“Doxorubicin Eluting Embolization for Desmoid Fibromatosis, Clinical trial.” Year 1 of 3

Lay Abstract

The present study is focused on evaluating the efficacy and safety of doxorubicin eluting
embolization (DEE) as a local therapy for Desmoid Fibromatosis (DF). DEE is
a technique that delivers doxorubicin to the tumor via micro partiles, minimizing
systemic toxicity. The study aims to build on previous reports of successful outcomes
of DEE in DF patients by standardizing the treatment protocol and evaluatng its
efficacy in a larger cohort of patients. The study also aims to address the limita.ons
in making DEE accessible to more patients, including the paucity of interventional
radiologists reporting on the technique and unfamiliarity of the technique among
referring clinicians. The study is designed to maximize the multidisciplinary
contributions of medical oncologists, surgeons, and interventional
radiologists from leading tertiary sarcoma centers to facilitate safe adoption of this
technique among practitioners.

Scientific Abstract

Doxorubicin is an effective treatment for Desmoid Fibromatosis but its use is limited
by systemic toxicity. Selective arterial Doxorubicin Eluting Embolization (DEE) can
be employed to achieve a high doxorubicin concentra.on in the target tissue while
maintaining low systemic exposure. In this technique, biocompatible microparticles
loaded with doxorubicin are released via catheter navigation into blood vessels that
supply desmoid tumors. These particles, which are typically 100-300 uM in diameter,
lodge within (embolize) the small arteries within a tumor and allow the doxorubicin to
penetrate via elution. We initially described this technique in a pediatric case series
in 2018 and in 2022 reported on a larger series of 24 patients treated with 52 DEE
sessions. The purpose of this study is to establish procedural, technical guidelines
for practicing interven.onal radiologists and for referring physicians to understand
which patients are potential candidates for DEE vs the other growing armamentarium
of systemic therapies and cryoablation.

Lay Abstract

Since the last consensus conference 2018 new drugs have come to patients and have been examined in prospective trials (f.e. nirogacestat, MTX/VIN vs pazopanib). An independent institute should analyze available data. Which medical treatments can be classified as active in desmoids and can a hierarchy of use of drugs be generated according to efficacy and toxicity. The latter is an important aspect from the patients’ view.

Scientific Abstract

Re-analysis of existing evidence (since 2018) with particular focus to results of recently conducted and published trials on medical treatment. A couple of recently conducted randomized trials and single-arm trials need to be evaluated with respect to efficacy versus toxicity of medical treatment

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.

Scientific Abstract

Cancer cells rewire metabolic pathways and energy production to support the enhanced proliferation, invasion and resistance to treatment. The three main glucose metabolism pathways that support growth of cancer cells are: a) the glycolysis pathway for energy production; b) the pentose phosphate pathway for biomass production; and c) the hexosamine biosynthesis pathway (HBP) for protein glycosylation. Activation of HBP leads to altered glycosylation of oncogenes, transcription factors and kinases in many types of cancer. These aberrations contribute to increased proliferation and survival of tumor cells, and are associated with resistance to treatment. Therapeutic targeting of GFPT2 (glutamine-fructose-6-phosphate transaminase 2, the first and rate limiting enzyme in HBP) and other components of HBP exhibits anti-tumorigenic effect and modulates sensitivity to chemo-, radio- and immunotherapy. Most of the studies of HBP up to date focused on carcinomas and the role of HPB in sarcoma has not been extensively explored. We recently reported a remarkable enrichment of genes involved in HBP in a subset of leiomyosarcoma (LMS) and demonstrated that expression of GFPT2 in LMS is associated with poor clinical outcome. We identified the c-Myc oncoprotein as a potential target of HPB that may be stabilized by aberrant glycosylation in LMS.

