Preventing Relapse by Minimal Residual Melanoma in an Environment of Reduced Cellular Heterogeneity
Abstract
Melanoma causes the majority of skin cancer-related deaths, and its incidence is on the rise. Melanoma is resistant to most traditional chemotherapies, but advances in targeted approaches have improved the lifespan for many patients. Unfortunately, despite an absence of tumor mass following targeted therapy, treatment cessation often eventually results in melanoma relapse and regrowth. This can be due to small populations of drug-tolerant cells, called minimal residual disease (MRD), that evade treatment and remain undetected. Research directed at understanding MRD in melanoma is an MRP Focus Area, and our specific interest is to prevent melanoma MRD cells from establishing themselves, a relatively unexplored topic. Despite the lack of understanding of this subject, identifying ways to prevent MRD represents a potentially transformative avenue to change the incidence of melanoma relapse and patient mortality. Importantly, this line of research is consistent with the MRP Challenge Statement to redefine prevention in new ways, such as in the context of MRD. We recently developed a method to precisely induce melanoma development in a mouse model. With this, it is possible to learn how melanoma develops, on a cellular and molecular level, from origin cells. Insight into these early stages of melanoma tumorigenesis is limited, since this process cannot be recapitulated in cell culture studies, and because patients are usually diagnosed when melanomas are at an advanced stage of development. Studies from our lab have also shown that mutant melanocyte stem cells, which normally create melanin-generating pigment cells, can be an origin cell for melanoma. These origin cells possess traits that are also found in melanoma MRD cells, as well as in other types of cancers. These traits, common to both origin and MRD cells, include absence of detection from the immune system and the ability to stop or slow down cell division. Both qualities can contribute to evasion of elimination by targeted therapy. It is the central objective of this proposal to identify cells with these MRD characteristics at the earliest stages of melanoma formation, and to experimentally alter and/or exploit these traits to determine if this results in a decrease in MRD. Furthermore, by re-engaging detection of melanoma origin cells with the immune system and inducing cell division, data will be generated on whether these strategies can also increase the duration to melanoma relapse upon targeted therapy cessation, or eliminate recurrence altogether. It is the ultimate goal of this research project to translate these findings to human patients to generate new strategies to prevent MRD cells from persisting and thus, decrease the incidence of melanoma relapse and progression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110434
Entities
People
- Andrew Dickson White
Organizations
- Cornell University
- United States Army