The EHE Foundation aims to identify and support impactful research that expands our understanding of EHE and accelerates the development of treatments and a cure for EHE. The 2024 EHE Research Grants funding cycle is open. We invite researchers to submit an application and join in our global commitment to promote collaboration, information, and resource sharing among the EHE community including patients, clinicians, and researchers. For more information or to apply for a grant, download the EHE Research Grant Submission Guidelines.
|Letter of Intent Deadline
|March 31, 2024
|Notification to Submit a Full Application
|April 30, 2024
|Full Applications Deadline
|June 15, 2024
|September 30, 2024
This proposed research builds upon data generated from the grant awarded to Dr. Pobbati in 2022, entitled Repurposing an FDA-approved Drug for EHE Treatment. The project aims to further investigate and understand the potential to regulate TAZ-CAMTA1 (TC) using FDA-approved drugs.
Epithelioid hemangioendothelioma (EHE) is caused by an unusual chromosomal rearrangement that causes the abnormal joining of two genes, generating the cancer-causing TAZ(WWTR1)-CAMTA1 (TC) fusion gene, which is the defining feature of EHE. TC is predominantly found in the nucleus, and its nuclear location plays a key role in causing EHE. We performed a screen on EHE cells grown in dishes, using ~4000 compounds that included ~2000 FDA-approved drugs to identify those that regulate the location of TC within the cell and those that cause it to be unstable. We identified drugs that could drive TC out of the nucleus and ultimately destabilize it, causing it to degrade and disappear, and in this grant, we proposed experiments that will help provide a molecular understanding of this phenomenon. One of the potent drugs uncovered in our pilot study is FDA-approved and has already been shown to have a good safety profile. Ultimately, we want to evaluate whether it can be used to treat unresectable aggressive EHE.
This proposed research leverages EHE tissue and fluids donated to the EHE Biobank, a project of The EHE Foundation, to actively collaborate with researchers for the development of EHE disease models - an essential component for research and the development of treatments.
Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma that lacks effective therapies. This cancer is defined by chromosomal translocations leading to either a TAZ-CAMTA1 or YAP-TFE3 fusion protein. These fusion proteins evade regulation of the Hippo pathway, a series of serine/threonine kinases that regulate full length TAZ and YAP. A significant limitation in the field is the lack of human EHE cell lines or extended primary cell culture, leading to a gap in knowledge. Our long-term goal is to create a cell line or extended primary cell culture of EHE cells, as well as the protocol for how to create them with the community of EHE investigators to help develop more specific therapies. Our objective is to characterize these primary cells and determine the role of the TAZ-CAMTA1 fusion protein (or YAP-TFE3 protein) for various hallmarks of cancer in EHE cells.
Award Amount: $200,000 over a three-year project (plus an additional matching a $250,000 private, designated donation toward this research). Award Year: 2022
Research Goal: To reveal pathways that can be targeted with existing FDA-approved drugs to either eliminate EHE or prevent its growth.
1 - Identify druggable pathways that are required for TAZ-CAMTA1 activity and EHE growth/viability.
2 - Establish and optimize an EHE transplant model system in mice for testing therapeutic compounds.
3 - Develop multiplexed in vivo assays in mice and use them to test multiple therapeutic targets.
July 2023 Update: Dr. Lamar reports that they made significant progress in their first year of funding:
Shortly after the project was funded the first EHE cell lines were established by Dr. Brian Rubin. In collaboration with Dr. Rubin, we have been working with these cell lines and have completed the extensive characterization and optimization necessary to effectively use these cells in assays required for this project. We have also demonstrated that inhibition of TAZ-CAMTA1-TEAD activity blocks the growth of these cells, indicating that targeting TAZ-CAMTA, TEADs, or other pathways that regulate them is a good therapeutic approach for EHE.
In addition, we have established pre-clinical tumor models of EHE in mice using these cells. This was important as it will allow us to perform preclinical experiments mentioned above. With all optimizations nearly complete we are in the process of performing a small drug screen that has the potential to identify compounds that could block EHE cell growth, but also serves as a proof-of-concept experiment to demonstrate that our screening approach will work on a larger scale.
The drug screen is ongoing, but preliminary results suggest we have identified some compounds that block EHE cell growth. These drugs will be evaluated further and if they remain promising, we will test them in our pre-clinical mouse models of EHE. In addition, these results show that our screening approach works well so we are preparing to do the larger RNAi screen that we proposed.
December 2023 Update
In Dr. Lamar’s end-of-year update he writes, “we have made significant progress on this project over the initial 18 months of funding. In collaboration with Dr. Rubin, we have been working with the first EHE cell lines ever developed and have completed the extensive characterization and optimization necessary to effectively use these cells for this project.”
Once key assays were optimized, the Lamar Lab used these EHE cells to perform a drug screen aimed at identifying compounds that could block EHE cell viability. This drug screen revealed 17 drugs that reduce EHE cell viability without impacting the viability of normal cells. Of the 17 drugs identified, four of these drugs belong to a family of drugs that are safe and have minimal side effects in humans. Ongoing work is investigating the mechanism through which these drugs inhibit EHE cell viability.