In this application, based on exciting unpublished preliminary results, we propose a new direction of research related to metabolic reprogramming and glycosylation in desmoid type fibromatosis (DTF). Our initial data indicates that HBP may be activated in the majority of DTF. Our transcriptomic analysis of a dataset composed of DTF and 9 other types of fibrotic lesions identified significant enrichment of multiple genes implicated in HBP in DTF compared to the other types of fibrotic lesions. We also found that ATF6 transcription factor may be a candidate effector of the activation of this pathway in DTF. The goals of this proposal are: 1) to thoroughly characterize expression of the components of HBP in DTF, 2) to study the effect of perturbations of HBP in DTF cell lines, and 3) to explore therapeutic targeting of HBP in preclinical models of DTF. In this study, we will characterize protein expression levels of HBP components in well-annotated tissue microarrays with specimens of primary and recurrent DTF from over 210 patients, and in 13 primary DTF cell lines. We will also perform knock out and knock down of selected enzymes of HBP in primary cell lines derived from desmoid tumors and we will study the effect of these perturbations on cell growth, invasive properties, transcriptional profile, proteomic profile, and post-translational modifications by glycosylation. We will also perform pharmacological inhibition of GFPT2 and other components of HBP in cell line models to study the potential therapeutic benefit of this strategy in DTF. Our study will provide new insights into metabolic reprogramming and mechanisms of tumorigenesis in DTF. Our study will also explore the potential of therapeutic targeting of HBP in DTF. The modulation of glucose metabolism through HBP, either alone or in combination with other treatment modalities, 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.

Summary

High-intensity focused ultrasound (HIFU) is a new way of treating desmoid tumors. It uses ultrasound waves to increase temperature and ablate tumors without surgery. If you have ever used a magnifying glass to burn a hole in a leaf, you have an idea of how this works. Instead of focusing light to heat up the leaf, HIFU focuses sound to heat up the tumor. Magnetic resonance imaging (MRI) is used with HIFU to target just the tumor cells, without affecting the surrounding normal tissues. There have been a few reports and studies that suggest HIFU is safe and effective. This study is the first prospective HiFU trial focused solely on desmoid tumors. Dr. Braat and team will be conducting a clinical trial based in The Netherlands to determine if HIFU is both safe and effective to treat desmoid tumors and leads to improved patient satisfaction. Over 2 years they will assess if HIFU-treated tumors shrink in response to HIFU in addition to several patient reported outcomes. If successful, this trial can lead the way for larger clinical trials in HIFU so that HIFU becomes more available for more patients who would benefit from this therapy.

Scientific Abstract

Background

Recently, magnetic resonance image-guided high intensity focused ultrasound (MR-HIFU) has emerged as a safe and effective treatment for control of desmoid tumors. MR-HIFU is a promising minimally invasive technique that uses focused ultrasound waves to thermally ablate tumors, while minimizing side effects to surrounding healthy tissues.

Aim/hypothesis

We hypothesize that desmoid tumor (DT) patients could benefit from treatment with MR-HIFU. The aim of this study is to assess efficacy, in terms of a newly developed personalized patient satisfaction score, of MR-HIFU as treatment modality for DT.

Plan of investigation

With this purpose, the plan is to set up a two-stage, open-label, single-arm, phase 2 prospective study. Adult patients with DT with failure of active surveillance for their current desmoid tumor are considered eligible for the study. Patients will undergo a MR-HIFU treatment procedure. Primary outcome of the trial will be the patient satisfaction rate 12 months after the completion of the MR-HIFU procedure(s). Secondary outcomes include the presence of non-perfused volume on MRI after the MR-HIFU procedure, change in tumor volume, the response rate according to the Response Evaluation Criteria in Solid Tumors version 1.1. (RECIST v.1.1), the number of patients who need a re-intervention, adverse events, pain scores, and health-related quality of life (HRQoL) in the first 12 months after treatment.

Expected outcome

The expected outcome is to have determined that it is both safe and effective to treat patients with DT with MR-HIFU, leading to improved patient satisfaction and thereby offering a new treatment strategy for desmoid patients. In addition, the expected outcome is to have determined that MR-HIFU will decrease tumor volume, thereby providing an insight into the effect of MR-HIFU on local tumor control.

Lay Abstract

Sorafenib is one of the most commonly used drugs in people with desmoid. Other than desmoid, it is used in metastatic (widespread) cancers like kidney cancer and thyroid cancers. The duration of treatment in these cancers is limited and also given the short life expectancy in these cancers, long term side effects of sorafenib on different body functions is not well known.

