Investigator: Ajaybabu Pobbati, PhD, Cleveland Clinic – Lerner Research Institute
In 2022, The EHE Foundation funded a grant to Dr. Pobbati for research that looks at a library of current FDA-approved drugs that act as TAZ-CAMTA1 (TC) or TEAD inhibitors, for use in EHE.
What does this mean for patients? This could mean a shorter path to an FDA-approved treatment for EHE, since these drugs have been tested and proven safe for other diseases.
Dr. Pobbati has provided a 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.