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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
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Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma

Caitlin D May1,2, Sharon M Landers1, Svetlana Bolshakov1

  • 1a Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.

Cancer Biology & Therapy
|November 4, 2017
PubMed

Insights

Targeting the IGF1R/PI3K/mTOR pathway with combined inhibitors shows promise for treating undifferentiated pleomorphic sarcomas (UPSs). This approach may overcome resistance and improve outcomes for patients with these aggressive cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Undifferentiated pleomorphic sarcomas (UPSs) are aggressive cancers lacking clear cellular origins and genetic markers.
  • These tumors are often resistant to chemotherapy, necessitating novel therapeutic targets.
  • High activated protein kinase B (AKT) levels correlate with poor survival in UPS patients.

Purpose of the Study:

  • To investigate the efficacy of inhibiting the phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway in UPS.
  • To explore potential adaptive resistance mechanisms, such as insulin-like growth factor 1 receptor (IGF1R) activation.
  • To evaluate the therapeutic benefit of combining PI3K/mTOR and IGF1R inhibition.

Main Methods:

  • Utilized a small molecule inhibitor targeting the PI3K/mTOR pathway.
  • Administered a dual PI3K/mTOR inhibitor combined with an anti-IGF1R kinase inhibitor in vivo.
  • Assessed cell proliferation, motility, xenograft growth, and p27 subcellular localization.

Main Results:

  • PI3K/mTOR inhibition reduced UPS cell proliferation, motility, and xenograft growth in vitro and in vivo.
  • Increased IGF1R phosphorylation was observed, suggesting adaptive resistance.
  • Combination therapy significantly reduced in vivo tumor growth and decreased UPS cell migration and invasion.

Conclusions:

  • Targeted inhibition of multiple components within the IGF1R/PI3K/mTOR pathway is more effective than single-agent therapy for UPS.
  • Co-targeting this pathway represents a potential therapeutic strategy to improve outcomes for UPS patients.
  • Combination therapy may overcome adaptive resistance mechanisms observed with single-agent treatment.
Keywords:
IGF1RPI3K/MtorSarcomacombinationundifferentiated

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