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This AAV vector treatment reduces the oncogenic effect of overexpressed thymidylate synthase to inhibit the development of pancreatic neuroendocrine tumors. Each year doctors diagnose about 1,000 people in the United States with pancreatic neuroendocrine tumors (PanNET), which account for about 3 to 5 percent of all pancreatic cancer. Though incidences of pancreatic neuroendocrine tumors continue to increase, few therapeutic options are available. The lack of animal models suitable to represent the human disease limits the development and testing of treatments. Elevated levels of thymidylate synthase (TS) accelerate tumor growth. These high levels correlate with poor prognoses and low overall survival rates of pancreatic neuroendocrine cancer patients.
Researchers at the University of Florida have developed an adeno-associated virus (AAV) particle vector that delivers and expresses TS-inhibiting small hairpin RNA (shRNA) into pancreatic islet cells. This treatment can reduce thymidylate synthase levels and incorporate within active pancreatic cancer treatment to inhibit tumor development and increase patient survival rates.
Cancer treatment that delays pancreatic neuroendocrine tumor growth by delivering shRNA directly to pancreatic islet cells
This treatment employs an AAV-TS vector that specifically targets pancreatic islet cells. The vector contains small hairpin RNA (shRNA) molecules and releases them into identified pancreatic islet cells. This reduces thymidylate synthase (TS) levels, significantly decreasing the progression of pancreatic neuroendocrine tumors (PanNETs). TS acts as a biomarker and therapeutic target. Although TS plays a central role in DNA synthesis/repair and is essential for cell proliferation, high levels of TS correlate strongly with tumorigenesis, poor therapeutic outcomes, and low overall survival rates in cancer patients. A mouse with an hTS/Men1 (-/-) allele established a model to replicate the human disease of PanNET to test how the interfering RNA targeted the TS.
These potential anticancer compounds offer an effective treatment that is less likely to cause resistance and recurrence of cancer and is less toxic to normal tissues than available chemotherapeutic agents. Thymidylate synthase inhibitors are a class of antineoplastic agents widely used in the clinical treatment of gastrointestinal, breast, ovarian and other cancers. While thymidylate synthase is essential for DNA biosynthesis and normal cell reproduction, the enzyme’s overexpression has been associated with a wide range of human cancers. Chemotherapy agent 5-flourouacil targets overexpression of thymidylate synthase and has some success in prolonging the survival of patients with colorectal, breast, and lung cancer, but it has been strongly associated with induction of thymidylate synthase expression that results in resistance to treatment and recurrence of cancer. Researchers at the University of Florida have discovered a strategy that takes advantage of high thymidylate synthase subunit cooperativity and used it to identify small allosteric inhibitors that will freeze the dimer structure and inhibit enzymatic activity.
Anticancer compounds that employ small molecules to inhibit growth of tumor cells
Thymidylate synthase is a key enzyme in synthesis of 2-deoxythymidine-5-monophosphate, an essential precursor for DNA biosynthesis. Disruption in enzyme’s activity in abnormally proliferating cancer cells impairs production of dTMP, a building block for DNA biosynthesis and results in thymineless death, a phenomenon by which cells undergo irreversible cell death, thus stopping the spread of cancer. Thymidylate synthase is an enzyme with two symmetrical active sites. Thymidylate synthase binding of a substrate at one active site initiates a conformational change in the activation loop that informs the interface to close the second active site. As a result the enzyme functions in a see-saw fashion; when one active site is occupied, the other is closed. This technology provides small molecule allosteric inhibitors designed to disrupt the thymidylate synthase cooperatively by over-stabilizing the structure and limiting see-saw-like motions to preserve the enzyme in the semi-open conformation so that the enzyme becomes unable to proceed through catalysis, further preventing the proliferation of cancer.
This combination strategy contains inhibitors and pharmaceutically acceptable excipients for the treatment of various forms of cancer, such as breast cancer, prostate cancer, brain cancer, or pancreatic cancer. Cancer is the second leading cause of death in the United States. As a result, the United States spends the most on cancer drugs worldwide, accounting for 42.2 percent of global spending in 2014. In the same year, the global market for cancer drugs hit $100 billion in annual sales, and is expected to reach $147 billion in annual sales by 2018. Although cancer treatment continues to make improvements, and cancer patients are living longer with treatment, more innovation is needed to better understand the disease and to more effectively treat patients. Researchers at the University of Florida have discovered a way to inhibit cancer growth by simultaneously targeting thymidylate synthase and oncogenic Ras signaling. Human thymidylate synthase is responsible for significantly accelerating the spread of cancer. This drug improvement has the potential to treat various forms of cancer by inhibiting cancer growth.
Combination strategy that inhibits cancer growth for the treatment of various forms of cancer
Simultaneously targeting human thymidylate synthase and oncogenic Ras signaling inhibits cancer growth. This combination strategy results in striking synergy in Ras mutant tumors. The combination of inhibitors and pharmaceutically acceptable excipients results in anti-tumor activity that is greater than that observed with either drug alone. Researchers at the University of Florida have discovered an improved method of treating various forms of cancer. Experimental results indicate that there are potential benefits in treating cancer patients that harbor mutant Ras and show overexpression of thymidylate synthase.
