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.

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 immune suppressive 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.

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 trunk. 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.