Game Changer Grant Awarded to Daphne Haas-Kogan and Brendan Price

The promise of novel approaches is greater now than at any time in the past as scientific discoveries have uncovered the molecular underpinnings of DIPG and identified therapeutic vulnerabilities on which we must capitalize. One vulnerability that we have identified is that, unlike most cancers, DIPGs have high levels of basal damage to their DNA. Further, DIPGs have learned to tolerate this DNA damage, allowing then to escape cell death, and explaining their resistance to chemotherapy and radiation. Most cells use two standard DNA repair pathways that fix the majority of DNA damage. However, there is a third, backup pathway, called alternate-end joining (alt-EJ), that normally accounts for less than 10% of cells’ DNA repair capacity. Our work demonstrates that DIPGs exhibit increased dependence on the alt-EJ DNA repair pathway, and that this activation of alt-EJ is further enhanced by the H3.3K27M mutation found in most (80%) DIPGs. As a result, H3.3K27M DIPGs are much more resistant to radiation, the only treatment modality which prolongs patient survival, than wild type H3.3 DIPGs. Here, we will target alt-EJ in DIPGs, thereby disrupting the ability of DIPG cells to repair DNA damage and evade cell death. Targeting alt-EJ therefore provides a new approach to directly kill DIPG and increase their sensitivity to radiation.

The alt-EJ pathway utilizes a unique set of DNA repair proteins, including DNA polymerase (POLQ). Inhibition of POLQ blocks the activated alt-EJ pathway and sensitizes both wild type and H3.3K27M DIPGs to radiation. Further, because alt-EJ is more active in H3.3K27M DIPGs, POLQ inhibition is significantly more effective in sensitizing H3.3K27M DIPGs to radiation than H3.3 DIPGs. Here, we have partnered with Artios Pharma, who have developed a series of highly specific POLQ inhibitors which have been validated in cell and animal models. We will use Artios Pharma’s POLQ inhibitors to target the hyper-active alt-EJ repair pathway in DIPGs, and study how POLQ inhibition alters therapeutic responses to radiation in both cell and animal models. This will allow us to determine: (i) if hyperactivation of the alt-EJ pathway accounts for the radiation and chemo-resistance of DIPGs, and (ii) if targeting POLQ and the alt-EJ pathway is a specific and effective therapy for DIPGs. Successful completion of these studies will allow us to move directly to clinical trials testing Artios Pharma’s POLQ inhibitor for DIPG treatment.