2020 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 and unfortunately the outcomes for these patients have not shown improvement in the last two decades. 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, led by Dr. Claire Wunker, M.Sc. candidate, University of Toronto and James J. Hammond Fellow, the Gladdy Lab has analyzed the pathology reports of 157 RMS patients in close collaboration with the Toronto Sarcoma clinical research team (S Burtenshaw), Sarcoma Pathologists (Dr. E. Demicco and Dr. I Weinreib) and biobanking facilities (Mount Sinai Hospital and University Health Network). In total they were able to collect 41 RMS samples from four different subtypes of RMS. RMS samples from these 41 patients were sent to Dr. Jack Shern at the National Institutes of Health National Cancer Institute (Frederick, MA), an expert in pediatric RMS, to determine the genetic alterations in adult RMS by whole exome sequencing.

Project 2 - Magnetic Resonance Image Guided High Intensity Focused Ultrasound (MRgHIFU) as novel therapy for advanced RMS

Temperature sensitive (TS) 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 released 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 release the TLD and would target the tumor 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. The lab is now investigating tumor growth and survival after treatment to determine if this treatment can be transferred to patients to reduce side effects.

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 our murine ERMS 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 MRIgHIFU is that heating is thought to activate immune cells that can be used to kill tumors and therefore may make non-immune stimulated tumors easier to treat. To determine if hyperthermia enriches immune infiltration of murine sarcoma models, we will continue our work in immune profiling treated tumors to determine the optimal timing in which immunotherapy should be administered compared to untreated tumors.

https://torontosarcoma.com/gladdy-lab/