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Targeting HER2-low breast cancer with 17p loss

靶向 17p 缺失的 HER2 低乳腺癌

基本信息

批准号：
10203209
负责人：
Xiongbin Lu
金额：
$ 53.54万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10203209
关键词：
17p Amanitins Animals Antibodies Antibody-drug conjugates Antigen Presentation Antineoplastic Agents BRCA mutations Biodistribution Bioinformatics Breast Cancer Cell Cancer Biology Cause of Death Characteristics Chromosome Deletion Clinic Clinical Clinical Research Code Colorectal Neoplasms Combined Modality Therapy Computational algorithm Cytostatics Data Defect Development Disease Drug Kinetics Drug toxicity ERBB2 gene Event Genes Genetic Variation Genomics Growth Hepatocyte Hepatotoxicity Human Immune Evasion Immune response Immunocompetent Immunotherapy In Vitro Laboratories Mammary Neoplasms Maximum Tolerated Dose Modeling Molecular Molecular Biology Monoclonal Antibodies Mus Mutation Nanotechnology Nature Outcome PDL1 inhibitors POLR2A gene Paclitaxel Patients Pattern Pharmaceutical Preparations Positive Lymph Node Precision therapeutics Prognostic Marker Proteins Public Health RNA Interference Reliability of Results Research Research Personnel Safety Small Interfering RNA Speed Stains T-Lymphocyte TP53 gene Testing The Cancer Genome Atlas Therapeutic Therapeutic Agents Therapeutic Studies Toxic effect Transgenic Mice Trastuzumab Tumor Antigens Tumor Suppressor Proteins Tumor-infiltrating immune cells Xenograft Model anti-PD-L1 therapy anti-tumor immune response base cancer genomics cancer immunotherapy chromosome 17p loss clinical application clinical heterogeneity cytotoxicity design drug discovery hormone therapy immune checkpoint blockade immunogenic cell death improved in vivo inhibitor/antagonist knock-down malignant breast neoplasm nanobomb nanoparticle neoplastic cell new therapeutic target novel novel therapeutics overexpression patient derived xenograft model precision medicine small molecule targeted agent targeted treatment triple-negative invasive breast carcinoma tumor tumorigenesis tumorigenic uptake

项目摘要

Project Abstract HER2 overexpression is a powerful prognostic marker in node-positive patients with breast cancer. Immunohistochemical (IHC) staining is the most widely used approach in the clinic for scoring HER2 status as positive (3+), equivocal (2+), and negative (0 or 1+). Breast tumors with low levels of HER2 (1+ or 2+) are not considered as positive for HER2 overexpression and such tumors do not well respond to HER2-targeted agents anti-HER2 antibody (trastuzumab) and ado-trastuzumab emtansine (T-DM1). Due to their genetic diversity and clinical heterogeneity, the therapeutic challenges for HER2-low breast cancer are the paucity of actionable targets and lack of targeted therapies. We found that heterozygous deletion of chromosome 17p (17p loss) is the most prevalent event in breast cancer (56%) as well as in TNBC (53%). Within the 17p deletion region is the tumor suppressor TP53 (encoding p53), whose deletion or mutation is known as a primary tumorigenic driver. Our recent study identified POLR2A in the TP53-neighboring region as a collateral vulnerability target in the TNBC tumors with 17p loss, suggesting that inhibition of POLR2A may be a precision therapy approach. To accelerate the translational development of our important finding, we are developing antibody-drug conjugates (ADC) with α-amanitin (POLR2A inhibitor) as a warhead. This approach inhibits the specific uptake of α-amanitin into hepatocytes and increases tumor-specific targeting using tumor-specific monoclonal antibodies. In this project, we will first develop α-amanitin-conjugated trastuzumab (T-Ama) and test their efficacy in treating 17ploss TNBC tumors with low levels of HER2. Second, we will determine how the 17p loss leads to reduced T cell infiltration and cytotoxicity, thereby leads to immune evasion of the TNBC tumor. To determine the underlying molecular mechanism, we will examine how the 17p loss negatively impacts tumor antigen presentation and tumor immune response in TNBC. Finally, we will determine the efficacy of T-Ama as a single agent or in combination with immune checkpoint blockade in treating TNBC with 17p loss.

项目摘要