Combined inhibition of PLK1 and NOTCH for melanoma management

联合抑制 PLK1 和 NOTCH 治疗黑色素瘤

• 批准号: 10481129
• 负责人: Nihal Ahmad
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481129
• 关键词: ABCB1 gene; ABCC1 gene; ANXA5 gene; Affect; BRAF gene; Biological; Blood Vessels; Cell Cycle; Cell Cycle Regulation; Cell Line; Cell Proliferation; Cells; Characteristics; Climate; Clinical; Clinical Management; Combined Modality Therapy; Data; Development; Diagnosis; Disease; Disease Progression; Drug resistance; Embryo; Epithelium; Evolution; Extracellular Matrix; FDA approved; Family member; Gene Expression Profiling; Genes; Genetic Engineering; Goals; Growth; Healthcare; Human; Immune checkpoint inhibitor; Immunotherapy; Laboratories; Link; MEKs; Malignant Neoplasms; Melanoma Cell; Mesenchymal; Metastatic Melanoma; Military Personnel; Mission; Mitosis; Modeling; Mutation; NOTCH1 gene; Neoplasm Metastasis; Neoplasms; Oncogenic; Outcome; PLK1 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphopeptides; Play; Preclinical Testing; Progression-Free Survivals; Proliferating; Protein-Serine-Threonine Kinases; Proteins; Proteome; Proteomics; Publishing; Relapse; Reporting; Research; Resistance; Resistance development; Role; Sampling; Serine; Signal Transduction; Techniques; Testing; Therapeutic; Tissues; Treatment Efficacy; Treatment outcome; Tumor Markers; United States National Institutes of Health; Validation; Veterans; Work; angiogenesis; anti-tumor immune response; cancer type; chemotherapy; combinatorial; efficacy evaluation; gamma secretase; genetic manipulation; high risk; human disease; improved; in vivo; inhibitor; insight; melanoma; melanomagenesis; mouse model; nano-string; novel; novel drug combination; overexpression; patient derived xenograft model; preclinical study; repository; research clinical testing; response; small molecule; success; survivin; targeted treatment; therapeutic target; therapy resistant; transcriptome sequencing; treatment response; tumor; tumor progression; ultraviolet

The overall objective of this study is to determine the therapeutic efficacy of concomitant inhibition of PLK1 and NOTCH against melanoma progression and drug resistance as well as to identify novel signaling mechanisms associated with drug response using two human-relevant melanoma mouse models. The available therapeutic strategies against melanoma have either failed to achieve >25% response in patients, or the responses are short-lived with developing resistance to therapy. For example, BRAF inhibitors Vemurafenib and Dabrafenib were found to achieve significant improvement over chemotherapy and were FDA-approved for melanomas with BRAF-mutations. Even with a combination of Dabrafenib with MEK inhibitor Trametinib (also FDA approved), the patients develop acquired resistance. More recently advancements in immunotherapy have improved melanoma treatment outcomes. Despite the success of immune checkpoint inhibitors durable responses are not seen in all patients due to drug resistance. Therefore, novel mechanism- based combinatorial approaches are needed for an effective management of this neoplasm. Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase that plays a key role in cell proliferation. We have previously reported that PLK1 is significantly overexpressed in melanoma and can be therapeutically targeted. Further, the NOTCH pathway, an evolutionally conserved pathway, which plays important roles in cell fate determination, proliferation, differentiation and survival, has been shown to regulate many aspects of melanomagenesis. NOTCH1 is considered a primary oncogenic factor in melanoma and activation of NOTCH1 and its target genes is linked with metastatic melanoma. Moreover, inhibition of PLK1 or NOTCH has been shown to modulate markers of epithelial mesenchymal transition (EMT) and metastasis. Interestingly, both PLK1 and NOTCH are also linked with drug resistance. Our recently published data suggest that PLK1 and NOTCH expressions have significant positive correlation in melanoma clinical tissues and simultaneous small molecule inhibition of PLK1 and NOTCH by BI 6727 (specific inhibitors of PLK1) and MK-0752 (γ-secretase inhibitor), respectively, caused a significant anti-proliferative response in multiple melanoma cell lines, warranting further pre-clinical testing in in vivo melanoma models. This data together with other published studies provide a strong scientific premise for our proposed hypothesis that combined inhibition of PLK1 and NOTCH will be therapeutically superior for the management of melanoma. We will challenge this hypothesis in two specific aims. In Aim 1, we will determine the in vivo therapeutic efficacy and mechanism of concomitant inhibition of PLK1 (by BI 6727 or PCM-075) and NOTCH (by MK-0752) on melanoma progression and metastasis in genetically engineered Braf-Pten melanoma mouse model, which recapitulates human disease progression from localized to metastatic disease. In Aim 2, we will determine therapeutic efficacy and mechanism of concomitant inhibition of PLK1 and NOTCH against melanoma drug resistant using patient derived xenograft (PDX) model, which conserve original tumor characteristics and offer relevant predictive insights into clinical outcomes, for direct relevance to clinical management of melanoma. Additionally, we will determine the novel mechanisms associated with treatment response using mutiple techniques such as Nanostring PanCancer Progression Panel, global proteomics and RNA-seq analyses in tumor samples followed by validation using RT-qPCR and ProteinSimple analyses. Overall, our study is expected to provide mechanistic insights and rationale for clinical testing of the combined PLK1-NOTCH inhibition to obtain superior anti-melanoma response and overcome resistance. Our proposed work is relevant and significant to the Veterans because melanoma is the fifth most diagnosed malignancy among Veterans, and the fact that the US military has been engaged, in missions all over the world, many US military personnel, who are deployed to high ultraviolet (UV) climates in tropical and subtropical zones are potentially at a higher risk for melanoma.

本研究的总体目的是确定同时抑制PLK1的治疗效果