Final Report Summary - RECURRENT GLIOMA TX (Phase I trial in recurrent high-grade glioma: High-dose vorinostat with concurrent hypofractionated radiation therapy) Primary brain tumors are generally highly aggressive and resistant to therapy; progress over recent decades has been limited, recurrent tumors are invariably fatal. Ionizing radiation, in the form of radiation therapy (RT), induces cell death through the induction of DNA damage, and remains a cornerstone of therapy. Unfortunately, often brain tumor cells develop resistance to radiation, allowing them to recur, even within the irradiated area. Recent advances in molecular biology have informed us regarding the pathways, both pro-survival and pro-death, activated following DNA damage. Modification of these pathways in the laboratory has enabled us to sensitize tumor cells to radiation-induced cell death. Nonetheless, therapies successful in the laboratory are not always successful transferred into the clinic. Challenges encountered include systemic toxicity, poor penetration of the brain and relative sensitivity of normal brain versus tumor tissue. The underlying goal of this project is to develop new treatments for recurrent brain tumors, by combining RT with systemic agents that will sensitize the tumor cells to radiation induced death. The original proposal was to combine RT with vorinostat, a new class of pharmacological agent that modulates epigenetic modulator (a histone deacetylase inhibitor). The primary objective was to perform a Phase I/II clinical trial in subjects with recurrent brain tumors; secondary objectives were to perform correlative studies to inform on the mechanism of action of the agent. Unfortunately despite repeated efforts we were unable to obtain the agent from the pharmaceutical company. In consultation with the FP7 project director the objectives were modified, while still focusing on a clinical trial examining the role of radiation in recurrent brain tumors. This change of plan was indeed fortuitous, since it allowed us to focus on the recent advances in the field of energy metabolism within brain tumors.Normal and cancer cells obtain energy in different ways; in particular brain tumors have an increased need and dependency on glucose. Recent evidence indicates that brain tumor cells starved of glucose grow poorly, and are very sensitive to radiation therapy. In the clinical trial that forms the basis of this project, patients receive glucose-lowering treatment over an eight-week period encompassing radiation therapy. Different cohorts will receive either dietary treatment (very low carbohydrate diet), pharmacological treatment (metformin – an anti-diabetic drug) or both. As an early phase trial, he primary aims of the trial are safety and tolerability. In addition, treatment response is monitored with brain MRI scans, and repeat metabolic profiles obtained from peripheral blood. State-of-the-art aspects of the project include: performance of a clinical trial with substantial correlative endpoints, incorporation of cutting-edge MRI technology (treatment response assessment maps) and a parallel in depth laboratory based project. At the time of writing the trial is ongoing, and results appear promising (an in depth analysis of results from ongoing clinical trials is inappropriate).The clinical trial has stimulated a parallel lab effort to interrogate mechanisms of radiation resistance, and understand the role of cellular bioenergetics / intermediate metabolism in modifying the radiation response. Early results indicate that compared to radiation resistance cells demonstrate increased expression of anti-apoptotic variants of key proteins in the DNA-damage response pathway, explaining their resistance to radiation induced cell death. Of critical importance to this project, we have also discovered that metabolic manipulation was able to reverse this phenotype.From a socio-economic perspective, the trial raises the possibility of improving medical outcomes through dietary interventions without need of additional medications. If this is proven to be the case, this would have a major impact on medical practice worldwide. A major barrier to medical innovation in both the developed and underdeveloped world is the significant cost of new medications. By contrast, dietary interventions are comparatively cheap, with the main cost involved being the time of dietician. It is important to stress that it is premature to conclude based upon this study that dietary interventions conclusively improve cancer outcomes. This study, and others across the globe are ongoing and hopefully with provide an answer in the coming years. Regarding career development, during the course of this grant Dr. Lawrence has established a research lab that is exploring the interaction between energy metabolism and the response to radiation. He has become a sought-after lecturer in the field of translational radiobiology - recently he was an invited lecturer to a European School of Oncology (ESO) course – “Innovations in radiation oncology”. A number of high level collaborations have been established with multiple national / international groups including the International Atomic Energy Agency (IAEA) and the NATO Science for Peace and Security (SPS) Programme. Dr Lawrence has received peer-reviewed funding from The Israel Cancer Association, the Rosetrees Trust and Gateway for Cancer Research. The latter is funding an international clinical trial to pilot a new radiation therapy technique for patients with pancreatic cancer, for which Dr Lawrence is the overall PI.
