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Systems pharmacology approaches for optimization of antiangiogenic therapies: challenges and opportunities

Satish Sharan1, Sukyung Woo1

  • 1Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center , Oklahoma City, OK, USA.

Frontiers in Pharmacology
|March 10, 2015
PubMed

Insights

Targeted therapies for cancer face resistance due to compensatory angiogenic pathways. Optimizing dosing regimens using systems pharmacology can improve therapeutic benefits and overcome tumor resistance.

Area of Science:

  • Oncology
  • Pharmacology
  • Biomedical Engineering

Background:

  • Targeted therapies are crucial for cancer treatment but face significant challenges from acquired resistance.
  • Resistance often arises from the activation of alternative proangiogenic pathways, particularly in response to anti-VEGF agents.
  • Tumor escape mechanisms and limited therapeutic efficacy are linked to compensatory signaling and drug dosing strategies.

Purpose of the Study:

  • To explore the mechanisms of resistance to anti-VEGF targeted therapies in advanced cancer.
  • To investigate the role of compensatory proangiogenic pathways and circulating biomarkers in treatment resistance.
  • To propose a systems pharmacology approach for optimizing antiangiogenic therapy dosing.

Main Methods:

  • Utilizing a systems pharmacology approach with multiscale computational modeling.
  • Integrating data on VEGF-targeted therapy resistance, circulating biomarkers, and pharmacodynamics.
  • Analyzing the dynamics of angiogenic biomarkers and their impact on tumor reduction and resistance.

Main Results:

  • Higher doses of anti-VEGF agents can paradoxically increase compensatory proangiogenic signaling.
  • Dose intensity and scheduling significantly influence the development dynamics of therapeutic resistance.
  • A mechanistic understanding of biomarker dynamics is key to predicting and overcoming resistance.

Conclusions:

  • Optimal dosing regimens are critical for maximizing the therapeutic benefit of antiangiogenic agents.
  • Systems pharmacology offers a powerful framework for understanding and mitigating VEGF-targeted therapy resistance.
  • Integrating biomarker data and pharmacodynamics can lead to improved antiangiogenic treatment strategies for cancer patients.
Keywords:
antiangiogenic therapybedbiologically effective dosebiomarkersdose selectionresistancesystems pharmacologytargeted therapies

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