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Principal Investigator: Subhash C. Chauhan
Organization: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
Fiscal Year: 2019
Award: $140,790
Funding agency: National Cancer Institute
The long-term goal of the proposed research proposal is to develop a targeted paclitaxel nanotherapy that
can be used for the treatment of pancreatic cancer (PanCa) in combination with Gemcitabine (GEM).
Although many conventional and combinational chemotherapies exist to treat PanCa, significant side
effects occur without increasing the survival of patients (not even 2 additional months). Desmoplasia
(characterized by excessive fibrosis and extracellular matrix deposition) causes suboptimal drug delivery in
tumors and thus induces chemo-resistance. Additionally, certain signaling pathways, abnormal tumor cell
membrane lipid structure/composition and restricted drug uptake due to overexpression of drug efflux
associated proteins also lead to cancer progression/metastasis and drug resistance. A recent FDA-
approved (on Sept. 6, 2013) combination treatment regimen [nab-nanoparticles (i.e., paclitaxel nanoparticles,
Abraxane®) plus GEM] has marginally improved (only 1.8 months) overall survival (8.5 months vs. 6.7 months
with GEM alone). Studies have also shown that PTX altered tumor microenvironment (TME) and reduced
desmoplasia, thus improved GEM uptake in pancreatic tumors. We believe that this PTX-mediated
marginally improved therapeutic outcome can be further enhanced by using an inimitable tumor specific
antibody targeted PTX nanoparticle formulation. We hypothesize that antibody-guided, tumor specific
targeted delivery of PPNPs will enhance the bioavailability of PTX in pancreatic tumors and macro/
micro metastatic lesions to attenuate tumor growth and sensitize tumor cells to GEM via decreased
desmoplasia, altered TME and SHH/CXCL12/CXCR4, miR-21 mediated oncogenic signaling pathways.
This proposal examines two levels of targeting PanCa. The first is MUC13 targeted delivery of PTX to
pancreatic tumors as our PPNPs selectively/preferentially reach and accumulate in the tumors/metastatic
lesions. Our preliminary data demonstrates that MUC13 targeted nanoparticles effectively target pancreatic
tumors. The second level of treatment is intravenous administration of GEM. The first level of targeting will
considerably alter TME which will thus promote a better response to GEM. This novel combination therapeutic
modality will enhance drug loading specifically to the tumor site, inducing greater anti-cancer effects while
minimizing side effects. To achieve these goals, three specific aims are proposed: AIM 1: To Evaluate Chemo-
sensitization and TME of PPNPs in PanCa Cells. AIM 2: To Investigate Pharmaco-kinetics/dynamics (PK/PD)
and Safety of PPNPs/GEM in a stromal component containing PanCa xenograft mouse model. AIM 3: To
Evaluate the Therapeutic Efficacy of MUC13 Targeted PPNP Formulation in clinically relevant transgenic
mice and patient derived xenograft (PDX) models. This proposal leads to a better treatment modality by
altering tumor-stromal (paracrine) cross-talk and chemo-sensitization in PanCa which are considered to be
major roadblocks in PanCa therapeutics. The proposed studies are based on recent clinical observations,
thus clinical translation of this approach will be easy and quick.
Terms: <Abraxane><Albumin-Stabilized Nano particle Paclitaxel><Albumin-Stabilized Nanoparticle Paclitaxel><Albumins><Anti-Cancer Agents><Antibodies><Antibody-drug conjugates><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Anzatax><Apoptotic><Asotax><Attenuated><Bioavailability><Biodistribution><Biologic Availability><Biological Availability><Bristaxol><CXC-R4><CXCL12><CXCL12 gene><CXCR-4><CXCR4><CXCR4 gene><Cancer Drug><Cancer Treatment><Cell Line><Cell Membrane Lipids><Cell-Extracellular Matrix><CellLine><Cessation of life><Chemosensitization><Chemosensitization/Potentiation><Clinical><Combination Drug Therapy><Coupled><D2S201E><Data><Death><Deposit><Deposition><Development><Diagnosis><Difluorodeoxycytidine><Disease><Disorder><Drug Delivery><Drug Delivery Systems><Drug Efflux><Drug Kinetics><Drug Transport><Drug resistance><Drugs><ECM><Engineering><Environment><Exhibits><Extracellular Matrix><FB22><FDA approved><Fibrosis><Formulation><Generalized Growth><Goals><Growth><HM89><HSY3RR><Heterograft><Heterologous Transplantation><In Vitro><Investigation><LAP3><LCR1><LESTR><Lead><Legal patent><Lipids><MUC-1><MUC1><MUC1 gene product><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Pancreatic Neoplasm><Malignant neoplasm of pancreas><Mediating><Medication><Membrane Lipids><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Micro RNA><MicroRNAs><Modality><Molecular><Muc1 Mucin><Mucin 1><Mucin 1 protein><NPY3R><NPYR><NPYRL><NPYY3R><Nanoparticle Paclitaxel><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Oncogenic><PBSF><PK/PD><Paclitaxel><Paclitaxel (Taxol)><Pancreas Cancer><Pancreas Neoplasms><Pancreas Tumor><Pancreatic Cancer><Pancreatic Tumor><Patents><Pathway interactions><Patients><Pb element><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Physiologic Availability><Pluronics><Polychemotherapy><Potentiation><Praxel><Proteins><Publishing><Regulation><Research Proposals><Resistance><SCYB12><SDF-1A><SDF-1B><SDF1><SDF1A><SDF1B><SHH><SHH gene><Safety><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Site><Sonic Hedgehog><Strains Cell Lines><Stromal Neoplasm><Stromal Tumor><Survival Rate><System><TLSF-A><TLSF-B><TPAR1><Taxol><Taxol A><Taxol Konzentrat><Testing><Therapeutic><Tissue Growth><Transgenic Mice><Transgenic Organisms><Treatment Efficacy><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tumor Cell><Tumor-Specific Treatment Agents><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><anti-cancer><anti-cancer drug><anti-cancer therapy><anticancer><anticancer agent><anticancer drug><anticancer therapy><base><cancer metastasis><cancer microenvironment><cancer progression><cancer therapy><chemotherapy><clinical relevance><clinical translation><clinically relevant><combination chemotherapy><combination pharmacotherapy><combined drug therapy><cultured cell line><dFdC><dFdCyd><developmental><drug development><drug resistant><drug/agent><effective therapy><effective treatment><gemcitabine><heavy metal Pb><heavy metal lead><improved><in vivo><innovate><innovation><innovative><intervention efficacy><intravenous administration><lipid structure><miRNA><miRNAs><mouse model><murine model><nano formulation><nano particle><nano particle Paclitaxel><nano therapy><nano-sized particle><nanoformulation><nanoparticle><nanosized particle><nanotherapy><neoplasm progression><neoplastic cell><neoplastic progression><novel><off-patent><ontogeny><overexpress><overexpression><pancreatic cancer cells><pancreatic cancer patients><pancreatic neoplasia><pancreatic neoplasm><pancreatic tumor cells><paracrine><pathway><patients with pancreatic cancer><pharmacokinetics and pharmacodynamics><resistance mechanism><resistance to Drug><resistant><resistant mechanism><resistant to Drug><response><side effect><site targeted delivery><targeted delivery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutic outcome><therapeutically effective><therapy efficacy><therapy outcome><transgenic><treatment choice><tumor><tumor cell metastasis><tumor growth><tumor microenvironment><tumor progression><uptake><xeno-transplant><xeno-transplantation>