle stem cell’s ability to regenerate functional muscle at treated tumor sites. Aim 2. Test transplantation of hPSC skeletal muscle to restore the stem cell pool and muscle function. It’s unclear whether the volumetric muscle loss following surgical tumor removal or irradiated tissue remnants, such as extracellular matrices, can support engraftment of muscle stem cells. We will perform cell transplantations at irradiated sites with or without hydrogel plugs to test cell replacement of functional skeletal muscles within the irradiated muscle environment. If successful, our immediate goal would be to leverage pilot funding toward the California Institute of Regenerative Medicine (CIRM) DISC2 Quest grant, which would enable us to pursue an Investigational New Drug Application (IND) for moving forward with translating muscle stem cell therapies for cancer survivors.
Amount: $74,050
Start date: 2023-10-01
Investigators: Michael Hicks, Michael Hicks
Institution: University of California, Irvine
Funded outputs count: 0
Funder award ID: g9129m
OpenAlex ID: G1146000532