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According to a study published in the journal Cellular and Molecular Gastroenterology and Hepatology, ProAgio, a drug developed by Georgia State University biology professor Zhi-Ren Liu and his team, is effective in treating pancreatic cancer and prolonging survival. in mice.
A second study, published in the Journal of Experimental Medicine, shows that the drug is also effective against triple negative breast cancer, a fast growing and difficult to treat type of breast cancer that carries a poor prognosis.
ProAgio, created from a human protein, targets the integrin of the αVβ? Cell surface receptor, which is expressed on fibroblasts associated with cancer. Fibroblasts are cells that generate collagen and other fibrous molecules and can be mobilized by a tumor, creating a thick physical barrier known as a stroma, which protects cancer and helps it grow. The drug works by inducing apoptosis, or programmed cell death, in cancer-associated fibroblasts that express αVβ ™ integrin.
Dense fibrous stroma is what makes pancreatic cancer, which has a five-year survival rate of just eight percent, so deadly and difficult to treat. Among patients with triple negative breast cancer, research shows that a denser stroma is associated with lower survival and higher recurrence rates.
All solid tumors use fibroblasts associated with cancer, but in pancreatic cancer and triple negative breast cancer, the stroma is so dense that it is often impossible for conventional drugs to penetrate it and effectively treat the cancer. “
Zhi-Ren Liu, professor, Georgia State University
The stroma also helps the tumor hide from your body’s immune system. Immunotherapy, a type of treatment that uses your immune system to fight cancer, is less effective against tumors protected by dense stroma rich in fibroblasts associated with cancer.
Fibroblasts associated with cancer promote angiogenesis or the development of new blood vessels. Angiogenesis plays an important role in the spread of cancer because solid tumors need a blood supply to grow. In both studies, Liu and his team show that roAgio has a profound effect on tumor vasculature. In the case of pancreatic cancer, he reopened the blood vessels that had collapsed due to high extravascular stress caused by the dense stroma. In the case of triple negative breast cancer, the anti-angiogenic activity of the drug shrinks irregular and leaky angiogenic tumor vessels. In both cases, ProAgio enabled the drugs to effectively reach the cancer.
Liu’s drug is unique in that it targets only cancer-associated fibroblasts – a subclass of cells actively involved in supporting cancer – rather than inactive fibroblasts. This reduces the side effects of the drug and increases its effectiveness.
“When you have an injury, for example, normal fibroblasts secrete fibers to limit damage and promote healing,” Liu said. “The tumor region is basically a wound that doesn’t heal. Resting fibroblasts can play a role in preventing the spread of cancer. You don’t want to kill the good guys, only the bad guys.”
ProAgio is licensed to ProDa BioTech, a research-based pharmaceutical company founded by Liu. In 2018, ProDa BioTech received $ 2 million from the National Cancer Institute to fund the necessary toxicology and pharmacokinetic studies before transferring the drug to early stage clinical trials. These studies have been completed and the company has submitted an Investigational New Drug Application (IND), a Food and Drug Administration clearance request to administer ProAgio to human subjects.
Once the IND is granted, Liu says the immediate next step is to begin clinical trials. The first trial, to determine patient tolerability and recommended Phase II dose, will begin in early 2021 at the National Institute of Health Clinical Center in Bethesda, Md., And will be led by Christine Alewine, MD, oncologist at National Cancer Institute. . At the end of 2021, Emory University is expected to begin a multi-site trial in patients with breast cancer and pancreatic cancer.
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