Christopher C. Porter, MD
Harnessing a tumor cell’s attributes for good rather than evil sounds akin to a fantasy movie plot highlighted at Universal Studios Theme Park® down the street. However, in yesterday’s Education Spotlight Session titled “DNA-Repair Pathways: Cancer Syndromes to Novel Therapies,” Drs. Michael Kastan and Alan D’Andrea discussed this possibility, presenting their insight and experience with diseases based on mutations of genes involved in DNA repair. The session highlighted the information gained by studying samples from patients with rare diseases to understand the molecular bases of diseases and the application of this knowledge in the development of therapies to treat these diseases — in essence, taking questions from the bedside to the bench and delivering potential answers back to the bedside.
DNA repair is a complex process with six independent pathways, and Drs. Kastan and D’Andrea outlined their functions and the diseases associated with mutations within these pathways. These pathways are critically important, not just in the patients with rare diseases such as Fanconi anemia (FA) and ataxia-telangiectasia (A-T), but also in patients receiving therapy for cancer. Many tumors have mutations in these pathways and most anticancer agents cause DNA damage. The speakers emphasized that in tumor cells, when one DNA-repair pathway is impaired by mutations, they are particularly sensitive to inhibition of a different repair pathway. Dr. Kastan said, “That makes targeting these repair pathways advantageous because it provides the type of ‘therapeutic index’ that we are always looking for in cancer therapies — maximizing toxicity to the tumor cells while minimizing toxicity to normal cells.”
To illustrate this point, Dr. D’Andrea used the FA/BRCA signaling pathway as an example. There are 13 genes involved in FA, a bone marrow failure and cancer predisposition syndrome, including the breast cancer susceptibility gene BRCA2. These gene products act together to confer resistance to DNA interstrand crosslinks. They can be mutated in patients with FA or in the tumor cells of patients with a variety of cancers. When this pathway is disrupted, cells are particularly sensitive to cross-linking agents such as mitomycin C and melphalan or inhibitors of DNA repair. Interestingly, cells with a defect in a DNA-repair mechanism called homologous recombination are highly dependent upon another repair process called base-excision repair. Base-excision repair can be targeted by Poly ADP-ribose polymerase (PARP) inhibitors, which are in clinical development.
Dr. Kastan focused on A-T as a rare disease from which much has been learned. The disease is characterized by progressive cerebellar ataxia and cancer predisposition and is the result of mutation of the A-T mutated gene (ATM) gene. The ATM protein is a kinase involved in cell-cycle control and repair of DNA-double-strand breaks, in part through activation of p53. Inhibiting ATM may sensitize tumor cells to chemotherapy or radiation. Dr. Kastan also discussed the potential to reduce the side effects of cancer therapy by inhibiting p53.
Not unlike Marty McFly, who went “Back to the Future,” bench research in rare diseases is coming full circle back to the bedside.
Dr. Porter indicated no relevant conflicts of interest.