DAVID LANGENAU, PhD

Massachusetts General Hospital

in collaboration with Duke University School of Medicine, The Hospital for Sick Children and the National Institutes of Health

CureSearch Acceleration Initiative Award: 2022-2025

Focus: Rhabdomyosarcoma

Project title: Targeting p53 in childhood rhabdomyosarcoma

My laboratory uses zebrafish genetic models, human cell lines, and patient derived xenografts to study pediatric cancer, most notably for this application, rhabdomyosarcoma. We have focused on 1) developing high-throughput cell transplantation approaches to uncover self-renewal mechanisms in both leukemia and rhabdomyosarcoma and 2) imaging self-renewal mechanisms directly within normal muscle, rhabdomyosarcoma, and other cancers. Our group has also 3) pioneered the use of adult immune compromised zebrafish for efficient engraftment of allogeneic and xenograft fluorescent-labeled cells into adult recipient fish, most notably to visualize tumor-propagating cells, invasion, and metastasis in ERMS and to preclinically model therapy responses in vivo.

Our work has detailed the remarkable conservation of molecular mechanisms in zebrafish, mouse, and human RMS and discovered novel biology underlying the human disease, including identifying roles for P53 loss in driving FN-RMS growth and metastasis. My laboratory also commonly extends our basic biology findings into patient tissues and clinical applications. For example, we have recently made the finding that a large fraction of human RMS are efficacy killed following combination Olaparib and temozolomide therapy (OT), leading to clinical trial evaluation of this combination for RMS patients at MGH and Dana-Farber Cancer Institute in Boston (NCT01858168). Work in this application will define new therapies that target aggressive Tp53 RMS and test their efficacy in our PDX mouse models available in the laboratory.

Collaborative Team

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence. This cancer forms in skeletal muscle tissue or sometimes hollow organs, such as the bladder or uterus, and can spread from where it started to other areas, including lungs and lymph nodes, making treatment and recovery more difficult. While it can occur at any age, it most often affects children and adolescents with more than 350 pediatric cases diagnosed annually in the U.S. Despite decades of study, the standard of care for RMS remains a chemotherapy regimen developed in the 1970s. Associated toxicities include bone marrow suppression, infection, liver damage, cardiotoxicity, and decreased kidney function. Long-term survival for high-risk RMS has remained less than 30% for over 40 years.

David Langenau, PhD, is a CureSearch Acceleration Initiative Awardee conducting research at Massachusetts General Hospital. TP53 is a transcription factor, the mutation of which is thought to be critical to the growth of a wide variety of cancers. TP53 mutations are associated with poor outcome in several pediatric cancers including choroid plexus carcinoma, osteosarcoma, medulloblastoma and RMS. For decades academic and industry partners have been investigating the clinical and phenotypic consequences of TP53 mutations, and druggability of p53, largely in adult cancers. However, because it is a transcription factor, p53 has been difficult to pharmacologically target. Dr. Langenau and his colleagues will test novel therapeutics that reactivate p53 protein function for their ability to restore treatment sensitivity in RMS. By identifying p53 stabilizing therapies that synergize with chemo-and radiation therapies in p53-mutant RMS, they aim to develop a combination therapy that requires less chemotherapy and radiation, reducing treatment-related toxicities, and improving outcomes for patients with RMS.

Research Update April 2024:

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence and the long-term survival for high-risk groups has remained <30% for over 40 years, despite decades of research devoted to studying RMS. Dr. Langenau is researching one of the most well-known tumor suppressors in cancer, p53, which has been shown to become mutated or functionally disrupted in many cancers, including RMS. To date, Dr. Langenau has demonstrated that a mutation in p53 is associated with poor outcomes in kids with RMS, discovered a new gene association for which he plans to develop novel therapies, and discovered that a new therapy currently in clinical trials at Massachusetts General Hospital (MGH) and Dana Farber Cancer Institute (DFCI) is likely to be effective against the aggressive P53 mutant tumors.

Additionally, Dr. Langenau and his team are developing new drug combinations to kill RMS tumors that relapse and become resistant to chemotherapy, irrespective of their p53 status, and are exploring a second therapy combination that will work in enhancing killing of tumor cells after irradiation.

“We are grateful to CureSearch for funding this consortium grant focused on developing new understanding and cures for aggressive pediatric muscle cancers - commonly called rhabdomyosarcoma.”

- David Langenau, PhD

DAVID LANGENAU, PhD – ACCELERATION INITIATIVE – RHABDOMYOSARCOMAma