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Principal Investigator: Chinthalapally V. Rao
Organization: OKLAHOMA CITY VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Summary
Pancreatic cancer (PC) has the highest mortality of any cancer, with a 5-year survival rate of less than 10%.
Despite progress in the development of targeted therapies, the survival rate is still unacceptably low. It is,
therefore, important to identify novel therapeutic approaches that could lead to a more effective treatment for
this malignant disease. This proposal explores the novel concept that a core 2 mucin synthesis gene, GCNT3,
regulates PC growth and survival, ascribing a new and critical role to GCNT3. We have shown that GCNT3
is overexpressed in PC patients and contributes to PC pathogenesis, indicating that GCNT3 is a promising
therapeutic target. However, how GCNT3 regulates PC is not clear. Using in silico small molecular docking
simulation approaches, we discovered that talniflumate is a novel inhibitor that selectively binds to GCNT3.
Examining the molecular mechanisms of GCNT3-mediated PC growth, we found that siRNA-mediated
knockdown of GCNT3 or treatment with talniflumate, inhibited xenograft tumors. Talniflumate also reduced
GCNT3 expression, leading to reduced production of mucins in vivo and in vitro, and improved cellular
gemcitabine uptake. Taken together, our findings strongly suggest that targeting mucin biosynthesis through
GCNT3 may improve responsiveness to drug treatment.
We, therefore, hypothesize that aberrant expression of GCNT3 will lead to excessive mucin synthesis
during PC development and cause chemoresistance. Hence, the inhibition of aberrant mucin synthesis is
sufficient to disrupt the barrier properties of the mucin mesh to efficiently increase the access of
chemotherapeutics to target sites. Three independent, yet interrelated, specific aims are proposed to address
this hypothesis. Aim 1: Generate GCNT3-deficient KPC mice and determine whether targeting GCNT3 ablates
the mucin barrier and inhibits PC progression/metastasis by increasing gemcitabine and nab-paclitaxel (NPT)
efficacy. Aim 2: Determine whether combinational therapy of talniflumate plus NPT are effective in treating PC
by a) evaluating the efficacy and dose-response effects of the combination administered in vivo in a clinically
relevant KPC model of spontaneous PC and b) determining mucin disruption and gemcitabine or NPT uptake
in combination-treated tumors. c) We will establish the GCNT3 and NPT levels in tumor tissue and their
correlation with mucin subtypes (Mucs) and PC treatment efficacy via whole genome transcriptome
sequencing and PET imaging. Aim 3: We will investigate the role of GCNT3 in gemcitabine resistance, mucin
overexpression and PC growth. a) For clinical relevance, we will assess the inhibition of human patient-
derived xenografts (PDX) and PC slice cultures by combinational therapy. b) Evaluate the efficacy of
combination against GCNT3 overexpressing human PC PDX tumors in vivo.
Veterans Health Relevance: Pancreatic cancer major health problem and many veterans and their
families suffered from this neoplastic disease. The results obtained from this study will have high impact, since
they will shed light on future development of novel therapeutic strategies for PC. Thus, this proposal is highly
translational in nature
Terms: <Ablation><Address><Adenocarcinoma><Anabolism><Anzatax><Asotax><Binding><Body Tissues><Bristaxol><CRISPR><CRISPR/Cas system><Cancer Treatment><Cancers><Carcinoma><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cellular Function><Cellular Physiology><Cellular Process><Chemoresistance><Clinical Research><Clinical Study><Clustered Regularly Interspaced Short Palindromic Repeats><Combined Modality Therapy><Development><Difluorodeoxycytidine><Disease><Disorder><Docking><Dose><Drug Delivery><Drug Delivery Systems><Drug Therapy><Drugs><Duct><Duct (organ) structure><Enzyme Gene><Enzymes><Epithelial cancer><Family><Future><Generalized Growth><Genes><Genetic><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Growth><Health><Heterograft><Heterologous Transplantation><Human><Impairment><In Vitro><Incidence><Intracellular