Diffuse intrinsic pontine glioma (DIPG) is a deadly pediatric brain cancer, and there is a dire need to develop new therapeutic strategies to improve the terrible outcomes for these patients. Looking at genes that are turned on or off in a cancer can be helpful to figure out what is causing cancer growth. While looking at genes that are turned on in DIPG, Dr. Tsai found a gene called FOXR2 that is turned on at very high levels in a subset of DIPGs. FOXR2 is usually turned off, and turning on FOXR2 makes tumors grow very quickly. FOXR2 is actually capable of turning on an entire set of genes that are called ETS transcription factors (TFs). This is surprising as these genes have never been shown to be activated in DIPGs. Others have shown that ETS TFs can turn on the MAPK signaling pathway. Dr. Tsai also has found that FOXR2 is able to activate MAPK signaling. The goal is to determine exactly how FOXR2 and ETS TFs cooperate together to turn on MAPK signaling to make DIPGs grow. This grant was awarded at Dana-Farber Cancer Institute and transferred to Children's Hospital of Los Angeles.

A portion of this grant is generously supported by Griffin's Guardians, a St. Baldrick's partner. Griffin's Guardians was created by the Engles in memory of their son, Griffin. Their mission is to provide support and financial assistance to children battling cancer in Central New York, raise awareness about pediatric cancer and provide funding for research.

Based on progress to date, Dr. Moghimi was awarded a new grant in 2023 to fund an additional year of this Scholar grant. In recent years, a very successful immunotherapy strategy to modify a patient's immune cells (called T-cells) to attack cancer has been developed for children with leukemia (cancer of blood cells). These modified immune cells are called Chimeric Antigen Receptor T cells (CAR-T cells). These CAR-T cells are very potent and do a better job than any chemotherapy at killing cancer. However, this life-saving tool has been available only to a small group of patients and for a handful of cancers. This is because most cancers don't have the targets those CAR-T cells aim for, or they have a target that can also be found on normal organs. As a result, these CAR-T cells could harm normal organs as collateral damage, a significant adverse effect of treatment that clinicians would want to avoid. In this proposal, Dr. Moghimi is striving to build the next generation of CAR-T cells that solely react to a combination of targets. These cells recognize a tumor only if they have both targets in sight and will not otherwise attack normal organs. CAR-T cells that operate based on a combination of two targets are more accurate than other targeting cells. Using this new generation of CAR-T cells, researchers would be able to significantly expand the availability of this powerful treatment to many more patients. Dr. Moghimi and colleagues will develop these special CAR-T cells for patients with Acute Myeloid Leukemia (AML), another common form of leukemia with a higher mortality rate for children. These results will provide pre-clinical evidence that could quickly translate to new clinical trials for children with relapsed AML through the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium, an international collaboration headquartered at CHLA.