PLK1 and EGFR targeted nanoconstruct as a monotherapy and a radiation sensitizer for lung cancer

Lung cancer is the leading cause of cancer mortality, exceeding deaths from colon, breast, and prostate cancers combined. Resistance to chemo and targeted therapy is very common. Radiation therapy (RT) remains a key treatment in about 60% of lung cancer patients. We seek to develop a novel nanotherapeutic (termed PETTRA) that homes to EGFR+ lung tumors and delivers siRNA against Polo-like kinase 1 (siPLK1). EGFR is an ideal homing target since it is routinely profiled; and is overexpressed in 50% of lung cancer patients. PLK1 is among the strongest cancer targets due to its crucial roles in cell division and DNA repair, and inhibiting PLK1 leads to G2/M cell cycle arrest and apoptotic death. Cells in G2/M arrest are also most sensitive to radiation. Thus, PETTRA is hypothesized to be effective as a monotherapy and as a radiation sensitizer for lung cancer. Or prototype PETTRA has demonstrated good safety and efficacy for such dual proposes in cells and in mice. Herein, we propose to further optimize the material to enhance the efficacy and safety. While lipid-based particles have been effective at delivering siRNAs to the liver with 4 FDA approved drugs in the past few years, no platform has been successful in solid tumors yet. We have solved the limitations of nanoparticle delivery and achieved long circulation half-life (e.g., 25 hrs in monkeys), 10-fold increased siRNA accumulation in tumors, specific delivery to target cells (by 5 to 8- fold over normal cells), excellent PLK1 gene knock-down (e.g., by 84%), and tumor inhibition (e.g., by 90%) in mouse models. Tech-transfer for GMP manufacturing of our nanoparticles has been accomplished. Phase I: In Aim 1, we will optimize (by evaluating various EGFR antibody drugs (Ab) and increasing the loading of EGFR antibody and siPLK1 by at least 3-fold) and screen for the lead constructs that yield hydrodynamic size <120 nm, 75% gene knockdown, 7-fold greater uptake to EGFR+ over EGFR- cells, >70% cell death in EGFR+ lung cancer cells, and safety to normal cells (<15% death). Proof of concept efficacy and safety of the lead nanoconstruct will be performed in metastatic lung tumor mice. Phase II: In Aim 2, efficacy of the optimal PETTRA will be assessed, both alone and in combination with RT. Clinically relevant orthotopic NSCLC mouse models will be utilized, and findings will be validated in humanized mice bearing patient-derived tumors. Free drug counterparts, nanoparticle delivering single agents, and first- line chemo will be used as benchmarks. In Aim 3, the pharmacokinetics, biodistribution, and safety profile of PETTRA will be evaluated in tumor-bearing mice and in non-human primates. Results will provide important data towards an investigational new drug application to the FDA. Successful siRNA delivery has the potential to create hundreds of new targeted therapies for difficult to drug genes at low costs, benefiting both precision and personalized medicines. This project is a collaboration among PDX Pharmaceuticals, Biomedical Engineering Department, and the Knight Cancer Institute of OHSU.