NOVEMBER 2017 (1) – Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors

Anton G. Henssen is fellow of the BIH Charité Clinician Scientist Program.

Abstract

Despite intense efforts, the cure rates of childhood and adult solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. We have found that the majority of childhood solid tumors, including rhabdoid tumors, neuroblastoma, medulloblastoma, and Ewing sarcoma, express an active DNA transposase, PGBD5, that can promote site-specific genomic rearrangements in human cells. Using functional genetic approaches, we discovered that mouse and human cells deficient in nonhomologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5. In a chemical screen of DNA damage signaling inhibitors, we identified AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis. We found that expression of PGBD5, but not its nuclease activity–deficient mutant, was sufficient to induce sensitivity to AZD6738. Depletion of endogenous PGBD5 conferred resistance to AZD6738 in human tumor cells. PGBD5-expressing tumor cells accumulated unrepaired DNA damage in response to AZD6738 treatment and underwent apoptosis in both dividing and G1-phase cells in the absence of immediate DNA replication stress. Accordingly, AZD6738 exhibited nanomolar potency against most neuroblastoma, medulloblastoma, Ewing sarcoma, and rhabdoid tumor cells tested while sparing nontransformed human and mouse embryonic fibroblasts in vitro. Finally, treatment with AZD6738 induced apoptosis and regression of human neuroblastoma and medulloblastoma tumors engrafted in immunodeficient mice in vivo. This effect was potentiated by combined treatment with cisplatin, including substantial antitumor activity against patient-derived primary neuroblastoma xenografts. These findings delineate a therapeutically actionable synthetic dependency induced in PGBD5-expressing solid tumors.

Interview

In November, BIH Charité Clinician Scientist Anton G. Hennsen and his team received the Paper of the Month award.

What are you researching? What is the core of your research?

My lab investigates the underlying causes of the emergence of tumors in childhood. We are trying to find out whether new options for treatment can be derived from these mechanisms. I am particularly motivated by the prospect of improving the treatment of children suffering from cancer

What is the core message of your publication and how does your study differ from the work of other scientists in this field?

We have found a new approach to the treatment of tumors in children. The approach is based on a tumor-specific factor, making this treatment more targeted and reaching the tumor at a very vulnerable site that does not exist in non-tumorous tissue. This makes the treatment more tolerable because it only destroys tumor tissue and does not affect healthy tissue.

Which cooperation partners have contributed to the publication? Who was significantly involved?

This work is based on an important collaboration with scientists from the Memorial Sloan Kettering Cancer Center in New York. Dr. Alex Kentsis and Dr. John Petrini have been lead collaborators on this project.

What are the next steps planned for the project and what are the possible implications of your results for patients?

The results are based on data from laboratory models that had not yet been tested on people. The next step is to investigate this treatment's effectiveness on people. If this proves to be successful, this treatment could be used to help children with serious tumors to overcome their illness. We still have a long way to go before that happens, but because of the very promising data we have, we are ready and motivated to take on this challenge.