A Tumor Agnostic Therapeutic Strategy for Hexokinase 1-Null/Hexokinase 2-Positive Cancers

Area of Science:

• Biochemistry
• Oncology
• Cancer Metabolism

Background:

• Warburg effect: Cancers exhibit elevated glycolysis.
• Hexokinase (HK) is a key enzyme in glycolysis; inhibiting it is a therapeutic goal.
• HK isoforms HK1 and HK2 are differentially expressed in normal tissues and tumors.

Purpose of the Study:

• To investigate the therapeutic potential of targeting Hexokinase 2 (HK2) in cancers.
• To evaluate the efficacy of HK2 inhibition in different tumor contexts, particularly HK1-negative subpopulations.
• To identify potential clinical translational agents for HK1-negative, HK2-positive cancers.

Main Methods:

• Utilized HK2 shRNA and isogenic cell pairs (HK1+HK2- vs. HK1+HK2+) to study tumor progression.
• Investigated HK2 inhibition combined with other metabolic inhibitors in liver cancer xenografts.
• Employed triple therapy (antisense HK2 oligonucleotides, metformin, perhexiline) in multiple myeloma xenografts and mouse models.

Main Results:

• Tumors expressing only HK1 showed reduced glucose consumption but similar progression to HK1+HK2+ tumors.
• HK2 suppression in HK1-HK2+ liver cancer cells reduced xenograft progression, unlike in HK1+HK2+ cells.
• Combined HK2 inhibition and metabolic drug therapies prevented HK1-HK2+ liver cancer xenograft progression and multiple myeloma progression in vivo.

Conclusions:

• HK2 plays a critical role in the progression of specific cancer types, particularly those lacking HK1.
• Targeting HK2, especially in HK1-negative cancers, presents a viable therapeutic strategy.
• A combination therapy including HK2 inhibition shows promise for an agnostic approach to treating HK1-HK2+ cancers across various tissue origins.