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

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.

Targeted Brain Tumor Radiotherapy Using an Auger Emitter

“…This central role has been successfully leveraged for the development of various PARP inhibitors, both as a monotherapy and in combination with other therapeutics (17,18). Modified PARP inhibitors have also been widely used for tumor detection and imaging due to their cancer specificity and their high target-to-background contrast (14,15,(19)(20)(21)(22)(23)(24)(25); more recently, they have found theranostic applications (26).…”

Targeted brain tumor radiotherapy using an Auger emitter

“…This central role has been successfully leveraged for the development of various PARP inhibitors, both as a monotherapy and in combination with other therapeutics (17,18). Modified PARP inhibitors have also been widely used for tumor detection and imaging due to their cancer specificity and their high target-to-background contrast (14,15,(19)(20)(21)(22)(23)(24)(25); more recently, they have found theranostic applications (26).…”

PARP1/2 imaging with 18F-PARPi in patients with head and neck cancer

“…These inflamed lymph nodes may mimic neck metastases on CT scans and are often 18 F-FDG PET avid (5)(6)(7)(8). On the other hand, some metastatic neck nodes may not be enlarged and show no abnormal 18 F-FDG uptake. For these reasons, elective neck dissection or irradiation are often recommended in patients with head and neck cancer for prophylactic treatment of occult metastases.…”

“…PARP1/2 is overexpressed in many malignancies, including oral and oropharyngeal squamous cell carcinoma (12,13), likely due to the enzyme's central role in DNA repair (14,15). Several radiolabeled PARP1/2 inhibitors were tested in preclinical studies (16,17), showing correlation of uptake with PARP1 expression (18,19), and suggesting that imaging is possible with little unspecific uptake in healthy head and neck tissue.…”

“…The purpose of this study was to clinically translate 18 F-PARPi, a PARP1/2 inhibitor derived from the core scaffold of olaparib (20), and to provide a first step toward validating the tracer as a clinical tool. Other PARP inhibitor-based imaging agents, based on different core scaffolds, were translated earlier (21)(22)(23).…”