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Strategically Timing Inhibition of Phosphatidylinositol 3-Kinase to Maximize Therapeutic Index in Estrogen Receptor

Wei Yang1, Sarah R Hosford1, Lloye M Dillon1

  • 1Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|January 7, 2016
PubMed
Abstract

Insights

Combining Phosphatidylinositol 3-kinase (PI3K) inhibitors with antiestrogens shows promise for treating estrogen receptor-positive breast cancer. Optimal scheduling of PI3K inhibitors is crucial for maximizing therapeutic benefits and improving patient outcomes.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Estrogen receptor-positive (ER+) breast cancer is a significant health concern.
  • Phosphatidylinositol 3-kinase (PI3K) inhibitors are emerging as a therapeutic strategy for ER+ breast cancer.
  • Combination therapy with antiestrogens is being investigated to enhance treatment efficacy.

Purpose of the Study:

  • To understand the temporal response and pharmacodynamic effects of PI3K inhibition in ER+ breast cancer.
  • To provide a rationale for optimizing treatment schedules of PI3K inhibitors combined with antiestrogens.
  • To maximize the therapeutic index of combination therapies.

Main Methods:

  • Utilized antiestrogen-sensitive and resistant ER+ human breast cancer cell lines and xenografts.
  • Administered fulvestrant (antiestrogen) and GDC-0941 (PI3K inhibitor) as single agents or in combination.
  • Varied doses and schedules of GDC-0941, ensuring consistent weekly drug amounts.
  • Monitored cell viability, signaling pathways, proliferation, apoptosis, and tumor volume.
  • Measured GDC-0941 concentrations in plasma and tumors over time.

Main Results:

  • Combination therapy with fulvestrant and GDC-0941 was significantly more effective than single-agent treatments, particularly in fulvestrant-resistant tumors.
  • Short-term, complete PI3K inhibition demonstrated superior cancer cell growth blockade in vitro compared to chronic, incomplete inhibition.
  • Prolonged PI3K inhibition led to hypersensitization to growth factor signaling upon drug withdrawal.
  • Different dosing schedules of GDC-0941 resulted in comparable tumor responses.
  • Continuous inhibition with weekly high-dose GDC-0941 induced apoptosis and inhibited proliferation, but PI3K reactivation upon washout caused a proliferative burst.
  • Metronomic daily low-dose GDC-0941 led to repeated, temporary apoptosis induction and proliferation inhibition, with subsequent rebound compared to fulvestrant alone.

Conclusions:

  • Both continuous and metronomic PI3K inhibition exhibit potent anticancer effects in ER+, PIK3CA-mutant breast cancer.
  • Further clinical investigation into alternative treatment schedules for PI3K inhibitors in combination with antiestrogens is warranted.
  • Optimizing PI3K inhibitor scheduling may improve therapeutic outcomes in ER+ breast cancer treatment.

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