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Principal Investigator: Sushanta K. Banerjee
Organization: KANSAS CITY VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
The Pancreatic ductal adenocarcinoma (PDAC), mostly a mutant K-Ras driven, in which hypoxia triggers
acidification of extracellular matrix, epithelial-to-mesenchymal transition (EMT)/cancer stemness (CSCs),
metastasis, desmoplasia, and chemoresistance. These pathological changes grim the prognosis of the disease.
Thus, EMT/CSCs and desmoplasia must be destructed to improve the prognosis. Emerging evidence indicates
that these processes are disrupted by targeting the extracellular signal-regulated kinases (ERKs) downstream
of the mutant K-Ras-signaling pathway. However, in the clinic, the weak bioavailability and dose-limiting toxicity
reduce ERK inhibitors' efficiency in halting tumor progression. Thus, there is a critical need to develop drug
carriers that selectively target PDAC tissues and suppress the growth of cancer cells via sustained drug release
deep into the tumor. We recently discovered that the efficacy of SCH 772984, an ERK-inhibitor (ERKi), can be
enhanced in systemic delivery if we encapsulated the ERKi in a pH/hypoxic-responsive nanocarrier (pHNPs)
attached with a tumor-penetrating peptide iRGD. Our preliminary studies suggest that ERKi suppresses the
production of CSCs and desmoplastic regulator protein CTGF/CCN2 in pancreatic cancer cells via blocking AP-
1-signaling. Finally, we also found that CTGF blockade by ERKi may participate in tumor fibroblast cell activation,
a hallmark of desmoplastic reaction. Building on these exciting preliminary findings, we propose finding the
optimal variant of ERKi-pHNPs, unraveling the mechanisms of response to ERKi therapy in human and murine
PDAC cell lines, and therapeutic efficacy alone or combined with gemcitabine and/or Nap-paclitaxel using
genetically engineered mouse models (GEMM) and Patient-derived xenograft (PDX) mouse models. The goal
of the project is to submit an investigational new drug application (IND) to the FDA with the long-term goal is to
translate this novel therapeutic product to the clinic to treat Veterans.
We propose three Aims. In Aim 1, we will synthesize different ERKi-pHNPs variants by modifying the
moieties, identifying an optimal variant from them by determining the in vitro and in vivo functional efficacy, and
evaluating the mechanism of action through the in vitro characterization in PDAC cells. In Aim 2, we will
determine the MTD, toxicity, and pharmacokinetics (PK) of an optimal variant of ERKi-PHNPs in the presence or
absence of chemotherapy in tumor-bearing CDX mice. Finally, in Aim 3, we will evaluate the effect of optimal
ERKi- pHNPs and free-GEM in translational studies using KPC and patient-derived tumor xenograft (PDX) models
for PC. The effect of Nab-paclitaxel with these combinations will also be tested. To realize these aims, we have
developed stimuli-responsive polymers (Mol. Pharmaceutics 2021, 18, 87−100 ), a unique in vitro desmoplastic
model (Mol Cancer Ther; 18, 2019), standardized non-invasive, high-resolution imaging, and high-thorough put
technologies to unveil various steps of tumor progression and associated molecular markers. We will use these
technologies and the outstanding collective expertise of our multi-disciplinary team to establish that ERKi-pHNPs
therapy is a powerful treatment strategy to target CSCs and desmoplasia and enhance the gemcitabine effect in
aggressive pancreatic cancer.
