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Principal Investigator: AJAY NMN RANA
Organization: JESSE BROWN VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Project Summary/Abstract:
The main focus of research in our group is to understand the underlying molecular mechanisms of pancreatic
and breast cancer pathogenesis. The overarching goal of our research is to investigate how the cellular pathways
(i.e. circuits) are dysregulated and can lead to uncontrolled cell growth (i.e. cancer). The ultimate goal is to
develop and use small molecules to target the dysregulated proteins that are the underlying cause of pancreatic
and breast cancers pathogenesis.
Our laboratory has been working with a group of proteins, called Mixed Lineage Kinases (MLKs). The roles of
MLKs in cancer is an emerging area and the inhibitor of this family has gone through clinical trial for Parkinson's
Disease. We have shown that inhibitor of MLKs can be repurposed to treat Triple Negative breast cancer (TNBC)
and pancreatic ductal adenocarcinoma (PDAC).
Our recent results (funded through VA-Merit) demonstrate that one of the MLK family member, MLK3 was highly
overexpressed in human pancreatic cancer tumors and was necessary for cell growth. Furthermore, using animal
models of pancreatic cancer, we have observed that MLKs inhibitor ameliorate PDAC and the animals survive
much longer, compared to vehicle treated animals. We plan to further explore how MLK3 dysregulation promotes
pancreatic cancer and ultimately use the inhibitors for therapeutic intervention.
The other two projects (funded through 2 NCI/NIH grants) are on breast cancer. We reported earlier that
suppression of MLK3 activity by Estrogen was necessary for ER+ breast cancer cell survival and growth. We
also observed that the other receptor, HER2 was also able to suppress MLK3 activity in HER2+ breast cancer
and this was also necessary for their survival. Taken together, these exciting results suggest that suppression
of MLK3 by ER and HER2 provides survival signals for breast cancer cell growth and proliferation. Therefore,
we developed a novel nanoparticle, loaded with MLK3 activator, ceramide (a lipid) that was able to induce
significant cell death in HER2+ and ER+ breast cancer cells. In animal models of ER+ and HER2+ breast cancer,
the ceramide-nanoparticle was able to reduce tumor burden. In addition, we also observed that in human TNBC
tumors, the activity of MLK3 was very high compared to ER+ breast cancer tumors. Through mechanistic studies,
we identified that MLK3 activity plays paradoxically a survival role in TNBC. Based on our cellular and human
tumor data, the animal transplanted with TNBC tumors (i.e. PDXs) were treated with MLKs inhibitors, indeed the
tumor burden was reduced and the animal life was prolonged. Our results are first in line to demonstrate that
MLK3/MLKs inhibitors can significantly reduce TNBC tumor burden and can prolog animals' life. Similarly,
following our cellular and human tumor data, the tumor burden of Herceptin (i.e. anti-HER2+ therapy) resistant
human tumors in animal (i.e. PDXs) was reduced.
Taken together, our results suggest conclusively that activator of MLK3/MLKs could be used to treat ER+ and
HER2+ breast cancer, whereas the inhibitor of MLK3/MLKs could serve as a therapeutic intervention for TNBC
and pancreatic ductal adenocarcinoma (PDAC). Our comprehensive studies also suggest that it is utmost
important to understand the detail underlying molecular mechanisms of a disease before using any targeted
therapy.
Terms: <ATP-protein phosphotransferase><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><African American Females><African American Women><Aging><Animal Model><Animal Models and Related Studies><Animals><Anti-ERB-2><Anti-HER2/c-erbB2 Monoclonal Antibody><Anti-c-ERB-2><Anti-c-erbB2 Monoclonal Antibody><Anti-erbB-2><Anti-erbB2 Monoclonal Antibody><Anti-p185-HER2><Area><Award><Basal Transcription Factor><Basal transcription factor genes><Breast Cancer><Breast Cancer Cell><Breast Cancer Treatment><Breast Cancer cell line><Breast tumor cell line><Cancer Cell Growth><Cancer Genes><Cancer cell line><Cancer-Promoting Gene><Cancers><Cell Body><Cell Communication and Signaling><Cell Death><Cell Death Induction><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell Survival><Cell Viability><Cell-Extracellular Matrix><Cells><Cellular Expansion><Cellular Growth><Cellular Proliferation><Ceramides><Clinical><Clinical Trials><Communication><Cyclic AMP-Dependent Protein Kinases><Cytotoxic agent><Cytotoxic drug><Data><Death Rate><Detection><Disease><Disorder><Drug Targeting><ECM><EGF Receptor><EGFR><ER Positive><ER+><ERBB Protein><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Estrogen Receptors><Estrogen receptor positive><Estrogens><Extracellular Matrix><Failure><Family><Family member><Female><Funding><Future><General Transcription Factor Gene><General Transcription Factors><Goals><Grant><HER1><HER2 Monoclonal Antibody><Healthcare><Herceptin><Human><Immunity><Incidence><Intracellular Communication and Signaling><Investigation><Journals><Kinase Family Gene><Kinases><Laboratories><Life><Link><Lipids><MAP Kinase Cascades><MAP Kinase Modules><MAP Kinase Signaling Cascades><Magazine><Malignant Breast Neoplasm><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Mediating><Mice><Mice Mammals><MoAb HER2><Modern Man><Molecular><Murine><Mus><NIH><National Institutes of Health><Nature><Oncogenes><PDA model><PDAC Model><PKA><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreas Neoplasms><Pancreas Tumor><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pancreatic Tumor><Paper><Paralysis Agitans><Parkinson><Parkinson Disease><Pathogenesis><Pathway interactions><Patients><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiological><Play><Primary Parkinsonism><Protein Kinase><Protein Kinase A><Proteins><Publishing><Receptor Protein><Regimen><Reporting><Research><Resistance><Resistance development><Resistant development><Role><Scientist><Seminal><Signal Transduction><Signal Transduction Systems><Signaling><Site><Structure><TGF-alpha Receptor><TNBC><Testing><Therapeutic><Therapeutic Estrogen><Therapeutic Intervention><Thick><Thickness><Time><Transcription Factor Proto-Oncogene><Transcription factor genes><Transforming Genes><Transforming Growth Factor alpha Receptor><Transphosphorylases><Transplantation><Trastuzumab><Tumor Burden><Tumor Cell><Tumor Load><United States National Institutes of Health><Urogastrone Receptor><Veterans><Viet Nam><Vietnam><War><Woman><anti-cancer research><biological signal transduction><breast tumor cell><c-erb-2 Monoclonal Antibody><c-erbB-1><c-erbB-1 Protein><cAMP-Dependent Protein Kinases><cancer research><career><cell growth><chemotherapy><developing resistance><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><glycogen synthase a kinase><health care><human tissue><hydroxyalkyl protein kinase><improved><inhibitor><inhibitor drug><inhibitor therapeutic><inhibitor therapy><interest><intervention therapy><kinase inhibitor><malignancy><malignant breast tumor><model of animal><mortality><mortality rate><mortality ratio><nano particle><nano-sized particle><nanoparticle><nanosized particle><necrocytosis><neoplasm/cancer><neoplastic cell><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><overexpress><overexpression><pancreatic cancer cells><pancreatic cancer model><pancreatic ductal adenocarcinoma model><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><pancreatic tumor cells><pancreatic tumor model><pathway><phosphorylase b kinase kinase><proto-oncogene protein c-erbB-1><receptor><resistance to therapy><resistant><resistant to therapy><rhuMAb HER2><small molecule><social role><standard of care><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapy resistant><transcription factor><translational cancer research><transplant><treatment resistance><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor growth><uncontrolled cell growth>