Future work will include developing mouse models of EHE to test if these drugs can prevent EHE tumor growth and metastasis. If these tests prove that these drugs are effective in pre-clinical models of EHE, it will provide the rationale for a clinical trial to test if these drugs are effective in patients with aggressive EHE. Dr. Lamar notes a consideration that since these drugs have minimal side effects in humans, they may also provide an effective and safe alternative to the current “watch and wait” strategy available to patients with inoperable chronic or indolent EHE.
Award Amount: $65,000 Award Year: 2022
Research Goal: To identify an FDA-approved drug that can sequester TAZ-CAMTA1 (TC), TEAD, or both in the cytoplasm and inhibit tumorigenesis.
1 - Identify drugs that relocate TC and/or TEAD to the cytoplasm using a subcellular localization screen.
2 - Perform preclinical characterization of shortlisted drugs.
July, 2023 Update: Dr. Pobbati has provided a mid-year report on his team’s progress:
Epithelioid hemangioendothelioma (EHE) is caused by an unusual chromosomal rearrangement that causes the abnormal joining of two genes, generating the cancer-causing TAZ(WWTR1)-CAMTA1 (TC) fusion gene, which is the defining feature of EHE. TC is predominantly found in the nucleus, and its nuclear location plays a key role in causing EHE. We performed a screen on EHE cells grown in dishes using ~4000 compounds that included ~2000 FDA-approved drugs to identify those that regulate the location of TC within the cell and those that cause it to be unstable. We identified drugs that could drive TC out of the nucleus and ultimately destabilize it, causing it to degrade and disappear. Currently, experiments are being designed to understand the underlying reasons for this. One of the potent drugs uncovered in our study was FDA-approved and has already been shown to have a good safety profile. Ultimately, our aim is to evaluate whether it could be used to treat unresectable aggressive EHE.
Another aspect of our research is to understand why EHE has an indolent or aggressive course. We have EHE cells that grow in dishes that model aggressive disease, but not indolent or less aggressive disease. The EHE cell lines that we have developed facilitate robust hypothesis testing, as they can be easily manipulated using genetic and pharmacological tools, and indolent cell lines will complement mechanism-based studies and studies that uncover therapeutic vulnerabilities. We plan to introduce clinically relevant tumor suppressor genes into aggressive EHE cells to investigate the possibility of generating EHE cell models for indolent/less-aggressive EHE.
December 2023 Update
The grant completed in the fall of 2023. Dr. Pobbati shared in his final project report that they have identified a class of drugs as regulators of TC localization and stability. He writes, “when EHE cells were treated with these inhibitors, TC was mobilized into the cytoplasm and ultimately induced apoptosis (death of EHE cells).” Overall, approximately 4000 drugs or small molecules were screened to identify an FDA-approved drug as a potent inhibitor of TC. Future aims of this work seeks to further characterize the identified drug in mouse models of EHE. If successful, it will serve as a basis to initiate a clinical trial to test the efficacy of this drug in patients with aggressive EHE who have no effective treatment options.
We are delighted that Dr. Pobbati has generated these hopeful results the results, which served to support his subsequent 2023 EHE research grant application to further expand these findings. The EHE Foundation has granted the 2023 award and we look forward to the team’s updates in mid-2024.
Award Amount: $26,600 Award Year: 2022
Research Goal: To understand further how TAZ-CAMTA1 interferes with the DNA damage response and whether this interference represents a therapeutic vulnerability that can be exploited.
Research Objective: Test the druggability of the DNA damage response interference by TAZ-CAMTA1.
July, 2023: Dr. Kouskoff and her team have completed the work under this grant and have provided the following conclusion:
TAZ-CAMTA-1-expressing (TC) endothelial cells are resistant to apoptosis and displayed little sensitivity to the inhibitors tested in this project. This effect was particularly marked in TC high populations and when cells have been expressing TC for a long time. One potential explanation for this is that over time TC-expressing cells acquire further genetic mutations, allowing for rewiring around pathways targeted by the inhibitors and survival. Of the inhibitors investigated, navitoclax, a BCL2 inhibitor, holds the most promise, both alone and in combination. Further investigation is warranted to determine optimal concentrations and dosing strategies for selectively inducing cell death in TC-expressing endothelial cells. It would also be important to perform more biological repeats of the experiments detailed in this report, particularly as the results were inconclusive for some inhibitors. Moreover, it would be of interest to examine the efficacy of these inhibitors in other model systems, including in vivo.
Read more information in our blog post, The EHE Foundation Funds Fellowship Travel Grants.
Award Amount: $150,000 over a three-year project (US Foundation award of $120,000 in partnership with EHE Rare Cancer Foundation Australia award of $30,000); Award Year: 2021
Aim 1: Test Calmodulin represses TAZ-CAMTA1 activity and tumorigenic function.
Aim 2: Determine the mechanism of Calmodulin regulation of TAZ-CAMTA1.
