Rebecca Gladdy

The long-term goal of the Gladdy Lab Research Program is to develop functional genomics platforms that allow us to better understand sarcoma biology so that we can translate this knowledge into more effective treatments for our patients.

Since joining the Lunenfeld-Tanenbaum Research Institute as an Associate Researcher in July 2008, Dr. Gladdy has established an independent laboratory that has focused on Translational Sarcoma Research. She is a full member in Lab Medicine and Pathobiology at the University of Toronto.

Dr. Gladdy’s clinical expertise is in the surgical management of soft tissue sarcoma. She is a member of the Toronto Sarcoma Program, which is the Centre of Excellence for Sarcoma Care in Canada and is affiliated with the Princess Margaret Cancer Centre, Mount Sinai Hospital, and the Hospital for Sick Children at the University of Toronto. In addition to having a translational research lab, Dr. Gladdy is part of an active clinical research group that is interested in advancing clinical care through engaging in clinical trials and improving quality of life in sarcoma patients.

Research summary

1. Whole genome sequencing defines leiomyosarcoma evolution and identifies therapeutic opportunities in the DNA damage pathway

Leiomyosarcoma (LMS) encompasses a genetically heterogeneous group of malignant neoplasms differentiating along smooth muscle lines. LMS is a common adult sarcoma whose outcome is limited by metastatic failure (Ann Surg Oncol. 2013, PMID: 23354568).

Currently, treatment is not informed by molecular subtyping and is associated with highly variable survival rates. While disease site represents an important prognostic factor, the contribution of genetic factors remains mostly unknown.

Thus, the overall goal of our LMS program is to perform comprehensive whole genome sequencing (WGS) and transcriptomic profiles to identify and validate actionable targets/pathways in primary and metastatic LMS. Our genomics approach, is focused on understanding the molecular signatures of primary tumors compared to their matched metastasis to determine what the common and disparate mechanisms are. This knowledge will be used to determine the clonal evolution and architecture of LMS.

2. The Impact of of Magnetic Resonance Guided High Intensity Focused Ultrasound and Chemotherapy on the Immune Profile of Rhabdomyosarcoma

In cases of relapsed or metastatic RMS chemotherapies include doxorubicin, which is cardiotoxic. An alternate form of doxorubicin has been developed that is encapsulated in a thermosensitive liposome (TLD). Magnetic resonance guided high intensity focused ultrasound (MRgHIFU) is an emerging therapy that combines visualization using MRI and computational control of the ultrasound, which generates localized hyperthermia.

We are currently pursuing this as a possible treatment for RMS through testing on our mouse models. We are evaluating the effectiveness of the treatment compared to vincristine, the first line standard of care chemotherapy, and doxorubicin. This project is in collaboration with the Center for Image Guided Innovation and Therapeutic Intervention at SickKids, the Spatio-Temporal Targeting and Amplification of Radiation Response Program at UHN, at the University of Toronto and the University of Calgary.

Our multidisciplinary team engages expertise from engineering, computer programming, imaging, pre-clinical RMS mouse models, pharmacy, and medical oncology.

We have other focus projects in Epigenetic Drug Therapy in RMS.

Selected publications

Wunker C, Piorkowska K, Keunen B, Babichv Y, Wong SM, Regenold M, Dunne M, Nomikos J, Siddiqui M, Pichardo S, Foltz W, Waspe AC, Gerstle JT, Drake J, Gladdy RG. Magnetic resonance-guided high intensity focused ultrasound generated hyperthermia: a feasible treatment method in a murine rhabdomyosarcoma model. Journal of Visualized Experiments. 2023 Jan. 13;(191) in press: doi: 10.3791/64544. 

Anderson ND, Babichev Y, Fuligni F, Comitani F, Layeghifard M, Venier RE, Dentro S, Maheshwari A, Guram S, Wunker C, Thompson JD, Yuki K, Hou H, Zatzman M, Light N, Bernardini MQ, Wunder JS, Andrulis IL, Ferguson P, Razak, ARA, Swallow CJ, Dowling JJ, Al-Awar RS, Marcellus R, Rouzbahman M, Gerstung M, Durocher D, Alexandrov LB, Dickson BC, Gladdy RA*, Shlien A*. Lineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival. Nature Communications. 2021 July 23. 12(1):4496. *denotes co-senior authors Senior Responsible Author. (PMID: 34301934) 

McKinnon T, Venier R, Yohe M, Sindiri S, Gryder B, Shern J, Kabaroff L, Dickson B, Schleicher K, Chouinard-Pelletier G, Menezes S, Gupta A, Zhang X, Guha R, Ferrer M, Thomas C, Wei Y, Davani D, Guidos CJ, Khan J, Gladdy RA. Functional screening of FGFR4-driven tumorigenesis identifies PI3K/mTOR inhibition as a therapeutic strategy in rhabdomyosarcoma. Oncogene. 2018 Feb 28; 37(20):2630-2644. Senior Responsible Author. (PMID: 29487419)

Babichev Y, Kabaroff L, Datti A, Uehling D, Isaac M, Al-Awar R, Prakesch M, Sun RX, Boutros PC, Venier R, Dickson BC, Gladdy RA. PI3K/AKT/mTOR inhibition in combination with doxorubicin is an effective therapy for leiomyosarcoma. J Transl Med. 2016 Mar 8; 14:67. Senior Responsible Author. (PMID: 26952093)

McKinnon T, Venier R, Dickson BC, Kabaroff L, Alkema M, Chen L, Shern JF, Yohe ME, Khan J, Gladdy RA. Kras activation in p53-deficient myoblasts results in high-grade sarcoma formation with impaired myogenic differentiation. Oncotarget. 2015 Jun 10; 6(16):14220-14232. Senior Responsible Author. (PMID: 25992772)

Appointments

Associate Professor, Department of General Surgery

Clinician Scientist, Lunenfeld-Tanenbaum Research Institute

Co-Chair, Sarcoma Disease Site Group, CCTG Sarcoma Committee

Chair, Transatlantic Retroperitoneal Sarcoma Working Group (TARPSWG), Translational Research Working Group

Honours and awards

David McCready Teaching Award. Best Clinical Teacher. Complex Abdominal Surgical Oncology Program, 2021

Best Clinical Mentor, Surgical Oncology Fellows. Department of Surgery, University of Toronto, Toronto, Ontario, Canada 2019

Litwin Scientist in Cancer Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada 2017