The projects featured below are the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center (GMTEC)’s current funding recipients.
Metabolic crosstalk between melanoma and its microenvironment
There have been astounding advances in the treatment of metastatic melanoma with both targeted therapy and immunotherapy, but unfortunately more than half of people with metastatic melanoma still die of the disease. Therefore, it is important to understand the mechanisms of melanoma metastasis. This wide-ranging effort will explore the role of cellular stress and immune responses on metastasis in melanoma. Researchers also will investigate how the melanoma microenvironment induces metabolic alterations within melanoma cells that directly facilitate cellular invasion and metastasis.
This is the first GMTEC award to include multiple projects. In addition, the research team has applied to the National Institutes of Health for a P01 grant related to this work.
Project 1: Molecular mechanisms, immune responses, and cancer cell metabolism
Santosha Vardhana and Craig Thompson
This project will explore the metabolic consequences of redox regulation and its effect on T cell function within the tumor. It aims to look at the connection between metabolic adaptation in the setting of chronic inflammation and the promotion of immune evasion and metastasis in melanoma. The researchers will examine the role of altered metabolism in promoting immune dysfunction in melanoma. They also seek to determine the contribution of exogenous fatty acids to altered melanoma-specific immune responses.
Project 2: Characterize the role of lipid uptake–induced ER stress in metastasis of melanoma
This project will examine the ability of melanoma cells to metabolize fat as an energy source despite BRAF inhibition. One tool in this research is transgenic zebrafish, which will be used to characterize the role of fat cells in the progression of melanoma. These models will also be used to assess the mechanism of lipid-mediated ER stress in melanoma invasion and study the effects that lipids have on immune cells within the tumor microenvironment. The project will also look at whether blocking SLC27A fatty acid transporter proteins has therapeutic potential, and may ultimately lead to clinical trials evaluating this approach.
Project 3: Enhancing immune-mediated control of melanoma metastasis by modulating glycolytic stress
This project will examine the LDH/lactate axis and the effect of lactate on immune suppression in melanoma. It aims to study the connection between lactate production and the anti-melanoma immune response. It will also investigate whether blocking lactate production can improve T cell responses against melanoma.
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.