The Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center is pleased to have funded the following MSK investigators and specific metastasis-related projects and resource acquisitions.
Identifying novel drugs that inhibit aRMS metastasis.
The most common pediatric soft tissue sarcoma is rhabdomyosarcoma (RMS), representing 3 to 5 percent of all childhood cancers. Alveolar RMS (aRMS) is its most aggressive form and is associated with expression of PAX3- or PAX7-FOXO1 fusion oncoproteins. Although successive clinical trials have improved survival rates for RMS patients, the outcome with standard treatment for those patients with metastatic or recurrent disease remains bleak. (The five-year survival rate is less than 20 percent.) Moreover, within the last 30 years, there have been no significant changes in treatment, and no precision treatments exist. Hence, there is a critical need to investigate RMS metastasis and to identify novel therapeutic agents for its treatment. This is the goal of the Baylies lab’s work.
With funding from MTECH, the Baylies lab has identified 17 FDA-approved or in-trial drugs that target aRMS metastasis. These drugs, combined with a novel, ongoing screen in a Drosophila aRMS model, reveal 11 pathways essential for disease development. The activity of eight of the identified drugs that affect the RAS-MAPK, PI3K-AKT, and NFkB signaling pathways has been confirmed in this in vivo model. Importantly, the Baylies lab has identified three combinations of these drugs that eliminate or significantly reduce the metastatic potential of aRMS.
Based on these and published data, the Baylies lab is testing the FDA-approved/in-trial drugs that target RAS-MAPK, PI3K-AKT, and NFkB for validation and further characterization in human RMS tumor cell lines and in an aRMS ‘metastasis’ xenograft model. For the human tumor cell lines, the Baylies lab has developed a high throughput, image-based approach in collaboration with Andrew Cohen at Drexel University to assess tumor cell behaviors upon drug treatment (single and combinatorial treatment). The Baylies lab has now identified several FDA-approved/in-trial drugs and drug combinations that preferentially affect different aspects of human metastatic tumor cell behavior, including adhesion, migration, proliferation, or survival. The Baylies lab is now examining these drug combinations in aRMS xenograft models that reproduce aspects of the metastatic process, including survival in the blood stream, extravasion, colonization of different tissue sites, and proliferation at these sites. These experiments provide the critical next step toward patient treatment. Successful completion of these experiments will provide new precision therapeutic agents and regimes for testing in the clinic.
Investigation of the Microenvironmental Transcriptome in Breast to Brain Metastasis.
Role of ESR1 Mutation in Breast Cancer Metastases
Scott W. Lowe
Dissecting the interactions between Smad4 and p53 inactivation in pancreatic cancer metastasis
Strip1 and STRIPAK complexes in cell migration and metastasis
Timothy A. Chan
Large-Scale Analysis and Clinical Application of the Breast Cancer Metastasis Epigenome
Nai-Kong V. Cheung
Genetic Analyses of Secondary CNS Metastases in Neuroblastoma (NB)
Identifying Clinical Tools to Detect SRC as a Critical Moderator of Bone Metastasis Latency in Women with ER Positive
Functional Genomics Analysis of Tumor Dormancy at Metastatic Sites