Improving Localized Radiotherapy for Glioblastoma via Small Molecule Inhibition of KIF11

Miranda M. Tallman; Abigail A. Zalenski; Ian Stabl; Morgan S. Schrock; Luke Kollin; Eliane de Jong; Kuntal De; Treg M. Grubb; Matthew K. Summers; Monica Venere

doi:10.3390/cancers15123173

Improving Localized Radiotherapy for Glioblastoma via Small Molecule Inhibition of KIF11

Miranda M. Tallman, Abigail A. Zalenski, Ian Stabl, Morgan S. Schrock, Luke Kollin, Eliane de Jong, Kuntal De, Treg M. Grubb, Matthew K. Summers, Monica Venere

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Glioblastoma, IDH-wild type (GBM) is the most common and lethal malignant primary brain tumor. Standard of care includes surgery, radiotherapy, and chemotherapy with the DNA alkylating agent temozolomide (TMZ). Despite these intensive efforts, current GBM therapy remains mainly palliative with only modest improvement achieved in overall survival. With regards to radiotherapy, GBM is ranked as one of the most radioresistant tumor types. In this study, we wanted to investigate if enriching cells in the most radiosensitive cell cycle phase, mitosis, could improve localized radiotherapy for GBM. To achieve cell cycle arrest in mitosis we used ispinesib, a small molecule inhibitor to the mitotic kinesin, KIF11. Cell culture studies validated that ispinesib radiosensitized patient-derived GBM cells. In vivo, we validated that ispinesib increased the fraction of tumor cells arrested in mitosis as well as increased apoptosis. Critical for the translation of this approach, we validated that combination therapy with ispinesib and irradiation led to the greatest increase in survival over either monotherapy alone. Our data highlight KIF11 inhibition in combination with radiotherapy as a new combinatorial approach that reduces the overall radioresistance of GBM and which can readily be moved into clinical trials.

Original language	English
Article number	3173
Journal	Cancers
Volume	15
Issue number	12
DOIs	https://doi.org/10.3390/cancers15123173
State	Published - Jun 2023
Externally published	Yes

Funding

This research was funded by an American Cancer Society Research Scholars Grant RSG-18-066-01-TBG, an Internal Research Program Grant from The Ohio State University Comprehensive Cancer Center, and funds from The Ohio State University Comprehensive Cancer Center/Department of Radiation Oncology (M.V.). Other funding includes the National Institute of General Medical Sciences of the National Institutes of Health under award number 2T32GM068412-11A1 (M.M.T.); an Ohio State University Graduate School Dean’s Distinguished University Fellowship (A.A.Z.); the Pelotonia Fellowship Program (M.M.T. and A.A.Z.); an American Brain Tumor Association Basic Research Fellowship supported by an Anonymous Corporate Donor (M.S.S.); and the National Institute of General Medical Sciences of the National Institutes of Health under award numbers R01GM112895 and R01GM108743 (M.K.S.). The APC was funded by M.V and the Department of Radiation Biology. The Small Animal Radiation Research Platform was purchased via a National Institutes of Health shared instrument grant, 1S10OD020006-01. The research reported in this publication was supported by The Ohio State University Comprehensive Cancer Center and the National Institutes of Health under grant number P30 CA016058. Any opinions, findings, and conclusions expressed in this material are those of the authors and do not necessarily reflect those of the funding agencies or The Ohio State University.

Funders	Funder number
Anonymous Corporate Donor	R01GM112895, R01GM108743
Department of Radiation Biology	1S10OD020006-01, P30 CA016058
Ohio State University Comprehensive Cancer Center
Ohio State University Comprehensive Cancer Center/Department
Ohio State University Graduate School Dean’s Distinguished University
National Institutes of Health	2T32GM068412-11A1
American Cancer Society	RSG-18-066-01-TBG
National Institute of General Medical Sciences
American Brain Tumor Association
Ohio State University

Keywords

KIF11
glioblastoma
radiotherapy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/cancers15123173

