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Principal Investigator: Worapol Ngamcherdtrakul
Organization: PDX PHARMACEUTICALS, INC.
Fiscal Year: 2023
Award: $400,000
Funding agency: National Cancer Institute
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.
Terms: <A549><ABX-EGF><ABX-EGF MAb><Abscopal effect><Accounting><Anti-EGFR Monoclonal Antibody><Anti-Epidermal Growth Factor Receptor Monoclonal Antibody><Antibodies><Apoptotic><Benchmarking><Best Practice Analysis><Bilateral><Bioavailability><Biodistribution><Biological Availability><Biological Markers><Biomedical Engineering><Blood><Blood Chemical Analyses><Blood Chemical Analysis><Blood Circulation><Blood Reticuloendothelial System><Bloodstream><Body Weight><Breast Cancer><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CDDP><Cancer Cause><Cancer Etiology><Cancer Patient><Cancer Treatment><Cancer cell line><Cancers><Cell Body><Cell Cycle Arrest><Cell Death><Cell Line><Cell Survival><Cell Viability><Cell division><CellLine><Cells><Cessation of life><Cetuximab><Circulation><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clinic><Clinical Trials><Collaborations><Colon Cancer><Colon Carcinoma><Cysplatyna><DNA Damage Repair><DNA Repair><Data><Death><Dichlorodiammineplatinum><Dose><Drug Kinetics><Drugs><EGF Receptor><EGFR><ERBB Protein><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Exhibits><FDA approved><G2/M Arrest><Genes><HER1><Half-Life><Health><Hematology><Histology><Home><Homing><Immune><Immunes><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><In Vitro><Investigational New Drug Application><Laboratories><Lead><Lipids><Liver><Luciferase Immunologic><Luciferases><Lung><Lung Neoplasms><Lung Respiratory System><Lung Tumor><M Phase><M cell><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant Tumor of the Prostate><Malignant neoplasm of lung><Malignant neoplasm of prostate><Malignant prostatic tumor><Medication><Methods><Mice><Mice Mammals><Mitosis><Mitosis Stage><MoAb ABX-EGF><Modeling><Molecular Target><Monitor><Monkeys><Monoclonal Antibody ABX-EGF><Murine><Mus><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Names><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Nonsmall Cell Lung Carcinoma><Normal Cell><Organ><Outcome><PDX model><PLK Gene><PLK1><PLK1 gene><Particle Size><Patient derived xenograft><Patients><Pb element><Peyrone's Chloride><Peyrone's Salt><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Phase><Physiologic Availability><Platinum Diamminodichloride><Polo-Like Kinase><Position><Positioning Attribute><Prostate CA><Prostate Cancer><Prostate malignancy><Prostatic Cancer><Pulmonary Cancer><Pulmonary Neoplasms><Pulmonary malignant Neoplasm><RT-PCR><RTPCR><Radiation><Radiation Sensitizers><Radiation induced damage><Radiation therapy><Radiation-Sensitizing Agents><Radiation-Sensitizing Drugs><Radiosensitization><Radiosensitizing Agents><Radiosensitizing Drugs><Radiotherapeutics><Radiotherapy><Radiotherapy sensitizer><Renal function><Resistance><Reverse Transcriptase Polymerase Chain Reaction><Role><SBIR><STPK13><Safety><Saline><Saline Solution><Serine/Threonine Protein Kinase 13><Short interfering RNA><Small Business Innovation Research><Small Business Innovation Research Grant><Small Interfering RNA><Solid Neoplasm><Solid Tumor><Specificity><Strains Cell Lines><Surface><T8 Cells><T8 Lymphocytes><TGF-alpha Receptor><Therapeutic><Therapeutic Agents><Therapeutic Index><Toxic effect><Toxicities><Toxicology><Transforming Growth Factor alpha Receptor><Tumor Burden><Tumor Load><Unscheduled DNA Synthesis><Urogastrone Receptor><abscopal activity><abscopal response><anti-cancer therapy><anticancer therapy><benchmark><bio-engineered><bio-engineers><bio-markers><bioengineering><biologic marker><biological engineering><biomarker><blood chemistry><c-erbB-1><c-erbB-1 Protein><cancer cell><cancer in the colon><cancer therapy><cancer-directed therapy><cell killing><chemo-/radio-sensitization><chemotherapy><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><clinical relevance><clinically relevant><cost><cultured cell line><drug/agent><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><homes><humanized mice><humanized mouse><in vivo><inhibitor><kidney function><knock-down><knockdown><lead candidate><liver function><lung cancer><lung cancer cell><malignancy><malignant breast neoplasm><malignant breast tumor><manufacture><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><mortality><mouse model><murine model><mutation status><mutational status><name><named><naming><nano><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><nanotherapeutic><necrocytosis><neoplasm/cancer><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><non-human primate><nonhuman primate><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><overexpress><overexpression><panitumumab><particle><patient derived xenograft model><personalization of treatment><personalized medicine><personalized therapy><personalized treatment><pharmaceutical><polo-like kinase 1><precision medicine><precision-based medicine><proto-oncogene protein c-erbB-1><prototype><pulmonary><radiation damage><radiation sensitization><radiation treatment><radio-/chemo-sensitization><radio-sensitization><radiosensitizer><radiotherapy sensitization><resistant><reverse transcriptase PCR><siRNA><siRNA delivery><site targeted delivery><small molecule inhibitor><social role><success><synergism><targeted agent><targeted delivery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic outcome><therapy outcome><treatment with radiation><tumor><tumor growth><uptake>