Research Grants Program

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.

Research Objectives:
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.

Research Objectives:
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.