Kchannel targeting impairs DNA repair and invasiveness of patient-derived glioblastoma stem cells in culture and orthotopic mouse xenografts which only in part is predictable by Kexpression levels.

in International journal of cancer by Katrin Ganser, Nicolai Stransky, Tayeb Abed, Leticia Quintanilla-Martinez, Irene Gonzalez-Menendez, Ulrike Naumann, Pierre Koch, Marcel Krueger, Peter Ruth, Stephan M Huber, Franziska Eckert

TLDR

  • The study investigates why glioblastoma, a type of brain tumor, is difficult to treat and why some treatments don't work. The study found that a certain type of brain tumor cell, called mesenchymal glioblastoma stem-like cells (GSCs), are particularly resistant to treatment. The study also found that a certain type of protein, called IKand BKCa-activated Kchannels, are involved in this resistance. The study then tested whether blocking these proteins with certain drugs could make the GSCs more sensitive to treatment. The study found that blocking these proteins did increase the number of damage to the DNA in the GSCs and decreased their ability to grow, but it did not work in all cases. The study also found that blocking these proteins slowed down the spread of the tumor in the mouse model. The study concludes that blocking these proteins concomitant to fractionated radiotherapy may be a promising new strategy in glioblastoma therapy.

Abstract

Prognosis of glioblastoma patients is still poor despite multimodal therapy. The highly brain-infiltrating growth in concert with a pronounced therapy resistance particularly of mesenchymal glioblastoma stem-like cells (GSCs) has been proposed to contribute to therapy failure. Recently, we have shown that a mesenchymal-to-proneural mRNA signature of patient derived GSC-enriched (pGSC) cultures associates with in vitro radioresistance and gel invasion. Importantly, this pGSC mRNA signature is prognostic for patients' tumor recurrence pattern and overall survival. Two mesenchymal markers of the mRNA signature encode for IKand BKCa-activated Kchannels. Therefore, we analyzed here the effect of IK- and BK-targeting concomitant to (fractionated) irradiation on radioresistance and glioblastoma spreading in pGSC cultures and in pGSC-derived orthotopic xenograft glioma mouse models. To this end, in vitro gel invasion, clonogenic survival, in vitro and in vivo residual DNA double strand breaks (DSBs), tumor growth, and brain invasion were assessed in the dependence on tumor irradiation and Kchannel targeting. As a result, the IK- and BK-blocker TRAM-34 and paxilline, respectively, increased number of residual DSBs and (numerically) decreased clonogenic survival in some but not in all IK- and BK-expressing pGSC cultures, respectively. In addition, BK- but not IK-blockade slowed-down gel invasion in vitro. Moreover, systemic administration of TRAM-34 or paxilline concomitant to fractionated tumor irradiation increased in the xenograft model(s) residual number of DSBs and attenuated glioblastoma brain invasion and (numerically) tumor growth. We conclude, that K-blockade concomitant to fractionated radiotherapy might be a promising new strategy in glioblastoma therapy.

Overview

  • The study investigates the prognosis of glioblastoma patients and the role of mesenchymal glioblastoma stem-like cells (GSCs) in therapy resistance. The study uses patient-derived GSC-enriched (pGSC) cultures to investigate the mesenchymal-to-proneural mRNA signature associated with in vitro radioresistance and gel invasion. The study also investigates the effect of IK- and BK-targeting concomitant to fractionated irradiation on radioresistance and glioblastoma spreading in pGSC cultures and xenograft models. The primary objective of the study is to identify a promising new strategy in glioblastoma therapy using K-blockade concomitant to fractionated radiotherapy.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, specifically the effect of IK- and BK-targeting concomitant to fractionated irradiation on radioresistance and glioblastoma spreading in pGSC cultures and xenograft models. The study identifies that IK- and BK-blockers increased the number of residual double-strand breaks (DSBs) and decreased clonogenic survival in some but not all IK- and BK-expressing pGSC cultures, respectively. BK-blockade also slowed down gel invasion in vitro. Systemic administration of TRAM-34 or paxilline concomitant to fractionated tumor irradiation increased the residual number of DSBs and attenuated glioblastoma brain invasion and tumor growth. These findings suggest that K-blockade concomitant to fractionated radiotherapy may be a promising new strategy in glioblastoma therapy.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they suggest a new strategy for glioblastoma therapy using K-blockade concomitant to fractionated radiotherapy. The study identifies limitations, such as the need to investigate the efficacy of K-blockade in vivo and the need to investigate the long-term effects of K-blockade on glioblastoma patients. Future research directions could include investigating the combination of K-blockade with other therapies, such as chemotherapy or immunotherapy, and investigating the long-term effects of K-blockade on glioblastoma patients.
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