Targeting HER2-low breast cancer with 17p loss

项目摘要 在淋巴结阳性的乳腺癌患者中，HER2的过度表达是一个强大的预后标志。 免疫组织化学(IHC)染色是临床上应用最广泛的HER2状态评分方法 阳性(3+)、可疑(2+)和阴性(0或1+)。HER2(1+或2+)水平低的乳腺肿瘤不是 被认为是HER2过表达阳性，这种肿瘤对HER2靶向药物反应不佳 抗HER2抗体(曲妥珠单抗)和阿多曲妥珠单抗(T-DM1)。由于它们的遗传多样性和 临床异质性，HER2-低乳腺癌的治疗挑战是缺乏可操作的 目标和缺乏有针对性的治疗。我们发现染色体17p杂合性缺失(17p丢失)是 在乳腺癌(56%)和TNBC(53%)中最常见的事件。在17P缺失区内有 肿瘤抑制基因TP53(编码P53)，其缺失或突变被认为是主要的致癌因素。 我们最近的研究发现，TP53邻近区域的POLR2A是 提示抑制POLR2a可能是一种精确的治疗方法。至 加速我们的重要发现的翻译开发，我们正在开发抗体-药物结合物 (ADC)，以α-Amanitin(POLR2a抑制剂)为弹头。这一途径抑制了α-氨甲酸特异性摄取 进入肝细胞，并使用肿瘤特异性单抗增加肿瘤特异性靶向性。 在这个项目中，我们将首先开发α-Amanitin-偶联曲妥珠单抗(T-Ama)，并测试它们在 低水平HER2治疗17例TNBC肿瘤。其次，我们将确定17便士的损失如何导致 减少T细胞的渗透和细胞毒作用，从而导致对TNBC肿瘤的免疫逃避。要确定 潜在的分子机制，我们将研究17P丢失如何对肿瘤抗原产生负面影响 TNBC的临床表现和肿瘤免疫反应。最后，我们将确定T-AMA作为单一药物的疗效 药物或联合免疫检查点阻断治疗17P丢失的TNBC。

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.