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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：
10399601
负责人：
Xiongbin Lu
金额：
$ 52.47万
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/10399601
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 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 HER 2过表达是淋巴结阳性乳腺癌患者的有力预后标志物。免疫组织化学（IHC）染色是临床上最广泛使用的用于对HER 2状态进行评分的方法，阳性（3+）、可疑（2+）和阴性（0或1+）。低水平HER 2（1+或2+）的乳腺肿瘤不是被认为是HER 2过表达阳性，并且此类肿瘤对HER 2靶向药物反应不佳抗HER 2抗体（曲妥珠单抗）和ado-曲妥珠单抗emtansine（T-DM 1）。由于它们的遗传多样性，临床异质性，HER 2-低乳腺癌的治疗挑战是缺乏可操作的目标和缺乏靶向治疗。我们发现染色体17 p的杂合缺失（17 p缺失）是乳腺癌（56%）和TNBC（53%）中最常见的事件。在17 p缺失区域内是肿瘤抑制因子TP 53（编码p53），其缺失或突变被认为是主要的致瘤驱动因子。我们最近的研究将TP 53邻近区域的POLR 2A确定为一个附带的脆弱性目标， TNBC肿瘤具有17 p损失，表明P0 LR 2A的抑制可能是精确的治疗方法。到为了加速我们重要发现的转化发展，我们正在开发抗体-药物偶联物 (ADC)用α-鹅膏蕈碱（POLR 2A抑制剂）作为弹头。这种方法抑制α-鹅膏蕈碱的特异性摄取并使用肿瘤特异性单克隆抗体增加肿瘤特异性靶向。在本项目中，我们将首先开发α-鹅膏蕈碱结合的曲妥珠单抗（T-Ama），并测试其在以下方面的疗效：用低水平的HER 2治疗1711 ss TNBC肿瘤。第二，我们将确定17便士的损失如何导致减少的T细胞浸润和细胞毒性，从而导致TNBC肿瘤的免疫逃避。以确定潜在的分子机制，我们将研究17 p丢失如何对肿瘤抗原产生负面影响， TNBC中的肿瘤呈现和肿瘤免疫应答。最后，我们将确定T-Ama作为单一药物的疗效。在治疗具有17 p损失的TNBC中，本发明的组合物可与免疫检查点阻断剂或与免疫检查点阻断剂组合使用。