Other than this the current duration of treatment in desmoid is not known and is continued indefinitely. In smaller studies, sorafenib has been shown to affect thinking, heart functioning, fertility even with limited duration. Through this study we want to see how sorafenib affects these organs systematically. We will assess cardiac functions, vascular functions, cognitive functions and hormonal function and see the trend during the first year. It will be a stepping stone for any intervention that can reduce the chances of long term complications.

We will try to continue this study for 3 years.

Scientific Abstract

So far, sorafenib has been used in various advanced cancers with limited life expectancy and long term side effects involving cognition, cardiovascular and reproductive functions have rarely been looked at. Currently, the duration of sorafenib therapy in desmoid is not evidence based and it is continued indefinitely. In a study by Mulder et al, comprised of patients with GIST and RCC, the effects of VEGF inhibitors was larger on learning, memory and executive functions as compared to patients not on these drugs. (1). So far, no studies have been published on the effects of the vascular endothelial growth factor receptor (VEGFR) inhibitors on cognitive functioning in desmoid. Once the cognition function is delineated then further research can be done on using neuroprotective strategies.(2)

In a meta analysis by Dai et al, VEGFR inhibitors are also significantly associated with hyperlipidemia. Similarly, it has been recently shown that sorafenib acutely affects cardiac contractility by reducing S16 PLN phosphorylation, leading to reduced SR calcium content, CaT amplitude, and slowed cytosolic calcium removal (3). Coronary artery disease has been also been described in patients on sorafenib especially associated with patients with preexisting cardiovascular comorbidity.(4)

Though menstrual abnormalities are not reported commonly with TKIs but in our unpublished data (ongoing study), it is one of the most common complaints on long term use. In a report by Sanctis et al, an 18 year old girl developed reversible ovarian insufficiency on pazopanib (5). . There is only one study of 17 women with desmoid tumor addressing fertility preservation using IVF, of which only one was on Sorafenib therapy. The study reported very poor yield of oocytes in her first IVF cycle (2.7 (±1.3) which improved significantly after stopping Sorafenib 13.2 (±3.3) (P = 0.02). (6)

We have devised comprehensive screening strategies at various time points as shown in the table below with the budget justification. We want this to be a recurring project for the next 3 years. It will be a prospective study which will be enrolling patients with fibromatosis more than 18 years old and have been started on sorafenib within 2-3 months. A total of 50 patients will be recruited in around 1 year duration.

Methodology

It will be a prospective study which will be enrolling patients with fibromatosis more than 18 years old and are preferably newly diagnosed (drug naïve) or have been started on sorafenib within 2-3 months. A total of 50 patients will be recruited in around 1 year duration.

Lay Abstract

Desmoid-type fibromatosis (DTF) tumors are soft tissue tumors arising from the fibroblast populations of connective tissue resulting in locally aggressive fibromatosis. While noninvasive, chances of relapse are high. Currently FDA approved strategies for treating DTF are scarce. The Wnt-β-catenin pathway is the major driver of DTF. However, targeting this pathway could severely damage normal cellular functions. Our group has pioneered studies on the AP-1 transcription factor aka JUN driving DTF by interacting with β-catenin. Our recent studies demonstrate that JUN transcriptionally modulates the expression of a novel pro-fibrogenic molecule called CD63. CD63 is a cell surface protein that belongs to the tetraspanin family. Molecular investigations in DTF show that JUN increases CD63 expression thereby promoting cell growth and survival of primary patient derived DTF cells. Furthermore, genetic knock down of CD63 in DTF cells significantly inhibits growth both in-vitro and in animals. Using next generation sequencing and cell-based assays we show that CD63 is high in the fibroblasts of DTF patients correlating with JUN and β-catenin expression. Our studies also reveal that JUN in concert with β-catenin transcriptionally modulates CD63. Finally, we aim to use novel 3-D cell-based assays and mouse models to show that JUN, CD63 and β-catenin all work in concert to promote the fibrotic phenotype in long term assays. This proposal is aimed at the hypothesis that the JUN- β- catenin-CD63 link is essential for the onset and progression of desmoid lesions in patients. Altogether, this study focuses on key mechanisms underlying JUN regulation of CD63 in DTF and explores the promising potential of targeting CD63 as an immunotherapeutic target to treat DTF.

