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Principal Investigator: Rakesh K. Srivastava
Organization: GLAX, LLC
Fiscal Year: 2024
Award: $55,000
Funding agency: National Cancer Institute
Abstract
Pancreatic cancer is a slow-growing disease with a 5-year survival rate of approximately 9%. It is the fourth
leading cause of cancer-related deaths in the US. Currently used pancreatic cancer drugs are not very
effective and exhibit severe side effects. Patients develop drug resistance and ultimately cancer relapse due to
the generation of cancer stem cells (CSCs), which play significant roles in tumor initiation, promotion,
metastasis, and chemotherapy failure. Thus, there is an urgent need to develop new non-toxic drugs to
improve pancreatic cancer patients’ outcomes. Special AT-rich binding protein 2 (SATB2) is a nuclear matrix
protein that acts as a key regulator of gene expression and chromatin remodeling. SATB2 is highly expressed
in pancreatic cancer cells and CSCs, but not in human pancreatic normal ductal epithelial cells. Nanog, a
transcription factor, is highly expressed in mouse and human pluripotent stem cells. Nanog overexpression
has been detected in cancer and CSCs, and is correlated with cell proliferation, tumor recurrence, clonogenic
development, tumorigenicity, invasiveness, and resistance to chemotherapy. STAB2 plays a significant role in
the pluripotency and self-renewal of stem cells and inhibits pancreatic cancer cell growth. SATB2 regulates
the expression of pluripotency maintaining and self-renewal factors (Oct-4, Sox-2, Nanog, cMyc, and KLF4).
Furthermore, overexpression of the SATB2 gene induces malignant transformation, and inhibition of SATB2
expression by shRNA inhibits pancreatic cancer growth; suggesting the oncogenic role of SATB2 in pancreatic
cancer. Unfortunately, there are no small organic molecule-based FDA-approved SATB2 inhibitors in the
market. The main objective of this application is to identify and validate SATB2 inhibitors for the treatment of
pancreatic cancer using molecular docking, molecular dynamics simulations, and in vitro cell culture
approaches. Our hypothesis is that the SATB2 inhibitor suppresses pancreatic cancer growth by inhibiting
Nanog expression. Aim 1. To perform molecular screening and docking studies to find selective SATB2
inhibitors. Aim 2. To examine the molecular mechanisms by which SATB2 inhibitors suppress human
pancreatic cancer growth in vitro. Molecular docking studies, molecular dynamics simulations, and QikProp
analysis will be performed to identify non-toxic and drug-like selective SATB2 inhibitors. Biding residues of
SATB2 which interact with specific compounds (SATB2 inhibitors, small organic molecules) will also be
identified. The effects of SATB2 inhibitors on binding to SATB2 proteins, Nanog transcription, cell viability,
apoptosis, spheroid and colony formation, and epithelial-mesenchymal transition (EMT) will be examined. The
effects of SATB2 inhibitors on the expression of pluripotency and self-renewal genes (Oct-4, Sox-2, KLF-4,
cMyc, and Nanog), and stem cell markers (CD24, CD44, and CD133) will be measured by qRT-PCR and/or
western blot analysis. SATB2 binding partners/targets will be identified by Chromatin Immunoprecipitation
Sequencing (ChIP-seq). In conclusion, our studies are highly innovative and offer significant preclinical
benefits by developing non-toxic SATB2 inhibitors for the treatment of pancreatic cancer.
