Document text
Principal Investigator: Leaf Huang
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2019
Award: $445,923
Funding agency: National Cancer Institute
Project 1 Abstract
Cutaneous melanoma accounts for the majority (~75%) of skin cancer deaths. Despite the
recent improvements in prevention and early detection, approximately 20% of patients with
melanoma still die from the diseases. Patients with metastases have a poor prognosis and a
very short life expectancy. About 50% of human melanoma harbor BRafV600 mutations.
Vemurafenib (Vem), a specific inhibitor of the mutated BRaf, is very effective for treating
metastatic melanoma. Unfortunately, drug resistance emerges 3-18 months post treatment due
to alternative mechanisms that reactivate the MEK/ERK pathway. Vem resistant melanoma,
however, exhibits elevated expression of melanoma associated antigens, gp100, MART-1 and
Tyrosinase. Thus, the drug resistant disease provides opportunity for two independent, yet
complementary, therapeutic approaches, i.e. synthetic lethality and cancer vaccine. To block the
alternative Raf kinase, we have discovered that the suppressor gene Sprouty4, when delivered
by LPH (lipid-polycation-hyaluronic acid) nanoparticles (NPs) developed in this group, could
effectively down-regulate MEK/ERK pathway, leading to reduced growth rate in Vem resistant
melanoma. We will follow up this novel gene therapy strategy by using a newly discovered
lipopolyplex containing polymetformin (aim 1) to demonstrate the mechanism of the synthetic
lethality (aim 2). Polymetformin is much less toxic than the equivalent polyethyleneimine and
inhibits mTOR to further suppress the survival mechanism of the tumor cells. Since our Vem
resistant tumor is also PTEN deficient, we will also develop a siRNA therapy to silence Akt. At
the same time, we will use a BRaf mutant melanoma in a syngeneic mouse model to study
tumor growth inhibition using a new mRNA vaccine formulation (aim 3). mRNAs of several
melanoma associated antigens, including those up-regulated in Vem resistant tumor, will be
formulated in LCP (lipid-calcium-phosphate) NPs and delivered to the dendritic cells in the
lymph nodes. Preliminary data indicate that this approach was very effective in inducing an
antigen-specific CTL response in the host and significantly inhibited the growth of the primary as
well as the metastatic melanoma in the lymph nodes. We will finally combine the gene/drug
therapy with the vaccine therapy to overcome Vem resistance in melanoma.
Terms: <ATGN><Active Follow-up><Address><After Care><After-Treatment><Aftercare><Antigens><Antineoplastic Vaccine><B7-H1><B7H1><Basic Research><Basic Science><CCNE><CCNE1><CCNE1 gene><CD274><CDDP><Cancer Treatment><Cancer Vaccines><Cations><Cell Body><Cell Membrane Lipids><Cells><Cessation of life><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clinical Trials><Complementary DNA><Cresolase><Cutaneous Melanoma><Cyclin E><Cyclin-E1><Cysplatyna><Cytoplasm><DNA><DNA Therapy><Data><Death><Dendritic Cells><Deoxyribonucleic Acid><Dichlorodiammineplatinum><Difluorodeoxycytidine><Dimethylbiguanidine><Dimethylguanylguanidine><Disease><Disease Resistance><Disorder><Dopa Oxidase><Down-Regulation><Downregulation><Drug Therapy><Drug resistance><Drugs><Early Diagnosis><Encapsulated><Endosomes><Exhibits><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Formulation><GP100><Gene Delivery><Gene Transfer Clinical><Generalized Growth><Genes><Genetic Alteration><Genetic Change><Genetic Intervention><Genetic defect><Glycolates><Goals><Growth><Human><Hyaluronic Acid><Immune><Immunes><Immunologically Directed Therapy><Immunotherapy><Life Expectancy><Lipid Bilayers><Lipids><Lymph Node Reticuloendothelial System><Lymph node proper><MAP-ERK Kinase><MAPK ERK Kinases><ME20><MEKs><MMAC1><Malignant Cutaneous Melanoma><Malignant