Drug Targets Cold Tumors' Achilles Heel

Immunotherapies have emerged as a powerful treatment modality for cancer. They join chemotherapy, surgery, radiotherapy, and other targeted therapies as the “fifth pillar” of cancer therapies. These treatments involve the use of vaccines, cell therapies, and antibodies to activate patients’ immune systems to attack and destroy tumors. 

Despite their immense potential, immunotherapies such as checkpoint inhibitors are no match against certain solid tumors termed “cold tumors”. Just how cold tumors resist immune attack and how to bypass these shields therapeutically has eluded scientists.

Cancer experts at Brigham and Women's Hospital have identified that a cellular protein known as SerpinB9, or Sb9, could represent cold tumors’ Achilles heel. In a study published in Cell, pharmacological agents to inhibit Sb9 have been found to poke holes in cold tumors’ defense mechanisms and ignite molecular pathways of cell death from within.

Reza Abdi, one of the investigators on the team said: "In this study, we showed proof of concept using a small molecule that is designed to kill the cancer using its own lytic enzyme machinery." 

"Immunotherapies like monoclonal antibodies or checkpoint inhibitors are promising, heavily studied strategies, but antibodies are very hard to engineer and can also pose toxic effects to patients. A small molecule that inhibits the function of Sb9 could be simpler to develop, and potentially be more effective."

The scientists took a closer look at the expression of Sb9 in mouse models of cancer and found that this protein protects tumors from immunological attack. Specifically, Sb9 resists the effects of an enzyme called granzyme B that is secreted by immune cells to destroy infected and malignant cells. This could be the reason why immunotherapies fall flat in Sb9-expressing cold tumors.

By leveraging gene-editing CRISPR-Cas9 technology, the team engineered tumors without the Sb9 gene and discovered that this negatively impacted their growth. However, it wasn’t just the tumor cells that synthesized the Sb9 shield — cells surrounding the tumor such as cancer-associated fibroblasts produced Sb9, protecting the cancer cells from immune attack.

"The initial findings showed that the tumor without the Sb9 protein grows slower. However, when we implanted knocked-out Sb9 tumors in mice which lack Sb9, we observed a more notable reduction in tumor size," said Abdi.

"These results suggested that if we could come up with a drug that systemically inhibits this protein in the tumor and in the cells of the host, we could get a synergistic benefit by simultaneously targeting various pathogenic arms of tumor formation, including the tumor, cancer-associated fibroblasts, and immunosuppressive cells."

Preliminary testing of small-molecule Sb9 inhibitors as oncology therapeutics has yielded promising results. Still, additional preclinical testing needs to be performed before the drug can be introduced into the clinic. 

"This protein could be extremely important for future cancer therapies, and the research community might have a better way to target this protein," Abdi said. 

"At the end of the day, we are excited to be amongst the very first to make a drug for this new target and show its potential as a novel approach to cancer therapy."

Sources: Cell, Medical Xpress via Brigham and Women’s Hospital.