title: Targeting hexokinase 2 enhances response to radio-chemotherapy in glioblastoma.
abstract: First-line cancer therapies such as alkylating agents and radiation have limited survival benefits for Glioblastoma (GBM) patients. Current research strongly supports the notion that inhibition of aberrant tumor metabolism holds promise as a therapeutic strategy when used in combination with radiation and chemotherapy. Hexokinase 2 (HK2) has been shown to be a key driver of altered metabolism in GBM, and presents an attractive therapeutic target. To date, no study has fully assessed the therapeutic value of targeting HK2 as a mechanism to sensitize cells to standard therapy, namely in the form of radiation and temozolomide (TMZ). Using cell lines and primary cultures of GBM, we showed that inducible knockdown of HK2 altered tumor metabolism, which could not be recapitulated by HK1 or HK3 loss. HK2 loss diminished both in vivo tumor vasculature as well as growth within orthotopic intracranial xenograft models of GBMs, and the survival benefit was additive with radiation and TMZ. Radio-sensitization following inhibition of HK2 was mediated by increased DNA damage, and could be rescued through constitutive activation of ERK signaling. This study supports HK2 as a potentially effective therapeutic target in GBM.
authors: MacFeeters Hamilton Center for Neuro-Oncology, Toronto, Canada.
authors: Alenoush
authors: A
authors: Vartanian
authors: MacFeeters Hamilton Center for Neuro-Oncology, Toronto, Canada.
authors: Sameer
authors: S
authors: Agnihotri
authors: MacFeeters Hamilton Center for Neuro-Oncology, Toronto, Canada.
authors: Mark R
authors: MR
authors: Wilson
authors: MacFeeters Hamilton Center for Neuro-Oncology, Toronto, Canada.
authors: Kelly E
authors: KE
authors: Burrell
authors: MacFeeters Hamilton Center for Neuro-Oncology, Toronto, Canada.
authors: Peter D
authors: PD
authors: Tonge
authors: MacFeeters Hamilton Center for Neuro-Oncology, Toronto, Canada.
authors: Amir
authors: A
authors: Alamsahebpour
authors: MacFeeters Hamilton Center for Neuro-Oncology, Toronto, Canada.
authors: Shahrzad
authors: S
authors: Jalali
authors: MacFeeters Hamilton Center for Neuro-Oncology, Toronto, Canada.
authors: Michael S
authors: MS
authors: Taccone
authors: MacFeeters Hamilton Center for Neuro-Oncology, Toronto, Canada.
authors: Sheila
authors: S
authors: Mansouri
authors: Arthur and Sonia Labatt Brain Tumour Research Centre, SickKids Hospital, Toronto, Canada.
authors: Brian
authors: B
authors: Golbourn
authors: MacFeeters Hamilton Center for Neuro-Oncology, Toronto, Canada.
authors: Kenneth D
authors: KD
authors: Aldape
authors: MacFeeters Hamilton Center for Neuro-Oncology, Toronto, Canada.|Arthur and Sonia Labatt Brain Tumour Research Centre, SickKids Hospital, Toronto, Canada.|University Health Network, Toronto Western Hospital, Toronto, Canada.
authors: Gelareh
authors: G
authors: Zadeh
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy; D004249:DNA Damage; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D057809:HEK293 Cells; D006593:Hexokinase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D034622:RNA Interference; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; C000609700:HK2 protein, human; D006593:Hexokinase; D000077204:Temozolomide
keywords: cell signaling; glioblastoma; metabolism; novel treatments