About the Grohar Laboratory

AddtoAny
Share:

WATCH THIS PAGE

Subscribe to be notified of changes or updates to this page.

8 + 4 =
Solve this simple math problem and enter the result. E.g. for 1+3, enter 4.

The fundamental goal of the Grohar laboratory is to impact disease outcomes. Despite the improvements in survival in localized Ewing sarcoma, there is a tremendous need to better understand and impact high-risk subtypes of patients including relapsed and metastatic disease. In addition, the therapy required to achieve favorable outcomes for localized Ewing sarcoma is associated with significant side effects. Therefore, there is a clear need for more effective and less toxic therapies for Ewing sarcoma. This situation is mirrored in a number of other pediatric solid tumor types thus reflecting a need to better understand high-risk disease on a fundamental molecular level. This will help us answer why we have not achieved better outcomes in these patients, what makes these patients different and how to effectively improve the translation of new therapies to the clinic.

Our lab seeks to develop and translate molecular targeted therapies focused on the defining molecular lesion of the tumor. In many solid tumors, this driver oncogene is often a challenging or difficult drug target. Therefore, our work spans the entire drug development process from discovery to clinical trial. We employ discovery science to identify novel approaches, compounds and targets. We then use mechanistic pharmacology to better understand the mechanism of action for these compounds. Finally, we develop clinical trials with correlative biology designed to more efficiently translate these therapies to patients and better understand the biology of high-risk disease.

Discovery Science

We use unbiased siRNA and small molecule screening to identify novel compounds and targets. Additionally, we use screening approaches to ask biological questions in an unbiased fashion to identify highly effective inhibitors and then understand underlying mechanisms. These studies have recently yielded novel drug targets and led us to studies in tumors driven by mutations related to EWS-FLI1.

Mechanistic Pharmacology

We have identified a number of candidate compounds that inhibit the EWS-FLI1 transcriptional program. Additionally, we have characterized the mechanism of trabectedin and analogs and are using the mechanistic information to launch a clinical trial evaluating this compound in the clinic on a schedule designed to inhibit and sustain inhibition of EWS-FLI1. Future work is focused on second and third generation analogs including lurbinectedin. We are further dissecting the mechanism of action with the hope of identifying additional vulnerabilities. We employ a similar approach to understand the mechanism of mithramycin and its second-generation analog EC-8042. Finally, we are extending these findings to other tumor driven by related transcription factors and the associated chromatin remodeling complex.

Clinical/Translational Studies

Our current clinical study is a multi-center phase I study evaluating trabectedin in combination with low-dose irinotecan on a dose and schedule designed to achieve and sustain suppression of EWS-FLI1 in patients. The study features significant correlative biology that will aid our preclinical studies. In addition, we employ 18F-FLT PET imaging as a biomarker that we have reported reflects EWS-FLI1 activity in Ewing sarcoma cells. This study will provide tissue and resources for our correlative biology and important collaborations and be the basis for future studies translating our laboratory findings to patients.

Lear more about our research