Mechanisms of UV-Induced Melanoma Initiation
Abstract
Our proposal addresses the overarching challenges to “redefine the concept of prevention” and to “prevent melanoma earlier in the disease cycle thus preventing metastasis.” We do so by addressing two Focus Areas: (1) Determining how UV exposure instigates melanoma initiation from moles. (2) Proposing novel strategies for prevention by inhibiting UV-induced melanoma initiation. There is an undeniable connection between exposure to ultraviolet (UV) light, such as sunlight or tanning beds, and the formation of moles. Similarly, there is an undeniable connection between exposure to UV light and the onset of melanoma. If fact, about 30%-50% of melanomas arise from moles. On the other hand, 99.9995% of moles will never become melanoma. Both moles and melanoma come from the same type of cell, and both contain the same change to their genome – so what makes them different? In this proposal, we seek to understand the difference between moles that will become melanomas and those that are stable for the lifetime of a patient, and to determine exactly what role UV exposure plays in increasing the rate of melanoma. We argue that with a thorough understanding of how UV causes melanoma formation, we can meet our objectives which are: (i) To identify clinically approved compounds that decrease the risk that a nevus will transform and (ii) To identify molecules that allow us to determine which moles are more likely to become melanoma, and which are stable. Redefining Prevention The concept of melanoma prevention usually refers to one of two critically important practices: either limiting UV exposure in the first place (promote sunscreen use or shade, change sun-seeking behavior, discourage tanning beds) or identifying melanomas soon after they form (routine dermatology visits, self-examination, teledermatology). If the only role that UV played in inducing melanoma was damaging the DNA of cells, then melanoma prevention is limited to these practices. However, in our proposal, we provide substantial published and preliminary evidence that UV-induced DNA damage is not the only way, and possibly not even the predominant way, that UV exposure induces melanoma. Completely independent of DNA damage, UV exposure changes how cells behave through altering two important biological pathways. Specifically, it causes cells to be more likely to initiate melanoma. Importantly, we have tools for both interrupting these biological pathways using clinically approved drugs and detecting when cells have changed their behavior. This opens a window of opportunity that redefines melanoma prevention. Instead of being limited to blocking UV or intervening only after a mole has already become a melanoma, we propose to develop methods that reduce the risk that cells exposed to UV will become melanoma and to identify moles that have are more likely to become melanoma, but have not done so yet. In doing so, we will be able to prevent primary melanoma from forming. Since a melanoma prevented is a melanoma cured, these results would benefit any future would-be melanoma patient. The reason we are able to conduct our proposed investigation is our toolbox. The majority of melanoma research focuses only on those cells that have already become melanoma, which misses this window of opportunity. We have three systems that allow us to study precursor cells, like the cells in a mole, prior to becoming melanoma. Our experimental systems include the single most relevant system – the human mole itself – which we have significant experience studying. Although we enroll patients from our clinic to collect the tissue for these studies, we are not conducting a clinical trial. Instead, we expect that by the end of this funding period: (1) We will have identified and validated in pre-clinical models compounds for preventing UV-induced melanoma initiation from moles. These results would then serve as the basis for a clinical trial to determine the efficacy for pre
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jun 29, 2021
- Source ID
- W81XWH2010528
Entities
People
- Douglas Grossman
Organizations
- United States Army
- University of Utah