Gap scheduling of a PARP inhibitor and nanoparticle TOP1 agent combination avoids synergistic bone marrow toxicity
Oplustil O'Connor, L.; Wang, A.; Sadler, C.; Barnes, J.; Odedra, R.; Smith, A.; Hughes, G.; Lau, A.; Tellez, A.; Eliasof, S.; Cadogan, E.; O'Connor, M. J.
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Although combinations of DNA damage response inhibitors (DDRi) and DNA damaging chemotherapy enhance cytotoxicity in cell-based systems, clinical success has been limited by overlapping bone marrow toxicities. Here, we show that a tumor-targeted nanoparticle camptothecin CRLX101, administered concurrently with DDRi, enhances anti-tumour efficacy but also increases bone marrow toxicity in preclinical models. Using rat bone marrow progenitor cells as biomarkers and leveraging differential repair kinetics of CRLX101-induced DNA damage in tumour and bone marrow, we identified a gap schedule of the PARP inhibitor olaparib and CRLX101 that enhanced efficacy over single agents but demonstrated a reduced combination marrow toxicity. A clinical trial has been designed using the gap schedule identified here and represents a template that can be used to successfully deliver DDRi with tumor-targeted chemotherapy in combination.
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