Repair proteins wrapped around a DNA double helix. These proteins prevent DNA damage from accumulating and causing cell death. (Source: NIGMS, Credit: Tom Ellenberger, Washington University School of Medicine in St. Louis and Dave Gohara, Saint Louis University School of Medicine)
Dr. Kevin Mills, a former researcher at The Jackson Laboratory and co-founder of Cyteir Therapeutics, presented a seminar on February 29th regarding the therapeutic role of genomic instability. His research at Cyteir Therapeutics focuses on two small molecules, AID and RAD51, which are involved in genomic damage and genomic repair, respectively. Dr. Mills believes that Cyteir Therapeutics’s therapeutic approach and research has the potential to treat chemotherapy-resistant B cell cancers and autoimmune diseases.
B cells are a type of white blood cell that normally help mediate the immune response by synthesizing antibodies. Cancers involving B cells, more commonly known as B cell lymphoma, can be treated with either chemotherapy or therapies designed to reverse the mutations that caused these cells to become cancerous. When patients relapse, however, their cancers often mutate further and no longer respond to conventional therapies.
Dr. Mills and his colleagues found that these treatment-resistant cancer cells often overexpress the AID protein. This DNA damaging enzyme increases the number of double-stranded breaks in DNA, whereby the phosphate backbone of the DNA double helix is cleaved, causing the DNA to separate into two segments. While there are mechanisms that the body can use to repair damaged DNA, these can cause harmful mutations and are primarily used as a last attempt to prevent cell death. These mechanisms keep cancer cells alive in spite of severe DNA damage.
Dr. Mills’s team realized that they could exploit this balance between molecules that damage the genome and those that repair the genome to selectively destroy cancer cells that overexpress AID and exhibit double stranded DNA breakage. Cyteir Therapeutics has proposed the use of a new class of molecules that inhibit RAD51, a DNA repair molecule, for use as a B cell lymphoma treatment. In vivo studies using these molecules have shown that they can significantly inhibit tumor growth with minimal side effects. Although the treatment has the highest penetrance in B cells, Dr. Mills believes that the treatment may also be effective for autoimmune diseases such as lupus or Type I diabetes, which also cause cells to overexpress AID.