Aim 3: Determine if Calcium-Calmodulin signaling represses TAZ-CAMTA1 in mouse EHE cells.
December 2023 Update
The EHE Foundation, in partnership with the EHE Rare Cancer Foundation Australia, awarded Dr. John Lamar a 3-year grant in 2021 to investigate if a protein called Calmodulin (CaM) can repress the oncogenic activity of the TAZ-CAMTA1 fusion protein that plays a causal role in more than 90% of all EHE.
The hypothesis is that CaM binds to the TAZ-CAMTA1 fusion protein and blocks its importation into the nucleus where it would normally bind to TEADs and promote the expression of other genes that are necessary for the survival and growth of EHE cells. Initially the project proposed to use fibroblasts expressing TAZ-CAMTA1 to study CaM because there were no EHE cell lines available. However, EHE cell lines have now been established and Lamar Lab has spent several months optimizing their use in all the critical assays necessary for this work.
The initial results reported using the EHE cell lines have found that CaM and TAZ-CAMTA1 co-localize in the cytoplasm, but not the nucleus, of EHE cells. This is consistent with their hypothesis that CaM binds to TAZ-CAMTA1 in the cytoplasm and prevents it from entering the nucleus. However, although CaM is expressed in all cells, the initial work suggests that the amount of CaM produced by EHE cells is not sufficient to prevent most of the TAZ-CAMTA1 from entering the nucleus. This is why CaM is not able to prevent EHE formation and growth in cells that have a TAZ-CAMTA1 fusion.
Dr. Lamar predicts that if they can increase CaM expression in EHE cells or treat EHE cells with a peptide that “mimics” CaM, it will reduce the amount of TAZ-CAMTA1 in the nucleus and inhibit its function.
Award Amount: $60,000 (US Foundation award of $52,500 in partnership with EHE Rare Cancer Foundation Australia award of $7,500); Award Year: 2021
Research Objectives: Aim 1: Investigate the transcriptional and epigenetic profile of EHE tumors. Aim 2: Establishing in vitro models of EHE to evaluate early steps of cellular transformation. Aim 3: Investigate the epigenetic landscape of cells expressing the fusion in various cellular contexts by comprehensive epigenome mapping. Aim 4: Developing in vivo models of fusion positive EHE.
Award Amount: $40,000 (US Foundation partnership with EHE Group funding); Award Year: 2021
Research Objectives: To assess 1) the profiles of circulating cytokines, hormones (and miRNAs), and ii) the ERα, Erβ and GPER expression and the YAP/TAZ activation in tumor tissues, as a function of the clinical course of the disease. To this end the analysis will be conducted on the whole study patient population compared to healthy controls, and by stratifying EHE patients who will enter the study in 3 subgroups according to disease behavior (non-growing disease, slow- growing disease, highly aggressive disease with evidence of pleural effusion and systemic symptoms), and 2) the identification and validation of novel biomarkers to inform patient management (prognosticators and predictors of response to medical agents) as well as potential therapeutic targets.
Award Amount: $10,000; Award Year: 2020
Project Overview: This project is initiated with the passion of EHE patient advocates, Lael Bellamy & Lynne Heckman Rabinowitz, to develop Foster’s mouse, a YAP-TFE3 genetically engineered mouse model (GEMM). Through generous gifts and contributions, Dr. Rubin will initiate the development of a YAP-TFE3 GEMM for EHE and also to provide insights into other cancer research. It is estimated that 90% of EHE tumors contain a WWTR1-CAMTA1 gene fusion, and the other 10% contain a YAP1-TFE3 gene fusion. This research will aim to further research in this very rare gene fusion.
Award Amount: $60,000; Award Year: 2020
Research Objectives: The ability to use serial blood-based monitoring to identify clinically relevant disease recurrence and/or progression should provide clinicians with a means by which to intervene when a true impact on survival is achievable. This research aims to develop and validate a highly specific cfDNA based assay to detect WWTR1-CAMTA1 and YAP1-TFE3 fusions in patients with a tissue biopsy confirmed diagnosis of EHE.
Award Amount: $20,000 (US Foundation partnership with EHE Group funding); Award Year: 2019
Research Objectives: This research aims to test the hypothesis that the TAZ-CAMTA1 fusion protein is subject to regulation by Hippo-pathway independent mechanisms that could be exploited to inhibit TAZ-CAMTA1 function and treat EHE. The research will test the hypothesis using the following aims: 1) identify regulators of the TAZ-CAMTA1 fusion protein and assess their therapeutic potential, and 2) establish model systems to assay TAZ-CAMTA1 function in in vitro and in vivo and use to test therapeutic potential of candidate TAZ-CAMTA1 regulators.
Award Amount: $120,000; Award Year: 2019
Research Objectives: A comprehensive study of EHE genetics and the tumor microenvironment. The study aims to map intra-tumoral molecular differences between various subtypes of EHE, as well as variations in immune cells infiltrating and surrounding EHE tumors. The objective of this research is to identify potential targets for various types of treatments including immunotherapy. Publications resulting from this grant include:
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