Scientific Abstract

The proposed research aims to elucidate the molecular mechanisms underlying desmoid tumor formation (DTF) and how this impacts the reversion of fibrosis observed in DTF patients. DTF tumors arise from fibrotic connective tissue which drive the onset of aggressive fibromatosis.

Current therapeutic modalities for DTF have solely focused on tumor monitoring, surgery, chemotherapy, and a few targeted therapeutics like sorafenib, pazopanib and nirogacestat but research on their mechanisms are still underway. However, targeting key signaling pathways like the WNT signaling pathway could have significant off-target and on-target effects that could be detrimental. This proposal investigates how the AP-1 transcription factor (aka JUN) works in concert with another key transcription factor β- catenin to drive the expression of a novel profibrogenic molecule called CD63 that is significantly elevated in desmoid tumor patients. Others and we have previously shown that JUN can promote the DTF phenotype via tumor survival and proliferation. Also, we have identified a novel molecule called CD63 to be significantly elevated in the cells of primary desmoid patients. Moreover, CD63 can be efficiently targeted using monoclonal antibody therapy with minimal to no side effects. As such, we will evaluate how JUN along with β- catenin mechanistically drives CD63 overexpression in DTF patients, how CD63 in turn promotes aggressive fibromatosis and what would be the most effective strategy to target CD63 for fibrosis reversal after onset of DTF. We expect that this work will provide knowledge pertinent towards understanding the underlying pathological mechanisms that promote fibrosis and contribute to aggressive DTF tumors ultimately providing a new avenue to develop a promising therapeutic to block tumor progression.

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 showed 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 multicenter Canadian retrospective study is to collect real world data to better guide physicians in managing these rare tumors.

Scientific Abstract

Desmoid tumors (DT) are locally aggressive neoplasms affecting predominantly young adults and are associated with considerable morbidity ranging from functional limb impairment, chronic opioid use, anxiety and depression and rarely mortality. Although a minority of DTs will undergo spontaneous remission throughout their disease course, a significant proportion of patients will require either surgery or systemic therapy. Over the last decades, a number of agents have shown some evidence of activity ranging from hormonal blockers like tamoxifen to chemotherapy like weekly methotrexate and vinblastine and doxorubicin and to targeted agents like imatinib. However, no convincing high level data was ever produced with these agents. Sorafenib and pazopanib, two protein kinase inhibitors, were the first drugs to have shown activity in randomized phase II and phase III trials. For sorafenib and pazopanib, the reported objective response rates were 33% and 37% respectively and the 6-month progression-free survival rates were 89% and 86%. Both drugs were well tolerated and associated commonly with rashes (73%), fatigue (67%), hypertension (55%), and diarrhea (51%). Although these new agents are now widely used for the treatment of DTs, there remains many unknowns. Duration of treatment is still ill defined. Outcomes of pediatric patients or patients who failed or stopped TKIs are unknown. Predicting which patients may respond to these novel therapies is still a challenge. The main objective of this multicenter Canadian retrospective study is to collect real world data to better guide physicians in managing these rare tumors. Overall response, 6-month and 12-month progression free rates and adverse events will be evaluated. Outcomes of patients stopping or failing TKIs will also be assessed.

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.

Scientific Abstract

Cancer cells rewire metabolic pathways and energy production to support the enhanced proliferation, invasion and resistance to treatment. The three main glucose metabolism pathways that support growth of cancer cells are: a) the glycolysis pathway for energy production; b) the pentose phosphate pathway for biomass production; and c) the hexosamine biosynthesis pathway (HBP) for protein glycosylation. Activation of HBP leads to altered glycosylation of oncogenes, transcription factors and kinases in many types of cancer. These aberrations contribute to increased proliferation and survival of tumor cells, and are associated with resistance to treatment. Therapeutic targeting of GFPT2 (glutamine-fructose-6-phosphate transaminase 2, the first and rate limiting enzyme in HBP) and other components of HBP exhibits anti-tumorigenic effect and modulates sensitivity to chemo-, radio- and immunotherapy. Most of the studies of HBP up to date focused on carcinomas and the role of HPB in sarcoma has not been extensively explored. We recently reported a remarkable enrichment of genes involved in HBP in a subset of leiomyosarcoma (LMS) and demonstrated that expression of GFPT2 in LMS is associated with poor clinical outcome. We identified the c-Myc oncoprotein as a potential target of HPB that may be stabilized by aberrant glycosylation in LMS.