Melanoma><Malignant Melanoma of Skin><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Skin Neoplasm><Mechanistic Target of Rapamycin><Medication><Melanocyte Protein 17><Melanoma Skin><Melanoma Vaccine><Membrane Lipids><Messenger RNA><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Melanoma><Metastatic Neoplasm><Metastatic Tumor><Metformin><Mice><Mice Mammals><Modeling><Modern Man><Molecular Weight><Monophenol Monooxygenase><Mouse Homolog of SILVER><Murine><Mus><Mutate><Mutated in Multiple Advanced Cancers 1><Mutation><N,N-dimethyl-imidodicarbonimidic diamide><Nanotechnology><Neoplasm Metastasis><Neoplasm Vaccines><Nucleotides><PD-1/PD-L1><PD-1/PDL1><PD-L1><PD1/PD-L1><PD1/PDL1><PDCD1 Ligand 1><PDCD1L1><PDCD1LG1><PDCD1LG1 gene><PDL1><PHTS gene><PHTS protein><PMEL gene><PMEL protein><PMEL17><PTEN><PTEN Hamartoma Tumor Syndrome><PTEN Hamartoma Tumor Syndrome With Granular Cell Tumor><PTEN gene><PTEN1><Particle Size><Pathway interactions><Patients><Peyrone's Chloride><Peyrone's Salt><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacotherapy><Phenol Oxidase><Phenoloxidase><Phosphatase and Tensin Homolog><Phosphatase and Tensin Homolog Deleted on Chromosome 10><Platinum Diamminodichloride><Polyaziridine><Polyethyleneimine><Polymers><Premelanosomal Protein><Prevention><Prognosis><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Proteins><RAFT1><RNA vaccine><Receptosomes><Resistance><SILV gene><SILV protein><Second-Site Suppressor Genes><Secondary Neoplasm><Secondary Tumor><Short interfering RNA><Skin Cancer><Small Interfering RNA><Structure><Suppressor Genes><Therapeutic><Time><Tissue Growth><Toxic effect><Toxicities><Tumor Cell><Tumor Rejection Antigen AB><Tumor Vaccines><Tyrosinase><VAC-TX><Vaccine Therapy><Vaccines><Veiled Cells><Xenograft Model><active followup><anti-PD-L1><anti-PDL-1><anti-PDL1><anti-cancer><anti-cancer activity><anti-cancer therapy><antiPD-L1><antiPDL1><anticancer><anticancer activity><anticancer therapy><cDNA><calcium phosphate><cancer metastasis><cancer therapy><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><clinical relevance><clinically relevant><combination gene therapy><dFdC><dFdCyd><develop a vaccine><development of a vaccine><drug resistant><drug treatment><drug/agent><early detection><follow up><follow-up><followed up><followup><gemcitabine><gene therapy><gene-based therapy><genetic therapy><genome mutation><genomic therapy><glycolic acid><glycoprotein 100><gp 100><gp100 Antigen><homopolymer Aziridine><immune check point><immune checkpoint><immune drugs><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><immunogen><in vivo><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><lipid bilayer membrane><lymph gland><lymph nodes><mRNA><mRNA vaccine><mTOR><malignant skin tumor><mammalian target of rapamycin><melanoma><melanoma-associated antigen><monophenol oxidase><mouse model><murine model><mutant><nano><nano particle><nano particle delivery><nano tech><nano technology><nano therapy><nano tool><nano-sized particle><nano-technological><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><nanotech><nanotechnological><nanotherapy><nanotool><neoplastic cell><new approaches><novel><novel approaches><novel strategies><novel strategy><ontogeny><outcome forecast><overexpress><overexpression><pathway><polycation><post treatment><raf Kinases><raf MAP Kinase Kinase Kinases><raf Proto-Oncogene Proteins><raf Serine-Theonine Protein Kinases><resistance to Drug><resistance to disease><resistant><resistant disease><resistant to Drug><resistant to disease><response><siRNA><siRNA therapy><siRNA-based therapeutic><therapeutic siRNA><therapeutic vaccination><therapeutic vaccine><tool><treatment vaccines><tumor><tumor cell metastasis><tumor growth><vaccine development><vaccine for cancer><vaccine for the treatment><vaccine for treatment><vaccine formulation>