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Principal Investigator: SNIGDHA BANERJEE
Organization: KANSAS CITY VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Pancreatic ductal adenocarcinoma (PDAC) remains one of the leading sources of cancer mortality worldwide,
including US Veterans. An initial response to chemotherapy, such as Gemcitabine (GEM) is often followed by
emergent resistance reflecting an urgent need for targeted therapies. Our studies have found that CYR61 is a
druggable PDAC driver, and it can be suppressed by Zoledronic acid (ZA) under tissue culture conditions.
Regrettably, the weak availability in the target tissue limits the therapeutic efficacy of ZA. Thus, the goal of this
proposal is to evaluate a new approach for an iRGD-mediated-hypoxic/pH-responsive nanocarriers (ZA-iPRNCs)
based therapy, which can efficiently release ZA from the nano-capsule exclusively in the hypoxic
microenvironment of PDAC. In our in vitro and in vivo preliminary studies, we have established the feasibility of
the proposed method. We have shown that like free-ZA, CYR61 expression can be blocked significantly by ZA-
iPRNCs in different PDAC cell lines. We have also obtained results indicating that after intravenous delivery to
tumor-bearing mice, ZA-iPRNCs lead to robust tumor uptake detectable by in vivo imaging and, importantly,
results in suppression of CYR61 expression and tumor growth. Building on these exciting preliminary findings,
we now propose to unravel the mechanism of regulation of CYR61 by ZA, and determine whether ZA, via
blocking CYR61, inhibits PDAC growth and metastatic progression as well as makes cancer cells sensitive to
GEM using genetically engineered cell lines and mouse models. Further, we will also explore an additive impact
of nab-paclitaxel (Abraxane, NPac) on GEM sensitivity in tumor-bearing mice treated with ZA-iPRNCs, GEM,
and NPac together. To accomplish these goals, we propose three aims. In Aim 1, we will dissect the mechanism
of regulation of CYR61 expression in PDAC cells by ZA. In Aim 2, we will determine the maximum tolerated
dose (MTD) and bioavailability of ZA using immunocompetent mice. Lastly, in Aim 3, we will evaluate whether
nano carrier-based ZA therapy alone or in a combination of ZA-iPRNCs, GEM, and NPac leads to improved
tumor control and mouse survival in KPC and PDX mouse models. To achieve these aims, we have standardized
a non-invasive ultrasound imaging technique that reveals the various steps of tumor progression in mouse
models. With the help of these techniques and the unique collaborative expertise of the multidisciplinary team,
we will establish a new therapeutic approach for future clinical trials.
Terms: <2-(imidazol-1-yl)-1-hydroxyethylidene-1,1-bisphosphonic acid><3' Untranslated Regions><3'UTR><Abraxane><Acute><Anzatax><Asotax><BALB C Mouse><BALB/c><Binding Sites><Bioavailability><Biological Availability><Biological Markers><Blood Plasma><Body Tissues><Bristaxol><C-K-RAS><Cancer Treatment><Cancers><Cell Communication and Signaling><Cell Line><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><CellLine><Cellular Expansion><Cellular Growth><Cellular Migration><Cellular Motility><Chemopreventive><Chemopreventive Agent><Clinical Trials><Combining Site><Desmoplastic><Desmoplastic Reaction><Difluorodeoxycytidine><Dose><Down-Regulation><Drug Exposure><Drug Kinetics><Echography><Echotomography><Encapsulated><Epithelium><Female><Fetal Diseases><Future><Generalized Growth><Goals><Growth><Heterograft><Heterologous Transplantation><Human><Hypoxia><Hypoxic><Imaging Procedures><Imaging Technics><Imaging Techniques><Immunocompetent><In Vitro><Inbred BALB C Mice><Intracellular Communication and Signaling><Intravenous><Invaded><Investigational Drugs><Investigational New Drugs><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Kidney><Kidney Urinary System><Lead><Liver><Luciferase Immunologic><Luciferases><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Measures><Mediating><Medical Ultrasound><Mesenchymal><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modern Man><Molecular><Murine><Mus><Neoplasm Metastasis><Oncogene K-Ras><Oxygen Deficiency><PDA model><PDAC Model><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><Patient derived xenograft><Pb element><Pharmacokinetics><Phenotype><Physiologic Availability><Plasma><Plasma Serum><Plasmids><Play><Praxel><Primary Neoplasm><Primary Tumor><Production><Property><Proteins><RASK2><Reactive Site><Regulation><Renal clearance function><Reporter><Research><Resistance><Reticuloendothelial System, Serum, Plasma><Role><Route><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Source><Spleen><Spleen Reticuloendothelial System><Standardization><Strains Cell Lines><Taxol><Taxol A><Taxol Konzentrat><Techniques><Testing><Time><Tissue Growth><Tissues><Toxic effect><Toxicities><Treatment Efficacy><Tumor Suppressor Proteins><Ultrasonic Imaging><Ultrasonogram><Ultrasonography><Ultrasound Diagnosis><Ultrasound Medical Imaging><Ultrasound Test><Veterans><Xenograft><Xenograft procedure><Xenotransplantation><Zoledronic Acid><anti-cancer therapy><anti-carcinogenic><anticarcinogenic><bio-markers><biologic marker><biological signal transduction><biomarker><bone><cancer cell><cancer metastasis><cancer progression><cancer therapy><cancer-directed therapy><cell growth><cell motility><chemoprevention agent><chemotherapy><cultured cell line><dFdC><dFdCyd><diagnostic ultrasound><embryo/fetus disorder><fetal disorders><fetus disorder><gemcitabine><genetically engineered cells><genetically modified cells><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><imaging in vivo><immune competent><improved><in vivo><in vivo imaging><intervention efficacy><intravenous administration><male><malignancy><miRNA><miRNAs><migration><mortality><mouse model><multidisciplinary><murine model><mutant><nanocapsule><nanocarrier><nanodrug><nanopharmaceutical><nanovessel><neoplasm progression><neoplasm/cancer><neoplastic progression><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ontogeny><overexpress><overexpression><pancreatic cancer cells><pancreatic ductal adenocarcinoma cell><pancreatic ductal adenocarcinoma model><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><pancreatic tumor cells><patient derived xenograft model><prognostic><renal><renal clearance><resistant><response><social role><sonogram><sonography><sound measurement><spheroids><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapy efficacy><tissue biomarkers><tissue culture><tumor><tumor cell metastasis><tumor growth><tumor progression><tumor suppressor><ultrasound imaging><ultrasound scanning><uptake><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><xeno-transplant><xeno-transplantation>