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Principal Investigator: Fekadu Kassie
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2023
Award: $345,230
Funding agency: National Cancer Institute
PROJECT SUMMARY
Lung cancer is the leading cause of cancer-related death in the United States. About 90% of lung cancer cases
are associated with genetic/epigenetic changes induced by tobacco smoke (TS). Although all types of lung
cells could be affected by TS, the effect on stem cells is particularly alarming owing to their longevity and
propensity for transformation. Therefore, selective targeting of altered stem cells known as cancer stem cells
(CSCs) could prevent the development of lung cancer. In this application, we will test the hypothesis that
targeting of uniquely tumorigenic putative CSCs expressing high levels of aldehyde dehydrogenase 1(ALDH1H)
and CD44 (CD44H) with the combination of the repurposed drugs disulfiram (DSF) and sulfasalazine (SAS)
which are nano-formulated to enhance bioavailability will suppress the development and progression of
carcinogen-induced and spontaneous lung tumor in mice. These hypotheses will be tested by the following
three specific aims:
Specific Aim 1: Determine the efficacy of SLN-DSF, SLN-SAS and SLN-DSF+SAS to suppress NNK- or
mutant K-ras induced lung tumorigenesis by targeting ALDH1HCD44H subpopulations of lung cells. In this aim,
mice treated with NNK or harboring mutations in K-ras gene will be given the drugs and modulation of tumor
burden, frequency of ALDH1HCD44H lung tumor cells and CSC-associated proteins will be analyzed.
Specific Aim 2: Determine the immunosuppressive effects of ALDH1HCD44H putative LCSCs and whether the
anti-cancer effects of SLN-DSF-SAS are mediated, at least in part, via immunomodulatory mechanism and its
potential to enhance the therapeutic efficacy of anti-PD-L1 immune checkpoint inhibitors. Hypothesis:
Overexpression of PD-L1 by ALDH1HCD44H lung tumor cells endows them immunosuppressive properties and
modulation of these properties by SLN-DSF-SAS could potentiate anti-PD-L1-induced rescuing of
dysfunctional cytotoxic T cells and tumor destruction.
Specific Aim 3: Determine the role of common NSCLC genetic alterations in the generation, proliferation, self-
renewal, and tumor propagating efficiency of ALDH1HCD44H putative CSCs and if these effects are modulated
by SLN-DSF+SAS. Hypothesis: The genotype of transformed lung cells could be an important determinant of
the self-renewal and tumor-propagating potential of ALDH1H CD44H fractions.
Impact: Targeting ALDH1H CD44H putative CSCs is a new paradigm shift in lung cancer prevention and
treatment as these cells are believed to be the cell of origin of cancer.
Terms: <4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone><ALDH1><ALDH1 enzyme><Affect><Antabuse><B7-H1><B7H1><Bioavailability><Biological Availability><Blood Serum><C-K-RAS><CD274><CD44><CD44 gene><Cancer Cause><Cancer Causing Agents><Cancer Etiology><Cancer Treatment><Cancers><Carcinogens><Cell Body><Cell-Mediated Lympholytic Cells><Cells><Cessation of life><Checkpoint inhibitor><Chemoprevention><Cystine><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Data><Death><Development><Disulfiram><Dose><Drugs><Encapsulated><Endowment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Erinaceidae><Exhibits><Frequencies><Generations><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genotype><Glutamates><Hedgehog (Hh) signal transduction pathway><Hedgehogs><Immune><Immune checkpoint inhibitor><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><K-ras Gene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><L-Cystine><L-Glutamate><Length of Life><Literature><Longevity><Lung><Lung Neoplasms><Lung Respiratory System><Lung Tumor><MDU3><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Medication><Mice><Mice Mammals><Murine><Mus><Mutation><NNK><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Nonsmall Cell Lung Carcinoma><Oncogene K-Ras><Oncogenesis><Oncogens><Oxidative Stress><PD-L1><PDL-1><PDL1><Pgp1><Pharmaceutic Preparations><Pharmaceutical Preparations><Physiologic Availability><Population><Progenitor Cells><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Proliferating><Property><Proteins><Pulmonary Cancer><Pulmonary Neoplasms><Pulmonary malignant Neoplasm><RASK2><Reporting><Role><Salazosulfapyridine><Salicylazosulfapyridine><Serum><Short interfering RNA><Signal Pathway><Small Interfering RNA><Solid><Sulfasalazine><Testing><Tetraethylthiuram Disulfide><Tobacco smoke><Treatment Efficacy><Tumor Burden><Tumor Cell><Tumor Load><United States><aldehyde dehydrogenase 1><anti-cancer><anti-cancer therapy><anti-tumor effect><anticancer><anticancer therapy><antitumor effect><cancer progenitor cells><cancer stem cell><cancer therapy><cancer-directed therapy><combinatorial><determine efficacy><developmental><drug repurposing><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><epigenetically><evaluate efficacy><examine efficacy><genome mutation><glutamatergic><hedgehog signaling><hedgehog signaling pathway><hh signaling pathway><immune check point><immune check point inhibitor><immune checkpoint><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive activity><immunosuppressive function><immunosuppressive response><intervention efficacy><killer T cell><life span><lifespan><lipid based nanoparticle><lipid nanoparticle><lung cancer><lung cancer cell><lung cancer prevention><lung development><lung tumorigenesis><malignancy><malignant stem cell><member><mutant><nano><neoplasm/cancer><neoplastic cell><oncogenic agent><overexpress><overexpression><pharmacologic><prevent><preventing><programmed cell death ligand 1><programmed cell death protein ligand 1><protein death-ligand 1><pulmonary><repurposing agent><repurposing medication><self-renew><self-renewal><siRNA><smoothened signaling pathway><social role><stem cell genes><stem cell population><stem cells><therapeutic efficacy><therapy efficacy><tumor><tumorigenesis><tumorigenesis in the lung><tumorigenic><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog>