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Target engagement imaging of PARP inhibitors in small-cell lung cancer

Brandon Carney1,2, Susanne Kossatz1, Benjamin H Lok3,4

  • 1Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Nature Communications
|January 14, 2018
PubMed

Insights

New PARP imaging accurately measures PARP inhibitor engagement in vivo for small-cell lung cancer (SCLC) patients. This technique allows real-time monitoring of drug delivery and target inhibition, potentially improving treatment strategies.

Area of Science:

  • Oncology
  • Molecular Imaging
  • Pharmacodynamics

Background:

  • Small-cell lung cancer (SCLC) treatment is challenged by insufficient chemotherapy response and rapid progression.
  • Current methods like CT scans and biopsies fail to assess in vivo target engagement of therapeutic agents.
  • There is a need for real-time methods to evaluate drug-target interactions within tumors.

Purpose of the Study:

  • To develop and validate a PARP1/2-targeted imaging method for quantifying PARP inhibitor engagement in vivo.
  • To assess the utility of this imaging approach in diverse preclinical models and with various PARP inhibitors.

Main Methods:

  • Utilized a panel of clinical PARP inhibitors with PARP1/2-targeted imaging.
  • Quantified target engagement in vitro and in vivo.
  • Measured PARP1/2 inhibition over time in patient-derived xenografts to determine effective doses and dosing regimens.

Main Results:

  • PARP imaging successfully quantified target engagement for chemically diverse small molecule PARP inhibitors.
  • The method allowed for the measurement of PARP1/2 inhibition dynamics over time.
  • Different therapeutics demonstrated similar integrated inhibition efficiencies under varied dosing schedules in xenograft models.

Conclusions:

  • PARP-targeted imaging provides a non-invasive, quantitative assessment of dynamic intratumoral target inhibition.
  • This imaging approach has the potential to enhance patient care by enabling real-time monitoring of drug delivery and target engagement.
  • May facilitate personalized treatment strategies for SCLC and other cancers treated with PARP inhibitors.

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