The combined efficacy of OTS964 and temozolomide for reducing the size of power-law coded heterogeneous glioma stem cell populations

// Michiya Sugimori 1, * , Yumiko Hayakawa 2, * , Ryoi Tamura 1 and Satoshi Kuroda 2 1 Department of Integrative Neuroscience, University of Toyama, Toyama, Toyama 930-0194, Japan 2 Department of Neurosurgery, University of Toyama, Toyama, Toyama 930-0194, Japan * These authors contributed equally to this work Correspondence to: Michiya Sugimori, email: sugimmic@med.u-toyama.ac.jp Satoshi Kuroda, email: skuroda@med.u-toyama.ac.jp Keywords: glioma stem cell (GSC); glioma sphere (GS); OTS964; temozolomide; population size Received: January 19, 2019      Accepted: March 04, 2019      Published: March 22, 2019 ABSTRACT Glioblastoma resists chemotherapy then recurs as a fatal space-occupying lesion. To improve the prognosis, the issues of chemoresistance and tumor size should be addressed. Glioma stem cell (GSC) populations, a heterogeneous power-law coded population in glioblastoma, are believed to be responsible for the recurrence and progressive expansion of tumors. Thus, we propose a therapeutic strategy of reducing the initial size and controlling the regrowth of GSC populations which directly facilitates initial and long-term control of glioblastoma recurrence. In this study, we administered an anti-glioma/GSC drug temozolomide (TMZ) and OTS964, an inhibitor for T-Lak cell originated protein kinase, in combination (T&O), investigating whether together they efficiently and substantially shrink the initial size of power-law coded GSC populations and slow the long-term re-growth of drug-resistant GSC populations. We employed a detailed quantitative approach using clonal glioma sphere (GS) cultures, measuring sphere survivability and changes to growth during the self-renewal. T&O eliminated self-renewing GS clones and suppressed their growth. We also addressed whether T&O reduced the size of self-renewed GS populations. T&O quickly reduced the size of GS populations via efficient elimination of GS clones. The growth of the surviving T&O-resistant GS populations was continuously disturbed, leading to substantial long-term shrinkage of the self-renewed GS populations. Thus, T&O reduced the initial size of GS populations and suppressed their later regrowth. A combination therapy of TMZ and OTS964 would represent a novel therapeutic paradigm with the potential for long-term control of glioblastoma recurrence via immediate and sustained shrinkage of power-law coded heterogeneous GSC populations.