A drug developed at the Georgia State University (GSU) could pave the way towards new treatment avenues for pancreatic and breast cancer, according to a pair of reports.
The drug, christened ProAgio, was developed by Zhi-Ren Liu, a biology professor at the GSU, and his team. Lab tests with mice showed that the compound is effective at treating pancreatic cancer. A second study shows that it is also effective against “triple-negative breast cancer”, a particularly aggressive and hard-to-treat type of breast cancer that had poor treatment prospects up to now.
Taking down the walls
The drug works by targeting not the disease’s cancerous cells themselves, but rather the ones they use for defense. Cancer cells use fibroblasts, a specialized type of cell that produces collagen and other mechanically-strong molecules, to build a shield around the tumor. This shield is called “stroma” and acts as a physical barrier preventing drugs from reaching inside and doing their job.
ProAgio targets these cells and forces them to undergo apoptosis — programmed cell death. This breaks down the stroma, leaving the tumor vulnerable.
According to the authors, it’s this stroma that makes pancreatic cancer extremely lethal and difficult to treat. The 5-year survival rate for this type of cancer is only 8%, they explain. Triple-negative breast cancer also tends to form a very dense stroma, and offers similarly poor prospects for patients. The team hopes that targeting these conditions’ most powerful asset and neutralizing it would finally give our current cancer treatments the upper hand.
“All solid tumors use cancer-associated fibroblasts, but in pancreatic cancer and triple-negative breast cancer, the stroma is so dense there’s often no way for conventional drugs to penetrate it and effectively treat the cancer,” said Liu.
Furthermore, the stroma is also involved in the tumor’s ability to confuse our immune systems. So it not only insulates from direct treatment but also makes immunotherapy — which uses our natural immune systems to fight cancer — much less effective.
Since cancer-associated fibroblasts also grow new blood vessels to supply the tumor, they speed up its spread through the body. Any cells that break off from the tumor can enter the bloodstream and start developing somewhere else, which we call metastasis. ProAgio, the team showed, has a pronounced effect on the vasculature of tumors. For pancreatic cancers, it helped reopen healthy vessels that were crushed by the stroma. For triple-negative breast cancer, it reduced the rate of new blood vessels being created by the tumor.
ProAgio is derived from a human protein and targets a specific receptor on the surface of cancer-associated fibroblasts to make sure it doesn’t attack any other, healthy tissues.
“When you have a wound, for example, normal fibroblasts will secrete fibers to limit the damage and promote healing,” said Liu. “The tumor region is basically a wound that won’t heal. Quiescent fibroblasts may play a role in preventing cancer from spreading. You don’t want to kill the good guys, only the bad guys.”
The drug is currently licensed to ProDa BioTech, a pharmaceutical research company founded by Liu. It has currently passed the toxicology and pharmacokinetic studies required before a drug can enter the first stages of clinical trials. These will start after ProAgio passes its Investigational New Drug (IND) Application, the process through which the Food and Drug Administration gives its approval for testing with human subjects.
The first trials will likely begin in early 2021 if everything goes well with the FDA, Liu says, and hopefully everything will progress to late-stage trials sometime by the end of the year.
The first paper “Simultaneously targeting cancer-associated fibroblasts and angiogenic vessel as a treatment for TNBC” has been published in the Journal of Experimental Medicine.
The second paper “Modulation of Cancer-Associated Fibrotic Stroma by An Integrin αvβ3 Targeting Protein for Pancreatic Cancer Treatment” has been published in the journal Cellular and Molecular Gastroenterology and Hepatology.