Cite this

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title = "Improving Localized Radiotherapy for Glioblastoma via Small Molecule Inhibition of KIF11",

abstract = "Glioblastoma, IDH-wild type (GBM) is the most common and lethal malignant primary brain tumor. Standard of care includes surgery, radiotherapy, and chemotherapy with the DNA alkylating agent temozolomide (TMZ). Despite these intensive efforts, current GBM therapy remains mainly palliative with only modest improvement achieved in overall survival. With regards to radiotherapy, GBM is ranked as one of the most radioresistant tumor types. In this study, we wanted to investigate if enriching cells in the most radiosensitive cell cycle phase, mitosis, could improve localized radiotherapy for GBM. To achieve cell cycle arrest in mitosis we used ispinesib, a small molecule inhibitor to the mitotic kinesin, KIF11. Cell culture studies validated that ispinesib radiosensitized patient-derived GBM cells. In vivo, we validated that ispinesib increased the fraction of tumor cells arrested in mitosis as well as increased apoptosis. Critical for the translation of this approach, we validated that combination therapy with ispinesib and irradiation led to the greatest increase in survival over either monotherapy alone. Our data highlight KIF11 inhibition in combination with radiotherapy as a new combinatorial approach that reduces the overall radioresistance of GBM and which can readily be moved into clinical trials.",

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year = "2023",

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doi = "10.3390/cancers15123173",

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AU - Kollin, Luke

AU - de Jong, Eliane

AU - De, Kuntal

AU - Grubb, Treg M.

AU - Summers, Matthew K.

AU - Venere, Monica

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N2 - Glioblastoma, IDH-wild type (GBM) is the most common and lethal malignant primary brain tumor. Standard of care includes surgery, radiotherapy, and chemotherapy with the DNA alkylating agent temozolomide (TMZ). Despite these intensive efforts, current GBM therapy remains mainly palliative with only modest improvement achieved in overall survival. With regards to radiotherapy, GBM is ranked as one of the most radioresistant tumor types. In this study, we wanted to investigate if enriching cells in the most radiosensitive cell cycle phase, mitosis, could improve localized radiotherapy for GBM. To achieve cell cycle arrest in mitosis we used ispinesib, a small molecule inhibitor to the mitotic kinesin, KIF11. Cell culture studies validated that ispinesib radiosensitized patient-derived GBM cells. In vivo, we validated that ispinesib increased the fraction of tumor cells arrested in mitosis as well as increased apoptosis. Critical for the translation of this approach, we validated that combination therapy with ispinesib and irradiation led to the greatest increase in survival over either monotherapy alone. Our data highlight KIF11 inhibition in combination with radiotherapy as a new combinatorial approach that reduces the overall radioresistance of GBM and which can readily be moved into clinical trials.

AB - Glioblastoma, IDH-wild type (GBM) is the most common and lethal malignant primary brain tumor. Standard of care includes surgery, radiotherapy, and chemotherapy with the DNA alkylating agent temozolomide (TMZ). Despite these intensive efforts, current GBM therapy remains mainly palliative with only modest improvement achieved in overall survival. With regards to radiotherapy, GBM is ranked as one of the most radioresistant tumor types. In this study, we wanted to investigate if enriching cells in the most radiosensitive cell cycle phase, mitosis, could improve localized radiotherapy for GBM. To achieve cell cycle arrest in mitosis we used ispinesib, a small molecule inhibitor to the mitotic kinesin, KIF11. Cell culture studies validated that ispinesib radiosensitized patient-derived GBM cells. In vivo, we validated that ispinesib increased the fraction of tumor cells arrested in mitosis as well as increased apoptosis. Critical for the translation of this approach, we validated that combination therapy with ispinesib and irradiation led to the greatest increase in survival over either monotherapy alone. Our data highlight KIF11 inhibition in combination with radiotherapy as a new combinatorial approach that reduces the overall radioresistance of GBM and which can readily be moved into clinical trials.

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Improving Localized Radiotherapy for Glioblastoma via Small Molecule Inhibition of KIF11

Abstract

Funding

Keywords

UN SDGs

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