Dataset Information

Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide (HL156A).

ABSTRACT: Studies have investigated biguanide-derived agents for the treatment of cancers and have reported their effects against tumorspheres (TSs). The purpose of this study was determining the effects of HL156A, a newly designed biguanide with improved pharmacokinetics, on glioblastoma TSs (GMB TSs) and assess the feasibility of this drug as a new line of therapy against glioblastoma, alone or combined with a conventional therapeutic agent, temozolomide(TMZ). The effects of HL156A, alone and combined with TMZ, on the stemness and invasive properties of GBM TSs and survival of orthotopic xenograft animals were assessed. HL156A, combined with TMZ, inhibited the stemness of GBM TSs, proven by neurosphere formation assay and marker expression. Three-dimensional collagen matrix invasion assays provided evidence that combined treatment inhibited invasive properties, compared with control and TMZ-alone treatment groups. TMZ alone and combined treatment repressed the expression of epithelial-mesenchymal transition-related genes. A gene ontology comparison of TMZ and combination-treatment groups revealed altered expression of genes encoding proteins involved in cellular adhesion and migration. Combined treatment with HL156A and TMZ showed survival benefits in an orthotopic xenograft mouse model. The inhibitory effect of combination treatment on the stemness and invasive properties of GBM TSs suggest the potential usage of this regimen as a novel strategy for the treatment of GBM.

SUBMITTER: Choi J

PROVIDER: S-EPMC5323181 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide (HL156A).

Choi Junjeong J Lee Ji-Hyun JH Koh Ilkyoo I Shim Jin-Kyoung JK Park Junseong J Jeon Jeong Yong JY Yun Mijin M Kim Se Hoon SH Yook Jong In JI Kim Eui Hyun EH Chang Jong Hee JH Kim Sun Ho SH Huh Yong Min YM Lee Su Jae SJ Pollak Michael M Kim Pilnam P Kang Seok-Gu SG Cheong Jae-Ho JH

Oncotarget 20161001 40

Studies have investigated biguanide-derived agents for the treatment of cancers and have reported their effects against tumorspheres (TSs). The purpose of this study was determining the effects of HL156A, a newly designed biguanide with improved pharmacokinetics, on glioblastoma TSs (GMB TSs) and assess the feasibility of this drug as a new line of therapy against glioblastoma, alone or combined with a conventional therapeutic agent, temozolomide(TMZ). The effects of HL156A, alone and combined w ...[more]

PMID: 27582539

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Project description:BackgroundThe impact of prolonging temozolomide (TMZ) maintenance beyond six cycles in newly diagnosed glioblastoma (GBM) remains a topic of discussion. We investigated the effects of prolonged TMZ maintenance on progression-free survival (PFS) and overall survival (OS).Patients and methodsIn this retrospective single-center cohort study, we included patients with GBM who were treated with radiation therapy with concomitant and adjuvant TMZ. For analysis, patients were considered who either completed six TMZ maintenance cycles (group B), continued with TMZ therapy beyond six cycles (group C), or stopped TMZ maintenance therapy within the first six cycles (group A). Patients with progression during the first six TMZ maintenance cycles were excluded.ResultsClinical data from 107 patients were included for Kaplan-Meier analyses and 102 for Cox regressions. Median PFS times were 8.1 months (95% confidence interval [CI] 6.1-12.4) in group A, 13.7 months (95% CI 10.6-17.5) in group B, and 20.9 months (95% CI 15.2-43.5) in group C. At first progression, response rates of TMZ/lomustine rechallenge were 47% in group B and 13% in group C. Median OS times were 12.7 months (95% CI 10.3-16.8) in group A, 25.2 months (95% CI 17.7-55.5) in group B, and 28.6 months (95% CI 24.4-open) in group C. Nevertheless, multivariate Cox regression for patients in group C compared with group B that accounted for imbalances of other risk factors showed no different relative risk (RR) for OS (RR 0.77, p = .46).ConclusionOur data do not support a general extension of TMZ maintenance therapy beyond six cycles. The Oncologist 2017;22:570-575 IMPLICATIONS FOR PRACTICE: Radiation therapy with concomitant and adjuvant temozolomide (TMZ) maintenance therapy is still the standard of care in patients below the age of 65 years in newly diagnosed glioblastoma. However, in clinical practice, many centers continue TMZ maintenance therapy beyond six cycles. The impact of this continuation is controversial and has not yet been addressed in prospective randomized clinical trials. We compared the effect of more than six cycles of TMZ in comparison with exactly six cycles on overall survival (OS) and progression-free survival (PFS) by multivariate analysis and found a benefit in PFS but not OS. Thus, our data do not suggest prolonging TMZ maintenance therapy beyond six cycles, which should be considered in neurooncological practice.

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Dataset Information

Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide (HL156A).

Publications

Inhibiting stemness and invasive properties of glioblastoma tumorsphere by combined treatment with temozolomide and a newly designed biguanide (HL156A).

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