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.

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

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…