In this application, based on exciting unpublished preliminary results, we propose a new direction of research related to metabolic reprogramming and glycosylation in desmoid type fibromatosis (DTF). Our initial data indicates that HBP may be activated in the majority of DTF. Our transcriptomic analysis of a dataset composed of DTF and 9 other types of fibrotic lesions identified significant enrichment of multiple genes implicated in HBP in DTF compared to the other types of fibrotic lesions. We also found that ATF6 transcription factor may be a candidate effector of the activation of this pathway in DTF. The goals of this proposal are: 1) to thoroughly characterize expression of the components of HBP in DTF, 2) to study the effect of perturbations of HBP in DTF cell lines, and 3) to explore therapeutic targeting of HBP in preclinical models of DTF. In this study, we will characterize protein expression levels of HBP components in well-annotated tissue microarrays with specimens of primary and recurrent DTF from over 210 patients, and in 13 primary DTF cell lines. We will also perform knock out and knock down of selected enzymes of HBP in primary cell lines derived from desmoid tumors and we will study the effect of these perturbations on cell growth, invasive properties, transcriptional profile, proteomic profile, and post-translational modifications by glycosylation. We will also perform pharmacological inhibition of GFPT2 and other components of HBP in cell line models to study the potential therapeutic benefit of this strategy in DTF. Our study will provide new insights into metabolic reprogramming and mechanisms of tumorigenesis in DTF. Our study will also explore the potential of therapeutic targeting of HBP in DTF. The modulation of glucose metabolism through HBP, either alone or in combination with other treatment modalities, 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.

Lay Abstract

Desmoid-type fibromatosis (DTF) tumors are soft tissue tumors arising from the fibroblast populations of connective tissue resulting in locally aggressive fibromatosis. While noninvasive, chances of relapse are high. Currently FDA approved strategies for treating DTF are scarce. The Wnt-β-catenin pathway is the major driver of DTF. However, targeting this pathway could severely damage normal cellular functions. Our group has pioneered studies on the AP-1 transcription factor aka JUN driving DTF by interacting with β-catenin. Our recent studies demonstrate that JUN transcriptionally modulates the expression of a novel pro-fibrogenic molecule called CD63. CD63 is a cell surface protein that belongs to the tetraspanin family. Molecular investigations in DTF show that JUN increases CD63 expression thereby promoting cell growth and survival of primary patient derived DTF cells. Furthermore, genetic knock down of CD63 in DTF cells significantly inhibits growth both in-vitro and in animals. Using next generation sequencing and cell-based assays we show that CD63 is high in the fibroblasts of DTF patients correlating with JUN and β-catenin expression. Our studies also reveal that JUN in concert with β-catenin transcriptionally modulates CD63. Finally, we aim to use novel 3-D cell-based assays and mouse models to show that JUN, CD63 and β-catenin all work in concert to promote the fibrotic phenotype in long term assays. This proposal is aimed at the hypothesis that the JUN- β- catenin-CD63 link is essential for the onset and progression of desmoid lesions in patients. Altogether, this study focuses on key mechanisms underlying JUN regulation of CD63 in DTF and explores the promising potential of targeting CD63 as an immunotherapeutic target to treat DTF.

Scientific Abstract

The proposed research aims to elucidate the molecular mechanisms underlying desmoid tumor formation (DTF) and how this impacts the reversion of fibrosis observed in DTF patients. DTF tumors arise from fibrotic connective tissue which drive the onset of aggressive fibromatosis.

