Chakravarti, Arnab

LBA2010 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

1 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

TPS2075 Background: IDH mutant astrocytomas express high levels of 2-hydroxyglutarate (2-HG), an oncogenic metabolite which drives gliomagenesis. Excess 2-HG inhibits branched chain amino acid transaminase, which catalyzes glutamate synthesis from branched chain amino acids. This defect causes these tumors to become more reliant on glutaminase for glutamate biosynthesis from glutamine. CB-839 (telaglenastat) is a novel glutaminase inhibitor which is well tolerated in humans. McBrayer et al have recently demonstrated that CB-839 further depletes intracellular glutamate and glutathione in IDH mutant glioma cells, and enhances RT (radiation therapy) efficacy in an orthotopic glioma model. Methods: NCI #10218 is a CTEP supported phase I clinical trial investigating the safety and tolerability of CB-839 when combined with RT/TMZ (temozolomide) in patients with previously untreated IDH mutant grade II/III astrocytoma. Patients with grade II and III astrocytomas will be treated with 50.4 and 59.4 Gy of RT, respectively, with standard doses of concurrent TMZ. CB-839 will also be administered orally concurrently with RT, with doses escalated in cohorts based on a standard 3+3 design. After defining the maximum tolerated dose (MTD) of CB-839, an expansion cohort will evaluate the pre- and post-CB-839 therapy metabolome of patients with IDH mutant astrocytoma. Enrollment to this cohort will require measurable disease and patients will additionally be treated with a 7 day run-in of CB-839 at MTD prior to RT. The effect of CB-839 on the metabolome will be studied in both plasma (LC/MS/MS) and tumor (magnetic resonance spectroscopy), along with PK to confirm adequacy of systemic exposure. Preliminary data on neurocognitive endpoints will also be acquired. NCI #10218 is currently activated for enrollment to cohort 1. Clinical trial information: NCT03528642.

Abstract PARP inhibitors (PARPi) are potentially effective therapeutic agents capable of inducing synthetic lethality in tumors with deficiencies in homologous recombination (HR)-mediated DNA repair such as those carrying BRCA1 mutations. However, BRCA mutations are rare, the majority of tumors are proficient in HR repair, and thus most tumors are resistant to PARPi. Previously, we observed that ionizing radiation (IR) initiates cytoplasmic translocation of BRCA1 leading to suppression of HR-mediated DNA repair and induction of synthetic PARPi lethality in wild-type BRCA1 and HR-proficient tumor cells. The tumor suppressor p53 was identified as a key factor that regulates DNA damage–induced BRCA1 cytoplasmic sequestration following IR. However, the role of p53 in IR-induced PARPi sensitization remains unclear. This study elucidates the role of p53 in IR-induced PARPi cytotoxicity in HR-proficient cancer cells and suggests p53 status may help define a patient population that might benefit from this treatment strategy. Sensitization to PARPi following IR was determined in vitro and in vivo utilizing human breast and glioma tumor cells carrying wild-type BRCA1 and p53, and in associated cells in which p53 function was modified by knockdown or mutation. In breast and glioma cells with proficient HR repair, IR-induced BRCA1 cytoplasmic sequestration, HR repair inhibition, and subsequent PARPi sensitization in vitro and in vivo was dependent upon functional p53. Implications: Implications: p53 status determines PARP inhibitor sensitization by ionizing radiation in multiple BRCA1 and HR-proficient tumor types and may predict which patients are most likely to benefit from combination therapy. Mol Cancer Res; 16(7); 1092–102. ©2018 AACR.

Purpose Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O 6 -methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM. Patients and Methods This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status. Results A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue. Conclusion This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.