6-thio-2'-deoxyguanosine in GBM: Evaluation of Pharmaco-dynamics, Effects of Prior Standard of Care and A Human Phase 0 Study

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PROJECT SUMMARY – Project 2 Glioblastoma (GBM) remains uniformly lethal, with an overall survival of <21 months despite standard of care therapies. Immunotherapy has remarkable efficacy in many cancers, but has been less successful in GBM due in part to the tumor’s immunosuppressive effects and high levels of intratumoral heterogeneity. The Duke/UT Southwestern Glioblastoma Therapeutics Network (GTN) team will complete pre-clinical development of a novel treatment for patients with glioblastoma (GBM) and investigate the biologic activity of this agent in an early-phase clinical trial. Project 2 will contribute to this goal by investigating biomarkers of response to the telomerase- targeted agent 6-thio-dG in pre-clinical models and by conducting a Phase 0 clinical trial to examine these biomarkers in humans. 6-thio-dG is a blood brain barrier (BBB)-penetrant purine analog pro-drug that is preferentially incorporated into newly synthesized telomeres under the control of telomerase. Incorporation of 6- thio-dG into telomeres induces DNA damage and activates innate immune signaling, resulting in cell death. Because roughly 90% of GBM express telomerase resulting from early and highly clonal TERT-promoter mutations, 6-thio-dG represents an exciting mechanism to overcome tumor heterogeneity and activate anti-tumor immune responses. Although we have shown that treatment with 6-thio-dG induces telomeric DNA damage and elicits immune-mediated cytotoxicity in telomerase-positive cells, the optimal time-point for measuring 6-thio-dG- induced DNA damage and innate immune activation as pharmacodynamic (PD) endpoints is unknown and will be rigorously determined using patient-derived xenograft models (Aim 1). Additionally, most GBM patients receive first-line treatment with temozolomide (TMZ), which can induce hypermutation and loss of telomerase activity at recurrence. We will therefore evaluate the efficacy of 6-thio-dG following prior TMZ treatment and identify mechanisms of therapy resistance in vivo (Aim 1). Based on experiments conducted in Aim 1 and in Project 1, we will establish preliminary biomarkers of sensitivity and response to 6-thio-dG treatment in a Phase 0 window-of-opportunity trial in adults with newly diagnosed, telomerase-positive GBM (Aim 2). Following a 2- day pre-surgical course of 6-thio-dG, we will examine GBM tissues for detectable increases in DNA damage (primary endpoint) and activation of immune responses. These studies will enable the design and conduct of a Phase 0 trial of 6-thio-dG, identify patient populations likeliest to benefit from therapy, and assess biomarkers of sensitivity and response to 6-thio-dG among newly diagnosed patients with telomerase-positive GBM. The GBM clinical trials infrastructures of Duke and UTSW, which treat a diverse patient population representing ~10% of all U.S. patients with GBM, is an excellent setting for this trial. Project 2 thus contributes to this GTN U19’s overall goal and to the NCI’s goal to develop novel therapies to improve treatment for adults with GBM.