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Principal Investigator: Gregory M Lanza
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2019
Award: $672,844
Funding agency: National Cancer Institute
MM responds well to initial chemotherapy but relapses occur in the majority of MM patients and nearly all
patients die from progressive disease within 6 years. We hypothesize that targeted nanotherapy will disrupt the
transformative influence of cMyc on myeloma progression and significantly impact on the care and extend
survival of MM patients. This proposal, invokes a targeted therapeutic nanoparticle approach to deliver potent
payloads of c-Myc-Max dimerization inhibitors specifically to myeloma cells in marrow while minimizing off-
target toxicities. Myc encodes a helix-loop-helix transcription factor upregulated in 50-80% of human cancers
that is associated with 100,000 US cancer deaths per year. Myc heterodimerizes with its partner Max to control
target gene transcription and is deeply integrated into the regulatory and control mechanisms governing cell
viability and proliferation. We and others have used animal models to demonstrate the cancer-inducing
properties of Myc as well as a dependence of the transformed phenotype on continued expression of Myc, a
phenomenon known as oncogene addiction. The loss of Myc proteins inhibits cell proliferation and growth,
accelerates differentiation, increases cell adhesion, and accentuates the response to DNA damage. MYC
activates transcription and represses target gene expression through Miz-1 transcription factor or by the
regulation of micro-RNAs (miRs). However, rather than initiating a specific transcriptional program, MYC
amplifies the output of existing transcriptional programs within a given cell. Myc is expressed by normal and
cancer cells, but the former are generally quiescent with minimal Myc expression.
Myc's increased expression in cancer has long made it an important but elusive target for anti-cancer
therapeutics, particularly in MM, which is highly susceptible to Myc-Max interference. Unfortunately, several
effective small-molecule inhibitors of the MYC-MAX interaction in vitro failed when applied in vivo due to rapid
systemic metabolism, poor bioavailability, and an inability to achieve effective drug levels in tumors. We have
demonstrated substantially increased survival in an aggressive metastatic mouse model of MM by delivering
Myc-Max dimerization antagonists as Sn 2 lipase labile prodrugs (MI1-PD) using a novel lipid-micellar
nanotherapeutic targeted to the VLA-4 integrin (α4β1) receptor. The overarching aim of this program will be to
select and develop a transformative and clinically translatable VLA-4 targeted cMyc-Max antagonist PD
nanotherapeutic candidate to maximize MM survival.
The specific aims of this translational project are:
Aim 1: Design, synthesize, develop, characterize and evaluate novel VLA-4 targeted Sn 2 lipase-labile cMyc-
Max inhibitor prodrug nanotherapies.
Selected small molecule cMyc-Max inhibitors that increase intracellular drug retention or bind differentially to
cMyc to antagonize dimerization will be synthesized into Sn 2 prodrugs, characterized analytically, and studied
physicochemically and biologically as nanotherapeutics to define in vitro potency, nanoparticle stability, and in
vivo toxicity, pharmacokinetics and biodistribution pharmacology.
Aim 2: Demonstrate optimized survival in preclinical mouse models of MM using VLA-4 Sn 2 cMyc-prodrug
nanotherapy and assess the basis for noncurative responses.
The efficacy of VLA-4 Sn 2 cMyc-prodrug nanotherapies will be compared and selected based on survival,
noninvasive imaging, and clinical biomarkers of disseminated MM in two separate preclinical models:
5TGM1/KaLwRij. We anticipate anti-Myc nanoparticles used as a single agent will prolonging survival, but
most animals will eventually succumb to MM. MM clones from mice relapsing following treatment will be
characterized using flow cytometry, RNA and DNA sequencing to determine the basis of therapeutic resistance
and potential susceptibility to complementary treatments.
Aim 3. Establish combinations of VLA-4-cMyc-PD nanotherapy with standard-of-care therapies to increase MM
sensitivity to cMyc-antagonism and to address MM surviving clonal populations following Myc-PD nanotherapy.
The efficacy of VLA-4 Sn 2 cMyc-prodrug nanotherapies used in combination with currently approved
chemotherapies will be compared and selected based on clinical biomarkers, noninvasive imaging, and
survival in preclinical animal models of MM. First, traditional chemotherapies will be dosed intravenously in
combination with VLA-4 Sn 2 cMyc-prodrug nanotherapies.
