In autumn of 2017, Vigeo Therapeutics Inc. began a phase I clinical trial of an anti-cancer agent that holds tremendous promise for cancer treatment, particularly for aggressive tumors. The agent is a peptide fragment of the prosaposin protein, which inhibits metastasis and tumor growth by stimulating the production of an inhibitory molecule called thrombospondin-1 in normal (non-cancerous) cells that make up the tumor microenvironment. While other cancer drugs have mimicked chemicals produced by the body, this first-of-its-kind drug stimulates the body’s natural resistance to cancer.
Randolph Watnick, PhD, of Boston Children’s Hospital, discovered the drug. “Our goal is to develop treatments that will benefit people without making them more ill,” says Dr. Watnick. “We want to find a way to treat people with cancer without having to rely on cocktails of cytotoxic drugs that have significant side effects.”
Dr. Watnick and his team have identified an additional mechanism by which the prosaposin peptide works. These new findings suggest that in addition to having activity on its own, the peptide could also be used in combination with other immuno-oncology drugs. Tumors are very good at hiding from the immune system. One of the tricks they use is to display a “do not attack” protein, called PDL1, on the surface of their cells. Two antibodies now on the market (for melanoma and non-small cell lung cancers) work by blocking PDL1, making the cancer cells once again vulnerable to an immune cell attack. The drugs work spectacularly well—but only in 15-20 percent of patients. The remainder of patients are not candidates for these drugs, for a variety of reasons, but most notably because many of them have “cold” tumors. These “cold” tumors have high levels of a subset of cells in the tumor microenvironment, called MDSCs, that suppresses the immune attack in additional ways. Thus, even though checkpoint inhibitors allow the immune system’s T-cells to see the tumor, their activity is blocked and they can’t get through.
The prosaposin peptide disarms the MDSCs, converting the tumor milieu from one that suppresses an immune attack to one that promotes it. Dr. Watnick is eager to conduct animal studies combining the prosaposin peptide with a PD1 antibody to determine if tumors that are resistant to the antibody will become vulnerable. He uses a football metaphor: “You have your linemen who go through and clear the way for the running back. We’re clearing away the tumor’s defense with the peptide, so then the body’s natural anti-tumor systems, as well as those induced by the peptide, can get through.” The Watnick lab, and the Vascular Biology Program at Boston Children’s Hospital, is constantly exploring ways to better understand how the tumor microenvironment is forced to cooperate with the tumor and, by doing so, open up new avenues of research and novel therapeutic strategies.