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ROLE OF MIDKINE IN MOLECULAR TARGETED THERAPY TO TIP1 FOR LUNG CANCER TREATMENT

Midkine 在 TIP1 肺癌分子靶向治疗中的作用

基本信息

批准号：
10212341
负责人：
Vaishali Kapoor
金额：
$ 15.32万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-07 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212341
关键词：
Antibodies Antibody Therapy Apoptosis Attenuated Binding Biological Biological Assay Blocking Antibodies Cancer Biology Cancer Model Cancer Patient Cause of Death Cell Death Cell Proliferation Cell physiology Cell surface Chemotaxis Clinical Treatment Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Data Data Set Development Diagnosis Disease-Free Survival Ensure Epitopes Event Exhibits Flow Cytometry Future Genomic approach Goals Heparin Binding Growth Factor Human Immunofluorescence Immunologic Immunoprecipitation In Vitro Investigation K22 Award Knock-out Knowledge Learning Libraries Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Mediator of activation protein Modeling Molecular Molecular Chaperones Molecular Target Mus Non-Small-Cell Lung Carcinoma Normal Cell Normal tissue morphology Outcome Pathway interactions Patients Play Pre-Clinical Model Prognosis Prognostic Marker Proteins Proteomics Reporter Research Research Personnel Research Training Rodent Role Scaffolding Protein Signal Transduction Survival Rate Taxes Techniques Testing The Cancer Genome Atlas Therapeutic Tissue Microarray Training Treatment Efficacy Tumor Tissue Up-Regulation WNT Signaling Pathway Xenograft procedure angiogenesis anti-cancer therapeutic base beta catenin cancer cell cancer therapy carcinogenesis chromatin immunoprecipitation cytotoxic cytotoxicity drug development efficacy evaluation evidence base improved in vivo inhibitor/antagonist innovation knock-down lung cancer cell midkine molecular targeted therapies mortality mouse model novel novel strategies novel therapeutic intervention novel therapeutics overexpression pre-clinical protein expression rho rhotekin skills small molecule inhibitor success targeted treatment tax Gene Products transcriptome sequencing treatment strategy tumor tumor growth

项目摘要

PROJECT DESCRIPTION/ ABSTRACT Non-small cell lung cancer (NSCLC) ranks among the highest cancer-related mortalities world-wide. Molecular targeted therapy is a growing topic of investigation to improve therapeutic efficacy for NSCLC. A few targeted therapies that exploit aberrant protein expression profiles have been approved for NSCLC. However, the marginal percentage of cancers with improved efficacy observed with these therapeutic approaches highlights the need for discovery of additional molecular targets. The proposed research is significant as it will generate new molecular targets and treatment strategies for NSCLC therapy. We propose targeting of the scaffold protein TIP1 that is a novel target for lung cancer as identified by analysis of the cancer genome atlas datasets and NSCLC tumor tissue microarrays. The functional domain of TIP1 (PDZ domain) caps the C-terminus of many different cellular proteins that regulate important cellular functions. Knocking down TIP1 revealed that it plays an important role in cell signaling, cancer development, and progression making it an attractive target for anticancer therapeutics. Comparing antibodies targeting different epitopes of TIP1, it was found that antibodies against the PDZ domain of TIP1 were most effective in inducing direct cytotoxicity of lung cancer cells but not normal cells. Anti-PDZ/TIP1 antibodies injected into mice bearing lung cancer bind specifically to cancer cells and substantially enhance tumor control. Quantitative mass spectrometry identified Midkine (MDK) as a putative protein that modulates this cytotoxicity by anti-PDZ/TIP1 antibodies. Additional studies suggested that the β-catenin/Wnt signaling may be involved in this up-regulation of MDK after blocking of TIP1. Together, these studies led to the central hypothesis that MDK is upregulated by the anti-PDZ/TIP1 antibody via the β- catenin/Wnt signaling pathway, which subsequently modulates downstream cell death mechanisms. Aim 1 will elucidate the mechanisms of induction of MDK following blockade of the PDZ domain of TIP1. This aim will lead to identification of novel molecular targets for NSCLC treatment that have never been considered before. Aim 2 will evaluate the efficacy of blocking TIP1 function while simultaneously blocking MDK function in mouse models of NSCLC. This aim will guide the development of combination therapies to optimize efficacy of NSCLC treatment. This research is innovative because we are studying a novel molecular target, TIP1. Blocking the functional domain of TIP1 leads to NSCLC cell death. We also propose an innovative strategy of dual targeting TIP1 and MDK to enhance the therapeutic efficacy of NSCLC. Building on my cancer biology background, this K22 award will allow me to train in cutting edge proteomic and genomic approaches with special emphasis on identifying novel NSCLC molecular targets. I have proposed a research and training plan that will equip me with the highest skills to ensure my success as an independent investigator. Overall, the long-term goal of my future research, is to provide new opportunities for the development of novel therapies to treat lung cancer.

项目描述/摘要