Terms: <AP-1><AP-1 Enhancer-Binding Protein><AP1><AP1 protein><Activator Protein-1><Acute><Anzatax><Asotax><Athymic Mice><Athymic Nude Mouse><Binding><Bioavailability><Biological Availability><Biological Markers><Blood Plasma><Body Tissues><Bristaxol><C-K-RAS><CCN2><CTGF><Cancer Cell Growth><Cancers><Cell Body><Cell Communication and Signaling><Cell Line><Cell Signaling><Cell Survival><Cell Viability><Cell-Extracellular Matrix><CellLine><Cells><Chemoresistance><Clinic><Clinical Trials><Combined Modality Therapy><Data><Desmoplastic><Desmoplastic Reaction><Development><Difluorodeoxycytidine><Disease><Disease Progression><Disorder><Dose><Dose Limiting><Drug Carriers><Drug Exposure><Drug Kinetics><Drugs><ECM><ERK MAP Kinases><Encapsulated><Enhancer-Binding Protein AP1><Extracellular Matrix><Extracellular Signal Regulated Kinases><Extracellular Signal-Regulated MAP Kinases><Female><Fibroblasts><Folate><Folic Acid><GEM model><GEMM model><Generalized Growth><Genetically Engineered Mouse><Goals><Growth><Growth Agents><Growth Factor><Growth Substances><Health><Human><Hypoxia><Hypoxic><IGF-binding protein-related protein-2><IGFBP-8><IGFBP-rP2><IP injection><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><In Vitro><Intracellular Communication and Signaling><Intraperitoneal Injections><Investigational New Drug Application><JUN Family Gene><JUN Proto-oncogene Family><JUN gene><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Kinases><Knowledge><Legal patent><MAPK ERK Kinases><Macrogols><Malignant><Malignant - descriptor><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Measures><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Mission><Modeling><Modern Man><Molecular Interaction><Molecular Target><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Napping><Neoplasm Metastasis><Nude Mice><Oncogene K-Ras><Outcome><Oxygen Deficiency><PDAC cancer cell><PDAC cell><PDX model><Paclitaxel><Paclitaxel (Taxol)><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreas Neoplasms><Pancreas Tumor><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pancreatic Tumor><Patents><Pathologic><Patient derived xenograft><Patients><Penetration><Peptides><Pharmaceutical Preparations><Pharmaceutics><Pharmacokinetics><Pharmacy (field)><Phenotype><Phosphotransferase Gene><Phosphotransferases><Physiologic Availability><Plasma><Plasma Serum><Polyethylene Glycols><Polyethylene Oxide><Polyethyleneoxide><Polymers><Polyoxyethylenes><Praxel><Process><Production><Prognosis><Proteins><Proteins Growth Factors><Pteroylglutamic Acid><RASK2><Ras Signaling Pathway><Receptor Protein><Research><Reticuloendothelial System, Serum, Plasma><Risk><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Standardization><Stem Cell like><Stimulus><Strains Cell Lines><Taxol><Taxol A><Taxol Konzentrat><Technology><Testing><Therapeutic><Threonine/Tyrosine Protein Kinase><Time><Tissue Growth><Tissues><Toxic effect><Toxicities><Transcription Factor AP-1><Translating><Transphosphorylases><Treatment Efficacy><Treatment Protocols><Treatment Regimen><Treatment Schedule><Variant><Variation><Veterans><Vitamin M><Xenograft Model><bio-markers><biologic marker><biological signal transduction><biomarker><c jun><c-jun Gene><cancer metastasis><cancer progression><chemoresistant><chemotherapy><chemotherapy resistance><chemotherapy resistant><combination therapy><combined modality treatment><combined treatment><connective tissue growth factor><cultured cell line><dFdC><dFdCyd><design><designing><develop drug resistance><developmental><disease prognosis><disease prognostication><drug discovery><drug resistance development><drug/agent><epithelial to mesenchymal transition><experience><experiment><experimental research><experimental study><experiments><extracellular><extracellular signal related kinase><fisp12 protein><frontier><fundamental research><gemcitabine><genetically engineered mouse model><genetically engineered murine model><high resolution imaging><human disease><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><in vivo><inhibitor><inhibitor drug><inhibitor therapeutic><inhibitor therapy><insulin-like growth factor binding protein 8><intervention efficacy><kinase inhibitor><male><malignancy><molecular biomarker><molecular marker><mouse model><multi-modal therapy><multi-modal treatment><multidisciplinary><murine model><mutant><nano particle><nano-sized particle><nanocarrier><nanoencapsulated><nanoencapsulation><nanoparticle><nanosized particle><nanovessel><neoplasm progression><neoplasm/cancer><neoplastic progression><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><optimal therapies><optimal treatments><overexpress><overexpression><pancreatic cancer cells><pancreatic ductal adenocarcinoma cell><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><pancreatic tumor cells><patient derived xenograft model><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><pharmaceutic><polymer><polymeric><pre-clinical><pre-clinical evaluation><preclinical><preclinical evaluation><prognostic><promoter><promotor><receptor><response><side effect><social role><stem cell characteristics><stemness><therapeutic efficacy><therapy efficacy><tissue biomarkers><translational study><treatment strategy><tumor><tumor cell metastasis><tumor growth><tumor progression><tumor xenograft><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><vitamin Bc><xenograft transplant model><xenotransplant model>