Targeting Acral Melanoma by Inducing TERT Degradation (ME190011)
Abstract
While targeted- and immune-therapies have revolutionized the treatment of melanoma, not all patients benefit from currently available therapies. Specifically, patients with rare but aggressive melanomas that develop in the hands, feet, or nails (collectively known as acral melanoma), respond poorly to current therapies. Therefore, effective treatments for acral melanoma patients are sorely needed. The overarching goal of this proposal is to develop a new class of drugs that induce degradation of a protein called TERT, which is essential for the survival of tumor cells, as a therapeutic approach for acral melanoma (ALM). Melanoma is one of the fastest growing tumor types in the US, with higher incidence for military personnel than for the general population. While acral melanoma affects all world populations, it is the most common type of melanoma in ethnic groups and often occurs in older patients. Since greater than 40% of the DoD personnel belong to racial and ethnic minority groups, a significant percentage of U.S. militaries and veterans are at risk for ALM. Additionally, injuries in the hands and feet have been reported to increase the risk of acral melanoma. Because military personnel are more susceptible to suffer injuries of the feet or hands due to intense physical activity, military personnel are vulnerable to ALM. Unfortunately, acral melanoma is often diagnosed at advanced stages, when tumors are generally more difficult to treat. Furthermore, drug targets for acral melanoma remain elusive and we do not have effective treatments for patients with this type of cancer. Our proposal is addressing this gap by developing a novel class of drugs to degrade a critical cancer target called TERT. TERT is a specialized protein whose canonical function is to extend and protect the ends of the chromosomes known as telomeres. Each time a cell divides, telomeres get shorter, leaving the ends of the chromosomes exposed and susceptible to damage. When telomeres get critically short, healthy cells become disabled and die. In contrast, cancer cells have evolved a mechanism to overexpress TERT, which protects their chromosomes, allowing them to become immortal, thereby facilitating tumor development. We are focusing on TERT because alterations in this gene are found in greater than 40% of ALM, indicating that TERT plays an important role in these tumors. Furthermore, TERT is an ideal target for cancer therapy, as it is highly expressed in tumors but silenced in most adult tissues. Therefore, TERT constitutes a compelling target for ALM. However, there are at this time no approved TERT-based anti-cancer therapies. Most approaches tested thus far, have focused on inhibiting the canonical activity of TERT and are associated with a long treatment period for efficacy. This lengthy period constitutes a potential disadvantage, as cancer cells can rapidly adapt and become drug resistant. Additionally, there is increasing evidence that TERT could have multiple roles contributing to oncogenesis. We have recently shown that depletion of TERT triggers rapid melanoma cell death. Thus, we posit that effective strategies blocking all TERT functions are required to achieve clinically significant antitumor responses. Our central hypothesis is that TERT constitutes a highly promising target for ALM. We postulate that strategies triggering TERT degradation will abolish all TERT functions and, therefore, will effectively eliminate the progression of this aggressive disease. Our overarching goal is to develop novel TERT degraders (T-deg), and establish their efficacy in ALM. To accomplish this, we are leveraging an emergent technology (a.k.a. PROTAC), which has great potential to destroy proteins regardless of their function. PROTACS induce protein degradation by bringing together the drug target and the cellular machinery that tags proteins for destruction. In contrast to conventional TERT inhibitors, which rely on blocking the canonical fun
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010356
Entities
People
- Jessie Villanueva
Organizations
- United States Army
- Wistar Institute