“To see the early effect of sorafenib on cognition, cardiovascular and reproductive functions in patients with fibromatosis.” Year 2 of 3

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 tumors consist of both tumor and non-tumor cells growing together. It remains unknown how the proportions and types of cells, or the interactions between them, affect the clinical behavior of a tumor. Advances in technologies called single-nuclei or single-cell RNA sequencing (sn/sc-RNAseq) now enable us to quantify the level of expression of genes in individual cells within the same tissue to compare their biological activity. These technologies have enabled significant advancement in our understanding of the behavior of other cancers. However, in desmoid tumors, we encounter a major challenge: the desmoid cells appear very similar to most of the non-tumor cells in the same area. Still, the most distinguishing feature of desmoid cells is the fact they carry a mutation in either the CTNNB1 gene or the APC gene. In this project, we propose to build a team that will work together to improve upon sn/sc-RNAseq technology by also sequencing the CTNNB1 or APC genes at the single-cell level. We will utilize this improved technology on tissues stored at the Dana-Farber Cancer Institute BioBank for desmoid tumors. We propose to combine this molecular information with clinical histories to understand the differences in gene activities between desmoid and non-desmoid cells in the same tissue and across different patients with different clinical behaviors. If successful, our study’s results will help answer whether gene activity levels can relate to spontaneous regression, and if so, which aspects of unique desmoid biology would be promising to pursue in future validation experiments.

Scientific Abstract

Desmoid tumors are fibroblastic neoplasms with differential clinical behavior often present as CTNNB1 or APC mutant cells intermixed with non-mutant cells. It remains unknown whether the cellular composition, or tumor-stromal interaction, can be used to infer tumor progression, therapeutic response, or spontaneous regression. While single-cell atlases have enabled valuable insights into the biology of many epithelial cancers, mesenchymal tumors, desmoid tumors in particular, are challenging to study because current references cannot distinguish between mutant and non-mutant fibroblasts. Since most patients present with CTNNB1 or APC mutations, we hypothesize that spontaneous regression can be detected by the transcriptional composition of desmoid tumors. We aim to test this hypothesis by concurrent genotyping of single cells to enable in sc/sn-RNAseq experiments. Here we propose to form a team of scientists and clinicians to study the clinical history of our biobank of 75 patients who donated tissues to identify cases of spontaneous regression, stable disease, and progression. Based on clinical history and onco-panel sequencing we will then nominate samples for parallel single-cell/nuclei genotyping and transcriptomics. We will then analyze the results to identify differentially expressed genes and pathways related to mutation status and clinical history. Preliminary data from 3 samples (2 tumors, and 1 adjacent normal) demonstrate the feasibility of our sequencing approach. If successful, expanding to a full project will create the first genotyped, clinically annotated single-cell reference of desmoid tumors.

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

Update to Global Consensus Paper

In June 2024, a revision to the Global Consensus Paper on desmoid tumor management was published thanks to the hard work and collaboration of an international group of physicians, scientists, and patient advocates (collectively known as “The Desmoid Tumor Working Group”). Peter Hohenberger, MD, PhD, Bernd Kasper, MD, PhD, and Alessandro Gronchi, MD, also DTRF Advisory Board members, led the group on this project.

Please note: Currently, the updated paper is only accessible with a subscription through JAMA Oncology. After one year, a full version will be publicly available. Patient guidelines are being developed, and we’re hopeful they will be published by early 2025, at which point we will make ammendments to the rest of this page to reflect this update. 

Read Updated Global Consensus Paper (2024)

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.