Project 1: Nanotherapies for Vemurafenib Resistant Melanoma

项目 1：维莫非尼耐药黑色素瘤的纳米疗法

• 批准号: 8960620
• 负责人: Leaf Huang
• 金额: $ 45.6万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8960620
• 关键词: Accounting; Address; Aftercare; Antigens; Basic Science; CCNE1 gene; Cancer Vaccines; Cells; Cessation of life; Cisplatin; Clinical Trials; Complementary DNA; Cutaneous Melanoma; Cytoplasm; DNA; Data; Dendritic Cells; Disease; Disease Resistance; Down-Regulation; Drug Formulations; Drug resistance; Early Diagnosis; Encapsulated; Endosomes; Exhibits; Gene Delivery; Genes; Glycolates; Goals; Growth; Human; Hyaluronic Acid; Immune; Immunotherapy; Life Expectancy; Lipid Bilayers; Lipids; MEKs; Malignant Neoplasms; Membrane Lipids; Messenger RNA; Metastatic Melanoma; Metformin; Modeling; Molecular Weight; Monophenol Monooxygenase; Mus; Mutate; Mutation; Nanotechnology; Neoplasm Metastasis; Nucleotides; PTEN gene; Particle Size; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Polyethyleneimine; Polymers; Prevention; Proteins; Resistance; Skin Cancer; Small Interfering RNA; Structure; Suppressor Genes; Therapeutic; Time; Toxic effect; Vaccine Therapy; Vaccines; Xenograft Model; abstracting; calcium phosphate; cancer therapy; clinically relevant; combination gene therapy; follow-up; gemcitabine; gene therapy; human FRAP1 protein; human SILV protein; in vivo; inhibitor/antagonist; innovation; lymph nodes; melanoma; melanoma-associated antigen; mouse model; mutant; nano; nanoparticle; nanotherapy; nanotool; neoplastic cell; novel; novel strategies; outcome forecast; polycation; raf Kinases; response; therapeutic vaccine; tool; tumor; tumor growth; vaccine development

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.

项目1