Development of a Targeted Cancer Gene Therapy for Metastatic Uveal Melanoma
Abstract
Background: Uveal melanoma (UM) is the most common form of cancer in the adult eye. Despite existing eye saving treatments of primary UM, half of all patients will go on to develop metastatic disease. As such, it is likely that micrometastases are present in most at the time of diagnosis and UM should be treated as a systemic disease upon presentation. New prognostic tests have become available to accurately predict the likelihood of patients developing future metastatic disease. While this may provide comfort to those patients with a low chance of metastasis, it is a time bomb for the 50% of patients diagnosed with the aggressive form of the disease who may have to wait up to 20 years for the metastasis to form – and have no effective treatment options, once formed. Survival from metastatic UM (mUM) is dismal, with a mean survival of just 7 months and a 2-year survival of 8%. New treatments for cutaneous melanoma like immunotherapy and targeted chemotherapy have been shown to be ineffective in mUM. There are currently no effective therapeutic options for mUM. New treatment options that can specifically target mUM are urgently needed, and the cancer’s strong affinity for the liver represents a substantial therapeutic opportunity. During the formation of cancer, the cells undergo significant changes in the expression of many genes induced by genetic and epigenetic factors. The changes can range from overexpression of normal (e.g., TERT, Survivin) or mutated proteins (e.g., p53), reactivation of oncofetal proteins (usually only seen in the fetus) or changes in MicroRNAs (miRNA) expression (e.g., miR122 and miR199a). These changes, coupled with the inherent differences between cells from an eye and cells from the liver, allow us to develop novel treatments with the potential to differentiate between UM and the liver. To this end, we are proposing a novel targeted gene therapy system to specifically target and express toxic genes in metastatic UM. This system is based on adeno-associated virus (AAV), a virus which is not known to cause any human disease. Therapies based on AAV vectors have been approved by the Food and Drug Administration for use in humans. In this project we will develop AAV vectors with three distinct but complimentary targeting motifs. The first is to use tumor specific promoters, which limits expression to tumor cells with active promoters, i.e., UM and not normal liver cells. The second method utilizes differences in miRNA expression between UM and normal liver cells to limit the production of the toxic protein to the cancer. The third method utilizes the AAV itself, which has been screened for UM specificity. The combination of this triple-targeted vector allows for the expression of toxic proteins only in the metastatic cancer and not normal cells, thus providing an effective treatment for mUM particularly in the liver. Our proposal describes the development of a novel therapeutic option using targeted gene therapy with the potential to change the way mUM is currently treated. Although cancer gene therapy using AAV vectors is still in its early stages, our expertise in the technologies utilized in developing our triple-targeted gene therapy has allowed this work to reach a stage where there is a high probability of success, making this the perfect time to undertake this work. Importantly, the technology being developed in this study has utility not just in UM, but could also be translated to other cancers with a high metastatic potential to the liver, such as colorectal or pancreatic cancers and as such may be a proof of principle for the treatment of several cancer types. Focus Areas: This Fiscal Year 2021 Rare Cancers Research Program Concept Award focuses on a rare cancer (uveal melanoma) and addresses a need to identify novel therapeutic strategies for this cancer (Targeted gene therapy).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210789
Entities
People
- Jason Steel
Organizations
- Central Queensland University
- United States Army