Microenvironmental Regulation of Melanoma Brain Metastasis
Abstract
Melanoma is a cancer that arises in the pigment-producing cells of the skin called melanocytes. American military personnel are at an increased risk for melanoma compared to the general population. While curable if treated early, it can be fatal due to rapid spread throughout the body, especially to the brain. Melanoma brain metastases occur in up to 75% of patients with advanced disease and are associated with very poor prognosis with near 100% mortality. Patients with brain metastases who progress or fail to respond to systemic therapy are currently managed with stereotactic radiation and neurosurgery, as chemotherapy has little effect. As such, there is an urgent unmet clinical need for additional systemic therapies to prevent and treat brain metastases. To establish a tumor in the brain, melanoma needs to interact with the brain environment to support its growth and survival. Research suggests that melanoma in the brain is very different to melanoma elsewhere in the body and therefore specific therapies need to be developed. Clinically, this results in difficulties treating brain metastases while simultaneously controlling disease outside the brain. We currently lack a deep molecular understanding of melanoma brain metastases. Our proposal aims to identify novel mechanisms to stop disease progressing to the brain and to alter how the brain environment impacts tumor seeding, response to therapy, progression, and dormancy - a Fiscal Year 2021 Melanoma Research Program Focus Area. We have identified that the interaction between the tumor cells and the brain is a relationship that can be manipulated to prevent tumor establishment and improve current therapies. Our proposal (1) builds models mimicking the environment within the brain to understand how the interactions between melanoma cells and their surroundings drive tumor cell seeding, survival, and resistance to therapies, and (2) applies clinically relevant therapies to block these interactions, in addition to identifying targets for new drug treatments. Most preclinical models used to assess anti-cancer agents are based on static end-point assessments, addressing the response to therapy at the end. These models miss important information about how therapy actively affects interactions between tumor cells and their local environments in real time. We will combine our models, including a bioengineered brain-on-a-chip device and a new avian preclinical animal model with biosensors that report the target activity as we expose it to drug. This will provide us with a dynamic readout of drug response as the drug is being administered, allowing us to better understand the biology of melanoma in the brain and its response to therapies. Our novel approach is made possible by our world-class international, interdisciplinary team with expertise in cancer biology, neuroscience, vascular biology, radiation oncology, physics, and materials chemistry. This could put us in a position to better understand the disease, to better predict which melanomas spread to the brain, and to identify druggable targets to prevent melanoma surviving in the brain. In the short term, we aim to provide insight to clinical trial stratification and provide support for inclusion of patients with melanoma. In the long term, we aim to identify new druggable pathways for patients who currently have an extremely poor prognosis, with little to no effective treatment options.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210612
Entities
People
- Samantha J. Stehbens
Organizations
- United States Army
- University of Queensland