Current therapeutic modalities for DTF have solely focused on tumor monitoring, surgery, chemotherapy, and a few targeted therapeutics like sorafenib, pazopanib and nirogacestat but research on their mechanisms are still underway. However, targeting key signaling pathways like the WNT signaling pathway could have significant off-target and on-target effects that could be detrimental. This proposal investigates how the AP-1 transcription factor (aka JUN) works in concert with another key transcription factor β- catenin to drive the expression of a novel profibrogenic molecule called CD63 that is significantly elevated in desmoid tumor patients. Others and we have previously shown that JUN can promote the DTF phenotype via tumor survival and proliferation. Also, we have identified a novel molecule called CD63 to be significantly elevated in the cells of primary desmoid patients. Moreover, CD63 can be efficiently targeted using monoclonal antibody therapy with minimal to no side effects. As such, we will evaluate how JUN along with β- catenin mechanistically drives CD63 overexpression in DTF patients, how CD63 in turn promotes aggressive fibromatosis and what would be the most effective strategy to target CD63 for fibrosis reversal after onset of DTF. We expect that this work will provide knowledge pertinent towards understanding the underlying pathological mechanisms that promote fibrosis and contribute to aggressive DTF tumors ultimately providing a new avenue to develop a promising therapeutic to block tumor progression.

Lay Abstract

Sorafenib is one of the most commonly used drugs in people with desmoid. Other than desmoid, it is used in metastatic (widespread) cancers like kidney cancer and thyroid cancers. The duration of treatment in these cancers is limited and also given the short life expectancy in these cancers, long term side effects of sorafenib on different body functions is not well known.

Other than this the current duration of treatment in desmoid is not known and is continued indefinitely. In smaller studies, sorafenib has been shown to affect thinking, heart functioning, fertility even with limited duration. Through this study we want to see how sorafenib affects these organs systematically. We will assess cardiac functions, vascular functions, cognitive functions and hormonal function and see the trend during the first year. It will be a stepping stone for any intervention that can reduce the chances of long term complications.

We will try to continue this study for 3 years.

Scientific Abstract

So far, sorafenib has been used in various advanced cancers with limited life expectancy and long term side effects involving cognition, cardiovascular and reproductive functions have rarely been looked at. Currently, the duration of sorafenib therapy in desmoid is not evidence based and it is continued indefinitely. In a study by Mulder et al, comprised of patients with GIST and RCC, the effects of VEGF inhibitors was larger on learning, memory and executive functions as compared to patients not on these drugs. (1). So far, no studies have been published on the effects of the vascular endothelial growth factor receptor (VEGFR) inhibitors on cognitive functioning in desmoid. Once the cognition function is delineated then further research can be done on using neuroprotective strategies.(2)

In a meta analysis by Dai et al, VEGFR inhibitors are also significantly associated with hyperlipidemia. Similarly, it has been recently shown that sorafenib acutely affects cardiac contractility by reducing S16 PLN phosphorylation, leading to reduced SR calcium content, CaT amplitude, and slowed cytosolic calcium removal (3). Coronary artery disease has been also been described in patients on sorafenib especially associated with patients with preexisting cardiovascular comorbidity.(4)

Though menstrual abnormalities are not reported commonly with TKIs but in our unpublished data (ongoing study), it is one of the most common complaints on long term use. In a report by Sanctis et al, an 18 year old girl developed reversible ovarian insufficiency on pazopanib (5). . There is only one study of 17 women with desmoid tumor addressing fertility preservation using IVF, of which only one was on Sorafenib therapy. The study reported very poor yield of oocytes in her first IVF cycle (2.7 (±1.3) which improved significantly after stopping Sorafenib 13.2 (±3.3) (P = 0.02). (6)

We have devised comprehensive screening strategies at various time points as shown in the table below with the budget justification. We want this to be a recurring project for the next 3 years. It will be a prospective study which will be enrolling patients with fibromatosis more than 18 years old and have been started on sorafenib within 2-3 months. A total of 50 patients will be recruited in around 1 year duration.

Methodology

It will be a prospective study which will be enrolling patients with fibromatosis more than 18 years old and are preferably newly diagnosed (drug naïve) or have been started on sorafenib within 2-3 months. A total of 50 patients will be recruited in around 1 year duration.

