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Principal Investigator: PAUL Anthony WENDER
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $409,237
Funding agency: National Cancer Institute
Project Summary/Abstract:
This renewal involves integrated and interdependent synthetic, mechanistic, structural, biochemical
mode of action, computer modeling, collaborative and preclinical studies directed at the design,
synthesis, assay and advancement of fundamentally new and unique therapeutic leads and strategies
directed at unsolved global human health problems: the eradication of HIV/AIDS, novel treatments for
Alzheimer's disease and multiple sclerosis, and the use of small molecules to enhance antigen density in
antigen-targeted CAR T/NK cell therapies and cancer immunotherapy. HIV is one of the most
catastrophic pandemics to confront mankind. Current antiretroviral therapy (ART) addresses the active
virus, allowing one to live with HIV/AIDS, but with cost, compliance, resistance and chronic
chemoexposure challenges. ART is not curative. Reservoir cells incorporating genomically encoded
provirus episodically resupply the active virus. Elimination of these reservoir cells if done with ART is
thus one of the most promising strategies to eradicate HIV/AIDS. Modulation of protein kinase C (PKC)
represents one of the best strategies to activate reservoir cells for subsequent clearance by the immune
system, antibodies or immunotoxins. PKC modulators are also leading candidates for treating
Alzheimer's disease (in current clinical trial), for cancer immunotherapy (clinical trial proposed for 2021),
for multiple sclerosis and for many other unmet therapeutic needs. The lead PKC modulator, bryostatin
1, has been entered into clinical trials for AIDS eradication and Alzheimer's disease and is expected to
be used clinically in a CRADA conducted by NCI scientists to enhance antigen expression in antigen
targeted CAR T cell therapies for children with acute lymphoblastic leukemia who fail cell therapy
because of low antigen density. Enabled by our scalable (now GMP) synthesis of bryostatin which
represents the sole major supply of clinical grade material and our computational and REDOR solid state
NMR structural studies relevant to bryostatin binding to PKC, plans are presented for the design,
synthesis and evaluation of uniquely accessible “close-in” bryostatin analogs, super simplified analogs
and two new families of clinically relevant PKC modulators, collectively directed at the identification of
more efficacious, better tolerated and more synthetically accessible clinical candidates. New candidates
will be evaluated in a range of “in house” assays and in advanced assays conducted by a network of
collaborators expert in the clinically targeted areas.
Terms: <0-11 years old><2019-nCoV vaccine><AD dementia><AIDS><AIDS Virus><AIDS/HIV><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Acute Lymphoblastic Leukemia><Acute Lymphocytic Leukemia><Acute Lymphoid Leukemia><Address><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Affinity><Affinotoxins><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Anabolism><Animals><Anti-HIV Positivity><Antibodies><Antigen Targeting><Antigens><Aquaculture><Area><Assay><Award><B-Cell Antigen CD22><B3 antigen><Binding><Bioassay><Biochemical><Biological><Biological Assay><Bryostatin-1><CAR T cell therapy><CAR T cells><CAR T therapy><CAR modified T cells><CAR-T><CAR-Ts><CD22><CD22 antigen><CD22 gene><COVID-19 vaccine><CRADA><CRISPR><CRISPR/Cas system><Calcium Phospholipid-Dependent Protein Kinase><Calcium-Activated Phospholipid-Dependent Kinase><Cancer Treatment><Cancers><Canine Species><Canis familiaris><Cell Body><Cell Function><Cell Physiology><Cell Process><Cell Therapy><Cells><Cellular Assay><Cellular Function><Cellular Physiology><Cellular Process><Child><Child Youth><Children (0-21)><Chronic><Clinical><Clinical Research><Clinical Study><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats><Computer Models><Computerized Models><Cooperative Research and Development Agreement><Cyclic AMP-Dependent Protein Kinases><Cytotoxin-Antibody Conjugates><DNA><Deoxyribonucleic Acid><Development><Disease><Disorder><Disseminated Malignant Neoplasm><Disseminated Sclerosis><Dogs><Dogs Mammals><Drug Delivery><Drug Delivery Systems><Drug