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.

Final Update:

Dr. Langenau’s CureSearch-funded work focused on the p53 protein (encoded by the TP53 gene), a critical tumor suppressor that helps control cell growth and prevent cancer but, when mutated or disrupted, can drive aggressive and treatment-resistant disease. Over the course of the project, Dr. Langenau and his team generated important new insights into how TP53 alterations contribute to poor outcomes in rhabdomyosarcoma (RMS). Through analysis of more than 600 patient tumor samples, they confirmed that TP53 mutations are strongly associated with worse prognosis. Overall, their findings challenged longstanding assumptions by showing that different types of TP53 mutations behave similarly and uniformly contribute to aggressive disease, refining how risk may be assessed in children with RMS. Importantly, the team also identified a previously unrecognized subgroup of high-risk RMS defined by co-occurring FGFR4 and TP53 alterations—an insight with immediate translational relevance, as therapies targeting FGFR4 are already emerging and could be applied to this particularly aggressive subset of patients.

Building on these discoveries, the team focused on identifying promising therapeutic strategies to overcome treatment resistance, prioritizing agents that are already FDA-approved or in pediatric clinical trials to help shorten the path from discovery to patient benefit. They demonstrated that the combination of olaparib, an FDA-approved targeted therapy, and temozolomide, a commonly used chemotherapy, effectively suppresses tumor growth across RMS models, regardless of TP53 status. Importantly, they showed that tumors relapsing after this treatment could be re-sensitized using alpelisib, a drug already in pediatric clinical trials, highlighting a clear path toward clinical translation. In parallel, the team identified another high-risk genetic change, the MYOD1L122R mutation, and discovered a promising new way to target these aggressive tumors using ozuriftamab vedotin, an antibody-drug conjugate currently being tested in clinical trials. Together, this work expands the pipeline of targeted treatment options, advances more clinically relevant approaches, and lays the groundwork for bringing safer, more effective therapies to children with RMS.

Research Update June 2025:

Dr. Langenau and his collaborator Dr. Linardic are making steady progress in developing new treatment strategies for children with rhabdomyosarcoma. In recent months, they completed studies in mice to test whether turning off a protein called MEST—known to block the body’s natural cancer-fighting gene, p53—can slow tumor growth. They are now analyzing the results to see how the tumors responded. In parallel, they have successfully delivered new, AI-designed molecules that help stabilize p53 in cancer cells and are testing which ones work best. Future experiments will explore whether combining this approach with chemotherapy makes treatment even more effective. This work could lead to safer, more targeted therapies for children facing this aggressive disease.

Research Update December 2024:

Dr. Langenau’s award is currently in a no-cost extension to allow for his collaborator, Dr. Corinne Linardic, to complete experiments exploring ways to target a genetic regulator of the p53 protein in rhabdomyosarcoma (RMS). Her team has identified a protein, MEST, that suppresses p53 activity and promotes metastasis in certain RMS cells. They are now testing how blocking this protein, alongside chemotherapy, affects RMS cells. Additionally, they are working with a collaborator using artificial intelligence to design molecules that stabilize p53, which will be combined with chemotherapy and radiation in future experiments. These efforts aim to uncover new treatment strategies for improving outcomes in children 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