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Mitigating temozolomide resistance in glioblastoma via DNA damage-repair inhibition

Inmaculada C Sorribes1, Samuel K Handelman2, Harsh V Jain3

  • 1Department of Mathematics, Duke University, Durham, NC 27708, USA.

Journal of the Royal Society, Interface
|January 23, 2020
PubMed

Insights

This study models glioblastoma treatment, identifying strategies to overcome resistance to temozolomide chemotherapy by inhibiting DNA repair enzymes alkylpurine-DNA-N-glycosylase (APNG) and methylguanine-DNA-methyltransferase (MGMT). These findings could improve glioblastoma patient survival.

Area of Science:

  • Oncology
  • Computational Biology
  • Cancer Research

Background:

  • Glioblastomas are highly lethal brain tumors with poor prognoses.
  • Temozolomide efficacy is limited by DNA repair enzymes alkylpurine-DNA-N-glycosylase (APNG) and methylguanine-DNA-methyltransferase (MGMT).
  • Inhibiting APNG and MGMT is a potential strategy to overcome chemotherapy resistance.

Purpose of the Study:

  • To develop a mechanistic mathematical model of glioblastoma response to chemotherapy.
  • To investigate the effects of dual treatment with temozolomide and APNG/MGMT inhibitors.
  • To identify optimal combination treatment strategies based on tumor cell phenotype.

Main Methods:

  • Developed a mechanistic mathematical model incorporating DNA damage, cell arrest, and DNA repair.
  • Parametrized and validated the model using existing data.
  • Simulated the response of heteroclonal glioblastomas to combined temozolomide and APNG/MGMT inhibition.

Main Results:

  • Identified four distinct combination treatment strategies tailored to tumor cell phenotypes.
  • Isolated a specific strategy with high potential for success in preclinical and clinical settings.
  • Demonstrated the model's capability to predict treatment outcomes.

Conclusions:

  • Mechanistic modeling can identify effective glioblastoma treatment strategies.
  • Targeting DNA repair pathways alongside chemotherapy offers a promising approach to overcome resistance.
  • Optimized combination therapies have the potential to improve glioblastoma patient survival.
Keywords:
alkylpurine-DNA-N-glycosylaseglioblastomamathematical modelmethylguanine-DNA-methyltransferasetemozolomide

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