This week we profile a recent publication in Cell from the laboratory of Dr. Reza Abdi at Brigham and Women’s Hospital.
(The lab is shown above, pre-COVID-19)
Can you provide a brief overview of your lab’s current research focus?
My research focuses on understanding the cellular and humoral mechanisms of immunity in transplantation, cancer, and autoimmune diseases. Our ultimate goal is to create clinically feasible approaches to tackle these refractory conditions by developing new drugs and antibodies. We are also interested in pioneering targeted drug delivery platforms to achieve transplant tolerance and to eradicate aggressive cancers. All these efforts are supported by cross-disciplinary collaborations with experts from the fields of bioengineering, transplantation, oncology, structural biology, and drug and antibody discovery.
What is the significance of the findings in this publication?
Immunotherapies have transformed the landscape of cancer treatment by permitting physicians to augment the immune responses in patients to attack malignant tumors. However, checkpoint inhibitors do not work well against some cancers, known as “cold tumors.” For over a decade, we have focused on a protein called serpin B9 (Sb9), which is known to inhibit a powerful enzyme called granzyme B (Grb). Grb can induce apoptosis in target cells. In this study, we found that Sb9 prevents cancer cells from killing themselves due to their own Grb. When we inhibited the expression of Sb9 by the cancer cells, we noted an increase in their death rate. However, when we implanted Sb9 knockout tumors in mice that also lack Sb9, we observed a more notable reduction in tumor size. These results suggested that systemic inhibition of Sb9 could simultaneously target various pathogenic arms of tumor formation, including cancer cells, cancer-associated fibroblasts, and immunosuppressive cells. Therefore, we developed a specific, small-molecule inhibitor of Sb9. Notably, this small molecule was effective in suppressing the growth of tumors in several murine cancer models. These data provided proof-of-concept evidence that supports the targeting of Sb9 as an exciting new mechanism for antineoplastic therapy.
What are the next steps for this research?
We must do a significant amount of work to optimize the binding kinetics of the small-molecule inhibitor of Sb9 and to determine the structural basis of its interactions with Grb. In addition, rigorous toxicity testing must be completed before any drug can be taken to clinic. We are also very interested in comparing the efficacy of our Sb9 inhibitor head-to-head with checkpoint inhibitors in suppressing cold tumors. We are extremely keen to test the efficacy of our compound in treating glioma and pancreatic cancer, for which current therapies have not demonstrated significant success.