2021 Research Update from the Gladdy Lab at Princess Margaret Cancer Centre

Project 1 - Genetic Landscape of Adult RMS

Rhabdomyosarcoma (RMS) is a tumor of the skeletal muscle that most commonly affects young adults. Although it is the most common pediatric soft tissue sarcoma, it generally has a worse prognosis in adults, however the reason behind this is unknown. Current treatment involves chemotherapy, radiation, and/or surgery. Previous research has demonstrated that recurrent genetic mutations are overexpressed in pediatric RMS tumours which provide targets for novel therapies. In order to develop new agents, the exact genes that are suspected to increase tumour formation must be elucidated in adult patients as well.

To date, currently led by Jen Dorsey, Ph.D candidate, UofT, the Gladdy Lab has analyzed the pathology reports of 169 RMS patients in close collaboration with Sarcoma Pathologists (Dr. Elizabeth Demicco and Dr. Ilan Weinreib) and biobanking facilities (Mount Sinai Hospital and University Health Network). Of these, 105 patients had sufficient clinical data, including translocation status, that Dr. Fahima Dossa, surgical resident, UofT, has clinically analyzed. RMS samples from 41 patients were sent to Dr. Jack Shern, an expert in pediatric RMS, at the National Institutes of Health National Cancer Institute (Frederick, MA), who has performed whole exome sequencing. Currently, Dr. Shern is analyzing this data to detect mutations that have been identified in pediatric RMS exomes and those that are unique to adult RMS. In summary, genomic data from this study will be used to better understand adult RMS and in the future improve therapy for adult RMS patients.

Project 2 - Magnetic Resonance Image Guided Focused Ultrasound as novel therapy for advanced RMS

Temperature sensitive forms of drugs have been studied in other cancers, such as breast and liver. This includes a drug called doxorubicin that works to treat many sarcomas but also affects the heart, leading to an increased risk of heart failure and heart attacks. In order to minimize this damage while still treating the tumor other drug delivery methods have been developed including a thermosensitive liposomal form of doxorubicin (TLD). This drug is activated when heated to a temperature of 41°C. An innovative way to heat the tumor to the drug release temperature is by performing magnetic resonance image guided high intensity focused ultrasound (MRgHIFU). MRgHIFU is a non-invasive heating method using MRI to map within the body and accurately target a location to send focused ultrasound waves which generate heat. MRgHIFU would heat the tumor to locally release the TLD while limiting the toxicity to the rest of the body. To test this method, the Gladdy Lab treated RMS tumors in mice with MRgHIFU and TLD. From their initial analysis, the lab found that mice treated with MRgHIFU +TLD has an increased survival.

Another possible novel treatment for RMS is immunotherapy. To develop treatments for these patients we need to have an appropriate model on which to test them. Currently the Gladdy Lab is characterizing the immune profile of a murine RMS model to understand what immune cells are present before treatment so we can better leverage the immune system as a novel treatment strategy. Additionally, a possible benefit of MRgHIFU is that heating is thought to activate immune cells that can be used to kill tumors and therefore may make non-immune stimulated tumors more responsive to immunotherapy. To determine if hyperthermia enriches immune infiltration of murine RMS models, the Gladdy lab will continue to immune profile MRgHIFU treated tumors, which will also allow them to determine the optimal timing in which immunotherapy should be administered. In summary, findings from this study would form the basis for the use of MRgHIFU and immunotherapy for RMS.