A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study

Abstract

Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted a molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-hour intravenous infusion at 285mg/m2, 12–24 hours before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285mg/m2. Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of 2 evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95% compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5%), lymphopenia (17.5%), neutropenia (12.5%), ALT (7.5%) and AST (5%) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.

Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts

“…Imetelstat, an antisense oligonucleotide that inhibits telomerase by binding to TERC , is the only telomerase‐targeting drug that has been evaluated in phase II clinical trials of brain tumors . Although telomerase inhibition was observed, no objective response of imetelstat was achieved in refractory pediatric brain tumors . An inherent problem of targeting telomerase is that the inhibition of telomerase in a cancer cell already having elongated telomeres would not yield an immediate anti–proliferative effect.…”

“…18 Although telomerase inhibition was observed, no objective response of imetelstat was achieved in refractory pediatric brain tumors. 19 An inherent problem of targeting telomerase is that the inhibition of telomerase in a cancer cell already having elongated telomeres would not yield an immediate anti-proliferative effect. Telomerase inhibition may also lead to the activation of alternative lengthening of telomeres (ALT), a homologous recombination-based telomerase-independent telomere elongation mechanism, which would abrogate the effects of telomerase-targeting anticancer therapy.…”

Therapeutic strategies for targeting telomerase in cancer

“…A total of 42 patients were enrolled, and evaluable patients experienced a 95% reduction in telomerase activity; however, no objective tumor responses were observed. In addition, two patients died of intratumoral hemorrhage secondary to thrombocytopenia, leading to the end of this study . In another phase II study, patients with advanced NSCLC developed neutropenia and thrombocytopenia treatment with GRN163L, and no improvement in PFS was observed in these patients .…”

In perspective: An update on telomere targeting in cancer

“…In other words, the length of time required to shorten the telomere length significantly affected the usage of GRN163L in a clinical setting, and has rendered the drug most useful in cases where telomeres are already shortened . Studies on patients with advanced non–small‐cell lung cancer (NSCLC) showed only limited efficacy, and in pediatric patients with brain cancer GRN163L (Imetelstat) was only able to be administered for an average of 13 days (a 6‐to‐21‐day range) before intolerable toxicity levels characterized by platelet nadir being established . Moreover, GRN163L drug holidays, due to these increased toxicities, lead to rapid reestablishment of telomere length and continuing cell growth .…”