The following 3 grants were funded jointly between DFC and DTRF.
Principal Investigator: Jonathan Noujaim, MD
Professional Title: Hematologist and Medical Oncologist, Assistant Clinical Professor of Medicine
Sponsoring Institution: Canadian Sarcoma Clinical and Research Collaboration (CANSARCC)
Proposal Title: Tyrosine Kinase Inhibitors in Desmoid-type Fibromatosis – A Canadian Multicenter Retrospective CanSaRCC Study
Total Budget/Length: $30,000 over 1 year
DFC Funding: $19,200 CDN
Lay Abstract: Desmoid tumors (DT) are aggressive tumors predominantly affecting young people. They can potentially cause significant pain, decreased limb mobility and invalidity. In certain individuals, DTs can even be life threatening. Although some tumors may spontaneously shrink or remain stable without any treatment, patients with growing tumors will require either surgery or chemotherapy. Over the last decades, a number of drugs including hormonal blockers like tamoxifen, intravenous chemotherapy like weekly methotrexate and vinblastine and doxorubicin and targeted therapy like imatinib have shown various degrees of success in treating DTs. Recently, two new targeted drugs, sorafenib and pazopanib, were approved to treat DTs. In clinical trials, DTs treated with either drug shown significant tumor shrinkage and control over time. Since their approval and routine use in practice, there remains many unknowns. Duration of treatment is still ill defined. Outcomes of patients who failed or stopped sorafenib or pazopanib are unknown. Predicting which patients may respond to these novel drugs is still a challenge. The main objective of this multicentre Canadian retrospective study is to collect real world data to better guide physicians in managing these rare tumours.
Principal Investigator: Joanna Przybyl, PhD
Professional Title: Assistant Professor, Department of Surgery, McGill University
Sponsoring Institution: Research Institute – McGill University Health Centre
Proposal Title: Targeting hexosamine biosynthesis pathway for the treatment of desmoid tumors
Total Budget/Length: $130,000 over 2 years
DFC Funding: $41,600 CDN/year for 2 years (total $83,200)
Lay Abstract: Cancer cells rewire metabolic pathways and energy production to support the enhanced proliferation, invasion and resistance to treatment. We recently found a remarkable enrichment of genes involved in hexosamine biosynthesis pathway (one of the glucose metabolism pathways) in a subset of leiomyosarcoma (LMS). We demonstrated that expression of GFPT2, the key enzyme of the hexosamine biosynthesis pathway, is associated with poor clinical outcome in LMS. Following the study on this pathway in LMS, we performed a large-scale immunohistochemistry screening of more than 30 different types of soft tissue tumors and we discovered nearly universal expression of GFPT2 in desmoid type fibromatosis (DTF). Our high-throughput transcriptomic analysis of DTF and 9 other types of fibrotic lesions identified significant enrichment of multiple genes implicated in hexosamine biosynthesis pathway in DTF compared to the other types of fibrotic lesions. We also found a candidate effector of the activation of this pathway in DTF, which may have a pro-oncogenic role and may be associated with resistance to treatment.
Targeting hexosamine biosynthesis pathway was demonstrated to provide therapeutic benefit in a number of preclinical models of cancer. Thus, our preliminary findings provide a rationale to explore the potential of therapeutic targeting of the hexosamine biosynthesis pathway in DTF. The modulation of glucose metabolism through hexosamine biosynthesis pathway is a promising direction of research and our proposal offers the first functional exploration of the role of this pathway in DTF. Successful completion of this study will hopefully lead to novel therapeutic options for patients with DTF.
Principal Investigator: Kris Vleminckx PhD, Ghent University
Professional Title: Professor (PhD) UGent, Department of Biomedical Molecular Biology
Sponsoring Institution: Ghent University, Belgium
Proposal Title: Investigating EXH2 as a druggable mediator of immune cell exclusion in desmoid tumours
Total Budget/Length: $65,000 (year 2 of 2)
DFC Funding: $41,600 CDN
Below is a lay-friendly summary of the findings and impact (or potential impact) in desmoid research and/or patient care. At this moment we have set up several experiments to test our central hypothesis that a molecular therapy that we found previously to mediate desmoid tumor shrinkage in a genetic frog model, is doing this by the activation of an anti-tumor immune response. The readouts for these experiments will become available in the next coming months. If the working hypothesis is confirmed, this opens roads for treatment of desmoid tumor patients via immune checkpoint inhibition therapy.
The following grant was funded by DFC.
Principal Investigator: Rebecca Gladdy, Luninfeld-Tanenbaum Research Institute/Sinai Health,
Professional Title: Dr Rebecca Gladdy, Assistant Professor, General Surgery, Mount Sinai Hospital
Sponsoring Institution: Luninfeld Institute/Mount Sinai Toronto
Proposal Title: Clinical Outcomes and Genetic Analysis of Sarcoma
Sub-study: Desmoid tumor and pregnancy: effect of pregnancy on disease control and effect of diagnosis on pregnancy history. An international multicenter retrospective observational study:
Investigating EXH2 as a druggable mediator of immune cell exclusion in desmoid tumours
Total Budget/Length: $15,000 year 1 of 1
DFC Funding: $15,000 CDN
A significant proportion of female patients with a diagnosis of Desmoid Tumours (DT) have a recent pregnancy history and on the contrary, the diagnosis of DT is often made during gestation or shortly thereafter. Although some evidences suggest that Desmoid is modulated by hormonal signalling (i.e. estrogens), the role of specific signalling pathways is not well understood.
Understanding the behavior of desmoids during or after pregnancy is crucial to define the safest management of the tumor itself and of the pregnancy. Defining the impact of DT on any decision to interrupt or avoid pregnancy and on obstetrics risk is pivotal to early define potentially worrisome conditions. Moreover, analyzing the impact of DT on decisions regarding the pregnancy (and in turn fertility), we will be able to implement new tools assisting and counselling women with Desmoids.
There is a growing interest in defining potential risk of recurrence or progression during or after pregnancy and in identifying potential obstetrical risks and infertility rate of desmoid patients.
Defining the impact of pregnancy on diagnosis, progression and recurrence of DT will help defining the best therapeutical approach to fertile patients. If we are able to define potential risk factors for tumor progression, we could adequate the follow-up regimen and the therapeutic sequence. Understanding the effect of Desmoids on pregnancy will also better define the risk of pregnancy/delivery and the eventual desire to avoid pregnancy. Finally, defining the potentially detrimental psychological effect of DT diagnosis on pregnancy planning would help providing our patients with the adequate tools for counselling.