A phase II multi-center trial evaluating dual targeting of the PI3K/AKT and NOS pathways for treating metaplastic breast cancer (MpBC)

一项评估 PI3K/AKT 和 NOS 通路双重靶向治疗化生性乳腺癌 (MpBC) 的 II 期多中心试验

基本信息

批准号：
10642669
负责人：
JENNY C-N CHANG
金额：
$ 59.26万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-10 至 2027-05-31
项目状态：
未结题

项目摘要

ABSTRACT Metaplastic breast cancer (MpBC) is a rare subset accounting for <1% of all breast cancers. However, MpBC is a significant health challenge as it exhibits the most dismal prognosis of all breast cancers, even worse than triple-negative breast cancer (TNBC), with a survival rate of 8 months or less in patients with metastatic disease. Due to a lack of druggable targets, the main therapeutic option for metastatic MpBC remains systemic chemotherapy, despite known resistance to most cytotoxic drugs. One common molecular alteration in MpBC is hyperactivation of the phosphoinositide 3-kinase and protein kinase B (PI3K/AKT) pathway. Additionally, we recently published that MpBC displays a gain-of-function oncogenic mutation in ribosomal protein L39 (RPL39), which is responsible for treatment resistance, stem cell self-renewal, and lung metastasis. The mechanistic function of RPL39 is mediated through inducible nitric oxide synthase (iNOS)-mediated nitric oxide production. In addition, we demonstrated in a completed clinical trial that inhibiting this nitric oxide synthase (NOS) pathway using pan-NOS inhibitor NG-methyl-L-arginine acetate (L-NMMA) may represent a highly effective therapeutic option for TNBC patients. Therefore, we hypothesize that a combinatorial targeted approach of inhibiting the two major oncogenic pathways implicated in MpBC, PI3K/AKT and NOS, would lead to significant tumor regression. To test this hypothesis, this U01 application brings together research teams from Houston Methodist Cancer Center (HMCC), The University of Texas MD Anderson Cancer Center, and the National Cancer Institute (NCI). Specific Aim 1 seeks to define whether dual inhibition of PI3K/AKT using alpelisib and NOS inhibition using L-NMMA combined with nab-paclitaxel will increase the objective response rate and survival in metastatic MpBC patients. In Specific Aim 2, using blood and core biopsy tissues collected in the trial, we will identify mechanisms of response to therapy to determine the efficacy of the targeted PI3K/AKT and NOS pathway inhibitory approach. Furthermore, the cell-cell interactions among tumor cells, myeloid cells, lymphoid cells, and stromal cells within the tumor microenvironment and their role in supporting cancer stem cell populations and drug-resistant cell development during treatment will be evaluated. The impact of distinct cellular localization patterns within the tumor ecosystem on the process of cancer stem cell maintenance and modulation, as well as the development of drug resistance, will be analyzed at the single-cell level using spatial transcriptomics, immunofluorescence, CyTOF imaging systems, and a multi-modal data analysis model. This study thus proposes a mechanistic investigation of a combinatorial targeted approach against the two key pathways in MpBC, develops unique crosstalk models, and identifies biomarkers of resistance and cell–cell interactions using specimens derived from MpBC patients.

抽象的化生性乳腺癌 (MpBC) 是一种罕见的亚型，占所有乳腺癌的比例<1%。这是一个重大的健康挑战，因为它的预后是所有乳腺癌中最差的，甚至比三阴性乳腺癌（TNBC），转移性疾病患者的生存率为 8 个月或更短。由于缺乏药物靶点，转移性 MpBC 的主要治疗选择仍然是全身治疗尽管已知对大多数细胞毒性药物具有耐药性，但 MpBC 的一种常见分子改变是化疗。磷酸肌醇 3 激酶和蛋白激酶 B (PI3K/AKT) 通路的过度激活。最近发表的文章称，MpBC 在核糖体蛋白 L39 (RPL39) 中显示出功能获得性致癌突变，它负责治疗抵抗、干细胞自我更新和肺转移。 RPL39 的功能是通过诱导型一氧化氮合酶 (iNOS) 介导的一氧化氮产生来介导的。此外，我们在一项已完成的临床试验中证明，可以抑制这种一氧化氮合酶 (NOS) 途径使用泛 NOS 抑制剂 NG-甲基-L-精氨酸乙酸酯 (L-NMMA) 可能是一种高效的治疗方法因此，我们争取采用组合的靶向抑制方法。 MpBC 涉及的两个主要致癌途径，PI3K/AKT 和 NOS，将导致显着的为了检验这一假设，U01 应用程序汇集了来自休斯顿的研究团队。卫理公会癌症中心 (HMCC)、德克萨斯大学 MD 安德森癌症中心和国家癌症中心癌症研究所 (NCI)。具体目标 1 旨在确定使用 alpelisib 和 PI3K/AKT 是否具有双重抑制作用。 L-NMMA 与白蛋白结合型紫杉醇联合使用 NOS 抑制将提高客观缓解率和生存率在特定目标 2 中，我们将使用试验中收集的血液和核心活检组织。确定治疗反应机制，以确定靶向 PI3K/AKT 和 NOS 的功效此外，肿瘤细胞、骨髓细胞、淋巴细胞之间的细胞间相互作用。肿瘤微环境中的细胞和基质细胞及其在支持癌症干细胞中的作用将评估治疗期间群体和耐药细胞发展的不同细胞的影响。肿瘤生态系统内的定位模式对癌症干细胞维持和调节过程的影响，以及耐药性的发展，将使用空间在单细胞水平上进行分析转录组学、免疫荧光、CyTOF 成像系统和多模式数据分析模型。因此，研究提出了针对两个关键的组合目标方法的机械调查 MpBC 中的通路，开发独特的串扰模型，并识别耐药性和细胞间的生物标志物使用来自 MpBC 患者的标本进行相互作用。