Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells.

Glioblastoma (GBM) is the most lethal and aggressive adult brain tumor, requiring the development of efficacious therapeutics. Towards this goal, we screened five genetically distinct patient-derived brain-tumor initiating cell lines (BTIC) with a unique collection of small molecule epigenetic modulators from the Structural Genomics Consortium (SGC). We identified multiple hits that inhibited the growth of BTICs in vitro, and further evaluated the therapeutic potential of EZH2 and HDAC inhibitors due to the high relevance of these targets for GBM. We found that the novel SAM-competitive EZH2 inhibitor UNC1999 exhibited low micromolar cytotoxicity in vitro on a diverse collection of BTIC lines, synergized with dexamethasone (DEX) and suppressed tumor growth in vivo in combination with DEX. In addition, a unique brain-penetrant class I HDAC inhibitor exhibited cytotoxicity in vitro on a panel of BTIC lines and extended survival in combination with TMZ in an orthotopic BTIC model in vivo. Finally, a combination of EZH2 and HDAC inhibitors demonstrated synergy in vitro by augmenting apoptosis and increasing DNA damage. Our findings identify key epigenetic modulators in GBM that regulate BTIC growth and survival and highlight promising combination therapies.

A feasibility study to assess the integration of a pharmacist into neurooncology clinic.

OBJECTIVE: A multidisciplinary approach is increasingly used in NeuroOncology clinics. Although this model has several advantages, patients report feeling overwhelmed by the complexity of their treatment protocol and staff feel rushed because each provider must evaluate the patient within the limited clinic hours. We hypothesized that the presence of a pharmacist in clinic could address these concerns by (1) reviewing all treatment protocols and side-effect management with patients, (2) being available to address questions outside of clinic and (3) answering staff related medication questions. METHODS: The pharmacist met with consenting patients at the initial clinic visit and followed up by telephone two additional times. The pharmacist was available to answer questions outside of clinic hours. Surveys were developed and given to patient and staff to evaluate their experience. RESULTS: Over 4 months, 13 patients were enrolled. The pharmacist interacted with each patient an average of 9 times with 55% of interactions occurring outside scheduled visits and two-thirds of pharmacist interventions directly involving patient care. A total of 85% of patients and staff responded to the evaluation survey and 90% of respondents indicated that the pharmacist should remain part of the NeuroOncology team. Patients reported less stress related to their treatment and clinical staff experienced improved clinical efficiency directly as a result of the presence of the pharmacist. CONCLUSION: Based on these results, a clinical pharmacist should become a permanent member of the outpatient NeuroOncology clinic.