Precursors><Drugs><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Evaluation><FDA approved><Family><Foundations><Genomics><Goals><Grant><HIV><HIV Positive><HIV Positivity><HIV Seroconversion><HIV Seropositivity><HIV antibody positive><HIV/AIDS><HTLV-III Seroconversion><HTLV-III Seropositivity><Health><Human><Human Immunodeficiency Viruses><Immune system><Immunology><Immunotoxins><In Vitro><Individual><Injections><Isoforms><Knowledge><LAV-HTLV-III><Lead><Letters><Licensing><Lymphadenopathy-Associated Virus><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mast Cell Neoplasm><Mast Cell Proliferative Disease><Mast Cells Tumor><Mastocytoma><Medication><Medicine><Messenger RNA><Metastatic Cancer><Metastatic Malignant Neoplasm><Mice><Mice Mammals><Modern Man><Modification><Molecular Interaction><Monoclonal Antibody-Toxin Conjugates><Multiple Sclerosis><Murine><Mus><NIH><NK cell therapy><National Institutes of Health><Natural Products><Neurology><PKA><Patients><Pb element><Penetration><Peptides><Pharmaceutical Preparations><Phospholipid-Sensitive Calcium-Dependent Protein Kinase><Precursor Cell Lymphoblastic Leukemia><Precursor Lymphoblastic Leukemia><Primary Senile Degenerative Dementia><Pro-Drugs><Prodrugs><Productivity><Protein Engineering><Protein Isoforms><Protein Kinase A><Protein Kinase C><Proviruses><Pseudo-natural product><Publications><Reporting><Research><Resistance><Role><SARS-CoV-2 vaccine><SARS-coronavirus-2 vaccine><SIGLEC2><SSNMR><Scientific Publication><Scientist><Seminal><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Short interfering RNA><Sialic Acid-Binding Immunoglobulin-Like Lectin 2><Small Interfering RNA><Source><Structure><Subcellular Process><T cells for CAR><T-Cells><T-Lymphocyte><Technology><Therapeutic><Time><Toxic effect><Toxicities><Toxin-Antibody Conjugates><Toxin-Antibody Hybrids><Trees><United States National Institutes of Health><Virus><Virus-HIV><Work><acute lymphatic leukemia><acute lymphogenous leukemia><acute lymphomatic leukemia><analog><anti-cancer immunotherapy><anti-cancer research><anti-cancer therapy><anticancer immunotherapy><antiretroviral therapy><antiretroviral treatment><biologic><biosynthesis><bryostatin><cAMP-Dependent Protein Kinases><cancer clinical trial><cancer immunotherapy><cancer research><cancer therapy><cancer-directed therapy><canine><career><cell assay><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><chimeric antigen T cell receptor><chimeric antigen receptor (CAR) T cell therapy><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cell therapy><chimeric antigen receptor T cells><chimeric antigen receptor T therapy><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><clinical candidate><clinical relevance><clinical significance><clinically relevant><clinically significant><comparative><computational modeling><computational models><computer based models><computerized modeling><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><cost><deliver mRNA><deliver messenger RNA><delivery system for mRNA><density><design><designing><developmental><domestic dog><drug/agent><epigenetically><exhaustion><genetic protein engineering><guanidinium><heavy metal Pb><heavy metal lead><humanized mice><humanized mouse><immune clearance><immune elimination><immune-based cancer therapies><immunogen><immunotherapy for cancer><immunotherapy of cancer><insular sclerosis><kids><mRNA><mRNA delivery><malignancy><marine><marine culture><marine environment><messenger RNA delivery><molecular transporter><mouse model><murine model><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><natural killer cell therapy><natural product inspired><natural product-like><naturally occurring product><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oncology clinical trial><pandemic><pandemic disease><phase 2 trial><phase II trial><pre-clinical><pre-clinical study><preclinical><preclinical study><primary degenerative dementia><programs><protein design><resistant><scaffold><scaffolding><scale up><senile dementia of the Alzheimer type><siRNA><small molecule><social role><solid state NMR><solid state nuclear magnetic resonance><thymus derived lymphocyte><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidates against SARS-CoV-2><vaccine for novel coronavirus><vaccines preventing COVID><vaccines to prevent COVID><virology><youngster>