Terms: <Ab response><Address><Alkylating Agents><Alkylators><Animal Model><Animal Models and Related Studies><Animals><Antibody Formation><Antibody Production><B cell differentiation><B lymphocyte differentiation><Basal Transcription Factor><Basal transcription factor genes><Basic Research><Basic Science><Binding><Bio-Informatics><Bioavailability><Biodistribution><Bioinformatics><Biologic Availability><Biological><Biological Availability><Blood Plasma Cell><Bortezomib><CD49d-CD29><Cancer Center><Cancer Genes><Cancer-Promoting Gene><Cancers><Caring><Cell Adhesion><Cell Body><Cell Growth in Number><Cell Line><Cell Multiplication><Cell Proliferation><Cell Survival><Cell Viability><CellLine><Cells><Cellular Adhesion><Cellular Expansion><Cellular Growth><Cellular Proliferation><Cessation of life><Chemoprotection><Children's Hospital><Clinical Treatment><Complementary therapies><Complementary treatment><DNA><DNA Damage><DNA Injury><DNA seq><DNA sequencing><DNAseq><Death><Deoxyribonucleic Acid><Dependence><Dimerization><Disease remission><Doctor of Philosophy><Dose><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Precursors><Drugs><Event><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Transcription><HTH DNA Binding Domain><HTH Motifs><Helix-Turn-Helix Motifs><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematologist><Hematopoietic Cancer><Heterodimerization><Human><IMiD><Image><Immunomodulators><Impairment><In Vitro><Integrin Heterodimer alpha4beta1><Integrin alpha(4)beta(1)><Integrin alpha4beta1><Integrin α4β1><Intermediary Metabolism><International><Intravenous><Investigators><Ligands><Lipase><Lipids><MYC Family Protein><MYC Protein><Malignant Cell><Malignant Hematologic Neoplasm><Malignant Neoplasms><Malignant Tumor><Marrow><Maryland><Medication><Medicine><Metabolic Processes><Metabolism><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modern Man><Molecular Genetics><Molecular Interaction><Multiple Myeloma><Murine><Mus><Normal Cell><Oncogenes><Oncology Cancer><Output><Patients><Pediatric Hospitals><Ph.D.><PhD><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology><Pharmacy Schools><Phenotype><Physiologic Availability><Plasma Cells><Plasma-Cell Myeloma><Plasmacytes><Population><Pre-Clinical Model><Preclinical Models><Predisposition><Pro-Drugs><Prodrugs><Progressive Disease><Property><Proteasome Inhibitor><Protein Dimerization><R-Series Research Projects><R01 Mechanism><R01 Program><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Regulation><Relapse><Remission><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Revlimid><Strains Cell Lines><Survival Rate><Susceptibility><Technology><Toxic effect><Toxicities><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transforming Genes><Translational Research><Translational Science><Triacylglycerol Hydrolase><Triacylglycerol Lipase><Triacylglycerol acylhydrolase><Tributyrinase><Triglyceridase><Triglyceride Lipase><Triolean Hydrolase><United States><Universities><VLA-4><Very Late Activation Antigen-4><Very Late Antigen-4><Washington><alpha helix><anti-cancer therapeutic><antibody biosynthesis><anticancer therapeutic><associate faculty><associate professor><base><c myc><c-myc Genes><cancer cell><cancer type><cell growth><chemotherapy><clinical biomarkers><clinical imaging><clinically translatable><clinically useful biomarkers><cmyc><cultured cell line><design><designing><differentiated B cell><differentiated B lymphocyte><drug/agent><flow cytophotometry><helix loop helix><helix turn helix><imaging><imaging biomarker><imaging marker><imaging-based biological marker><imaging-based biomarker><imaging-based marker><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulatory agents><immune modulatory drugs><immunoglobulin biosynthesis><immunomodulating agents><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><in vivo><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><interdisciplinary collaboration><malignancy><medical college><medical schools><miRNA><miRNAs><mid-career faculty><midcareer faculty><model of animal><model organism><mouse model><murine model><myeloma><myelomatosis><nano medicinal><nano medicine><nano particle><nano therapeutic><nano therapy><nano-sized particle><nanomedicinal><nanomedicine><nanoparticle><nanosized particle><nanotherapeutic><nanotherapy><neoplasm/cancer><non-invasive imaging><noninvasive imaging><novel><oncogene addiction><oncology><personalization of treatment><personalized medicine><personalized therapy><personalized treatment><plasmocyte><pre-clinical><preclinical><professor><programs><receptor><relapse patients><resistance to therapy><resistant to therapy><response><school of medicine><small molecule><small molecule inhibitor><standard of care><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic nanoparticles><therapeutic resistance><therapy resistant><transcription factor><transcriptome sequencing><transdisciplinary collaboration><translation research><treatment resistance><trial regimen><trial treatment><tributyrase><tumor><v-myc Avian Myelocytomatosis Viral Oncogene Cellular Homolog><virtual><α-helix>