Terms: <Affect><Amino Acids><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Apoptosis><Apoptosis Pathway><Assay><Basal Transcription Factor><Basal transcription factor genes><Binding><Binding Proteins><Bioassay><Biological Assay><Body Tissues><CD44><CD44 gene><Cancer Cause><Cancer Cell Growth><Cancer Drug><Cancer Etiology><Cancer Relapse><Cancers><Cell Culture Techniques><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Survival><Cell Viability><Cellular Proliferation><Cessation of life><ChIP Sequencing><ChIP-seq><ChIPseq><Chemotherapy and Radiation><Chemotherapy and/or radiation><Conduct Clinical Trials><Data><Death><Development><Disease><Disorder><Distant><Docking><Dose><Drug Combinations><Drugs><Ductal Cell><Ductal Epithelial Cell><ES cell><Epithelium><Exhibits><FDA approved><Future><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Generations><Genes><Genetic Transcription><Goals><Growth><Human><Immunoblotting><In Vitro><Inhibition of Cell Proliferation><International><Laws><Ligand Binding Protein><Ligand Binding Protein Gene><MDU3><Malignant><Malignant - descriptor><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Marketing><Measures><Medication><Mesenchymal><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modern Man><Molecular><Molecular Dynamics Simulation><Molecular Interaction><Murine><Mus><Negative Control of Cell Proliferation><Negative Regulation of Cell Proliferation><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Normal Cell><Nuclear Matrix Proteins><Nuclear Matrix-Associated Proteins><Nuclear Scaffold Protein><Oncogenic><Organ><PDX model><PK/PD><Pancreas><Pancreas Cancer><Pancreas Neoplasms><Pancreas Tumor><Pancreatic><Pancreatic Cancer><Pancreatic Tumor><Pancreatic duct><Pathway interactions><Patient derived xenograft><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pgp1><Pharmaceutical Preparations><Play><Primary Neoplasm><Primary Tumor><Prognosis><Programmed Cell Death><Proliferating><Property><Protein Binding><Proteins><Quantitative RTPCR><Quantitative Reverse Transcriptase PCR><RNA Expression><Recurrent Neoplasm><Recurrent tumor><Regulator Genes><Resistance><Role><STAT1><STAT1 gene><STAT91><Secondary Neoplasm><Secondary Tumor><Structure><Survival Rate><Testing><Time><Tissue Growth><Tissues><Toxic effect><Toxicities><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Regulatory Elements><Treatment Failure><Tumor-Specific Treatment Agents><Tumorigenicity><Western Blotting><Western Immunoblotting><Wirsung canal><aminoacid><anti-cancer drug><bound protein><c myc><c-myc Genes><cancer metastasis><cancer progenitor><cancer progenitor cells><cancer stem cell><cell culture><cell cultures><chemo/radiation therapy><chemotherapy><chemotherapy and radiotherapy><chromatin immunoprecipitation-sequencing><chromatin remodeling><cmyc><design><designing><develop drug resistance><developmental><drug detection><drug resistance development><drug testing><drug/agent><effective therapy><effective treatment><efficacy validation><embryonic progenitor><embryonic stem cell><human pluripotent stem cell><improved><in vivo><inhibitor><innovate><innovation><innovative><malignancy><malignant progenitor><malignant stem cell><meter><molecular dynamics><neoplasm recurrence><neoplasm/cancer><novel><ontogeny><overexpress><overexpression><pancreatic cancer cells><pancreatic cancer model><pancreatic cancer patients><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><pancreatic tumor cells><pancreatic tumor model><pathway><patient derived xenograft model><patient oriented outcomes><patients with pancreatic cancer><pharmacokinetics and pharmacodynamics><pluripotency><pluripotent state><pre-clinical><preclinical><progenitor cell markers><progenitor cell regeneration><progenitor cell self renewal><progenitor markers><progenitor regeneration><progenitor self renewal><progenitor stem cell markers><protein blotting><qRTPCR><radiation or chemotherapy><regulatory gene><resistant><screening><screenings><self-renew><self-renewal><shRNA><short hairpin RNA><side effect><small hairpin RNA><social role><spheroids><stem and progenitor cell regeneration><stem and progenitor cell self renewal><stem cell biomarkers><stem cell markers><stem cell of embryonic origin><stem cell regeneration><stem cell self renewal><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapy failure><trans acting element><transcription factor><tumor cell metastasis><tumor initiation><v-myc Avian Myelocytomatosis Viral Oncogene Cellular Homolog><validate efficacy>