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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1)
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University of North Carolina Chapel Hill
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Zhou, Jingying; Liu, Man; Sun, Hanyong et al. (2018) Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy. Gut 67:931-944
Wan, Xiaomeng; Beaudoin, James J; Vinod, Natasha et al. (2018) Co-delivery of paclitaxel and cisplatin in poly(2-oxazoline) polymeric micelles: Implications for drug loading, release, pharmacokinetics and outcome of ovarian and breast cancer treatments. Biomaterials 192:1-14
Collier, Michael A; Junkins, Robert D; Gallovic, Matthew D et al. (2018) Acetalated Dextran Microparticles for Codelivery of STING and TLR7/8 Agonists. Mol Pharm 15:4933-4946
Liu, Lina; Wang, Yuhua; Miao, Lei et al. (2018) Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer. Mol Ther 26:45-55
Cheng, Ning; Watkins-Schulz, Rebekah; Junkins, Robert D et al. (2018) A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1-insensitive models of triple-negative breast cancer. JCI Insight 3:
Liu, Qi; Chen, Fengqian; Hou, Lin et al. (2018) Nanocarrier-Mediated Chemo-Immunotherapy Arrested Cancer Progression and Induced Tumor Dormancy in Desmoplastic Melanoma. ACS Nano 12:7812-7825
Wan, Xiaomeng; Min, Yuanzeng; Bludau, Herdis et al. (2018) Drug Combination Synergy in Worm-like Polymeric Micelles Improves Treatment Outcome for Small Cell and Non-Small Cell Lung Cancer. ACS Nano 12:2426-2439
Zhang, Maofan; Hagan 4th, C Tilden; Min, Yuangzeng et al. (2018) Nanoparticle co-delivery of wortmannin and cisplatin synergistically enhances chemoradiotherapy and reverses platinum resistance in ovarian cancer models. Biomaterials 169:1-10
Myung, Ja Hye; Eblan, Michael J; Caster, Joseph M et al. (2018) Multivalent Binding and Biomimetic Cell Rolling Improves the Sensitivity and Specificity of Circulating Tumor Cell Capture. Clin Cancer Res 24:2539-2547
Liu, Qi; Zhu, Hongda; Tiruthani, Karthik et al. (2018) Nanoparticle-Mediated Trapping of Wnt Family Member 5A in Tumor Microenvironments Enhances Immunotherapy for B-Raf Proto-Oncogene Mutant Melanoma. ACS Nano 12:1250-1261

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