Communication and Signaling><Investigation><KPC genetically-engineered mouse><KPC model><KPC mouse><KPC murine><Knock-out><Knockout><LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre><LSL-KrasG12D/+;LSL-p53R172H/+;Pdx-1-Cre><Lesion><MUC-1><MUC1><MUC1 gene product><MUC2><MUC5AC><MUC5AC gene><Malignant><Malignant - descriptor><Malignant Adenoma><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Mediating><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Mice><Mice Mammals><Modern Man><Molecular><Molecular Interaction><Muc1 Mucin><Mucin 1><Mucin 1 protein><Mucin 2><Mucin-2 Staining Method><Mucins><Mucus Glycoprotein><Multimodal Therapy><Multimodal Treatment><Murine><Mus><N-Acetylglucosamine Transferases><N-Acetylglucosaminyltransferases><NGS Method><NGS system><Nature><Neoplasm Metastasis><Neoplasms><Oncogenesis><Oncogenic><Outcome><PDX model><PET><PET Scan><PET imaging><PETSCAN><PETT><Paclitaxel><Paclitaxel (Taxol)><PanIN><Pancreas><Pancreas Cancer><Pancreas Neoplasms><Pancreas Tumor><Pancreatic><Pancreatic Cancer><Pancreatic Duct Dysplasia><Pancreatic Ductal Dysplasia><Pancreatic Intraepithelial Neoplasia><Pancreatic Tumor><Pathogenesis><Patient derived xenograft><Patients><Pharmaceutical Preparations><Pharmacotherapy><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Praxel><Production><Proliferating><Property><RNA Seq><RNA sequencing><RNAseq><Rad.-PET><Recombinant DNA Technology><Research><Resistance><Role><Secondary Neoplasm><Secondary Tumor><Short interfering RNA><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Slice><Small Interfering RNA><Source><Subcellular Process><Survival Rate><Taxol><Taxol A><Taxol Konzentrat><Testing><Therapeutic><Therapeutic Effect><Tissue Growth><Tissues><Treatment Efficacy><Tumor Cell><Tumor Promotion><Tumor Tissue><Tumor Weights><Up-Regulation><Upregulation><Veterans><Xenograft><Xenograft procedure><Xenotransplantation><anti-cancer therapy><biological signal transduction><biosynthesis><cancer metastasis><cancer progression><cancer therapy><cancer-directed therapy><chemoresistant><chemotherapy><chemotherapy resistance><chemotherapy resistant><clinical relevance><clinical translation><clinically relevant><clinically translatable><combination therapy><combined modality treatment><combined treatment><dFdC><dFdCyd><determine efficacy><developmental><drug treatment><drug/agent><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><entire genome><epithelial carcinoma><evaluate efficacy><examine efficacy><female patients><full genome><gemcitabine><gene synthesis><genetically engineered><human data><improved><in silico><in vivo><inhibitor><intervention efficacy><knock-down><knockdown><male><malignancy><mortality><multi-modal therapy><multi-modal treatment><neoplasia><neoplasm progression><neoplasm/cancer><neoplastic><neoplastic cell><neoplastic growth><neoplastic progression><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next gen sequencing><next generation sequencing><next generation therapeutics><nextgen sequencing><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><ontogeny><overexpress><overexpression><pancreas duct dysplasia><pancreas ductal dysplasia><pancreatic PDX models><pancreatic cancer cells><pancreatic cancer patients><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><pancreatic patient derived xenograft><pancreatic tumor cells><patient derived xenograft model><patients being female><patients being women><patients who are female><patients with pancreatic cancer><pharmacologic><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><pre-clinical study><preclinical study><resistant><response><response to therapy><response to treatment><siRNA><simulation><social role><spheroids><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutic response><therapeutic target><therapy efficacy><therapy response><transcriptome sequencing><transcriptomic sequencing><translation strategy><translational approach><translational strategy><treatment response><treatment responsiveness><treatment strategy><tumor><tumor cell metastasis><tumor growth><tumor progression><tumor xenograft><tumorigenesis><uptake><whole genome><women patients><xeno-transplant><xeno-transplantation>