Abstract
Insufficient chemotherapy response and rapid disease progression remain concerns for small-cell lung cancer (SCLC). Oncologists rely on serial CT scanning to guide treatment decisions, but this cannot assess in vivo target engagement of therapeutic agents. Biomarker assessments in biopsy material do not assess contemporaneous target expression, intratumoral drug exposure, or drug-target engagement. Here, we report the use of PARP1/2-targeted imaging to measure target engagement of PARP inhibitors in vivo. Using a panel of clinical PARP inhibitors, we show that PARP imaging can quantify target engagement of chemically diverse small molecule inhibitors in vitro and in vivo. We measure PARP1/2 inhibition over time to calculate effective doses for individual drugs. Using patient-derived xenografts, we demonstrate that different therapeutics achieve similar integrated inhibition efficiencies under different dosing regimens. This imaging approach to non-invasive, quantitative assessment of dynamic intratumoral target inhibition may improve patient care through real-time monitoring of drug delivery.
Highlights
Insufficient chemotherapy response and rapid disease progression remain concerns for smallcell lung cancer (SCLC)
The imaging agents generally exhibited comparable or higher specificity for PARP1/2 compared to the therapeutic molecules
Using PARP1 specific antibody staining on tissue microarrays, we found that all SCLC PDX exhibited elevated PARP1 expression compared to lung, kidney, muscle, liver and brain
Summary
Insufficient chemotherapy response and rapid disease progression remain concerns for smallcell lung cancer (SCLC). Using patient-derived xenografts, we demonstrate that different therapeutics achieve similar integrated inhibition efficiencies under different dosing regimens This imaging approach to non-invasive, quantitative assessment of dynamic intratumoral target inhibition may improve patient care through realtime monitoring of drug delivery. The combination of PARP inhibitors and DNA damaging agents, such as temozolomide, has seen recent success and sufficient delivery of both drug classes potentiates their therapeutic effects[2,3] One reason for this is that DNA damage repair plays an important role in the sensitivity of SCLC to chemotherapeutic agents, and current standard of care therapies for SCLC contain at least one DNA damaging agent. On the basis of these observations and the underlying genetics of the disease, PARP inhibition is gaining considerable attention as a novel systemic treatment for SCLC (i.e., NCT02289690, NCT02734004, NCT01286987)
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