Summary

Immunotherapy is the process of activating a person’s own immune system to attack their cancer. It has been successful in some types of cancers, like melanoma and lung cancer, but little has been done in desmoid tumors. Dr. Gerlinde Wernig will investigate whether desmoid tumors express certain proteins that help it avoid the immune system. These proteins that help tumor cells avoid the immune system are called immune checkpoints and include CD47, PDL1, and CTLA4 (among others). If Dr. Wernig’s group finds these immune checkpoints are expressed on desmoid tumor cells, they will determine if desmoid tumors respond to certain drugs that block these proteins, called immune checkpoint inhibitors. This may lead the way for further research in immunotherapy in desmoid tumors, including possible trials with immunotherapies – several of which are already approved for other cancers.

Scientific Abstract

Desmoid-type fibromatosis (DTF) is a rare, low-grade, soft-tissue tumor affecting the extremities and the trunc. As DTF does not progress after diagnosis in most cases, no specific initial treatment is recommended. However, a minority of patients develop progressive DTF with debilitating and life-threatening complications. In these cases, therapies include chemotherapy, surgery, radiation, or targeted therapy. Immunotherapy either targets immune checkpoints, thereby increasing the efficiency of the adaptive immune system, or don’t-eat-me signals, thereby enhancing the phagocytosis of tumor cells through the innate immune system. Though immunotherapy has significantly increased survival in a variety of cancers, it has not been explored in DTF yet. This is why we propose to investigate whether immunotherapy, more specifically blocking CD47 as a don’t-eat-me-signal, as a potential therapy for DTF. To this end, we will first determine through ATAC Seq if CD47 and immune checkpoint regulatory proteins such as PDL1 are differentially regulated in DTF. Then, we will use a unique adaptive transfer model to explore whether CD47 blockade eliminates ectopic human DTF grafts under the kidney capsule of immunocompromised mice. These results will not only expand knowledge on how don’t-eat-me-signals and immune checkpoints are regulated in DTF but will also explore CD47 blockade as a new therapy for DTF.

Summary

In previous research funded by the DTRF, Dr. Kris Vleminckx has developed a desmoid tumor model in the frog Xenopus tropicalis. Desmoid tumors can suppress the ability of the immune system to attack it and the current project will investigate if tazemetostat can reverse this suppressive ability in their frog model. Tazemetostat is currently approved for use in epithelial sarcomas, but the mechanism in desmoid tumors is unknown. Dr. Vleminckx has found that the drug affects the WNT/β-catenin pathway, but that mechanism does not kill or decrease the tumor cells. However, it is possible that this drug is affecting the immune system and allowing the immune system to attack the tumor. If successful, this research may lead to combinations of therapies or new therapies that involve activating the immune system to attack tumor cells.

Scientific Abstract

Using a genetic CRISPR/Cas9 based desmoid tumor model in the frog Xenopus tropicalis we have identified the gene EZH2, which encodes a member of the polycomb repressive complex 2 and is thereby involved in epigenetic regulation, as a dependency factor for desmoid tumors. Furthermore, a four-week treatment of Xenopus tropicalis carrying established desmoid tumors with the EZH2 inhibitor Tazemetostat caused a significant reduction in desmoid tumor volume. At the moment, the mode of action of Tazemetostat in this anti-tumor response is unknown. Interestingly, we found that Tazemetostat reduces Wnt pathway activity in human desmoid cell cultures but does not have an overt effect on cell proliferation or cell death in vitro. Therefore, given the well-established fact that solid tumors in which the Wnt/β-catenin pathway is activated are immunologically cold and thereby insensitive to immune checkpoint inhibition, we postulate that the regression in desmoid tumor volume observed in the Xenopus model upon Tazemetostat treatment counters this immunosuppressive environment and allows the engagement of a natural anti-tumor immune response. We hypothesize that the reduced Wnt signaling activity induced by Tazemetostat alleviates the immune checkpoint controls and allows the occurrence of a T-cell mediated immune response towards the desmoid tumor. Using a range of genetic experiments in Xenopus tropicalis this hypothesis will be investigated.