Sugimori Michiya, Hayakawa Yumiko, Tamura Ryoi, Kuroda Satoshi
Department of Integrative Neuroscience, University of Toyama, Toyama, Toyama 930-0194, Japan.
Department of Neurosurgery, University of Toyama, Toyama, Toyama 930-0194, Japan.
Oncotarget. 2019 Mar 22;10(24):2397-2415. doi: 10.18632/oncotarget.26800.
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.
胶质母细胞瘤对化疗产生耐药性，随后会复发成为致命的占位性病变。为改善预后，应解决化疗耐药性和肿瘤大小的问题。胶质瘤干细胞（GSC）群体是胶质母细胞瘤中一种异质性的幂律编码群体，被认为是肿瘤复发和进行性扩张的原因。因此，我们提出一种治疗策略，即减小GSC群体的初始大小并控制其再生长，这直接有助于胶质母细胞瘤复发的初始和长期控制。在本研究中，我们联合使用了抗胶质瘤/GSC药物替莫唑胺（TMZ）和T-Lak细胞源蛋白激酶抑制剂OTS964（T&O），研究它们是否能有效且显著地缩小幂律编码的GSC群体的初始大小，并减缓耐药GSC群体的长期再生长。我们采用详细的定量方法，使用克隆胶质瘤球（GS）培养物，测量球的存活率以及自我更新过程中的生长变化。T&O消除了自我更新的GS克隆并抑制了它们的生长。我们还研究了T&O是否减小了自我更新的GS群体的大小。T&O通过有效消除GS克隆迅速减小了GS群体的大小。存活的T&O耐药GS群体的生长持续受到干扰，导致自我更新的GS群体长期显著缩小。因此，T&O减小了GS群体的初始大小并抑制了其后期再生长。TMZ和OTS964的联合疗法将代表一种新的治疗模式，有可能通过立即和持续缩小幂律编码的异质性GSC群体来长期控制胶质母细胞瘤的复发。
