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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10642669
• 关键词: 3-Phosphoinositide Dependent Protein Kinase-1; Accounting; Acetates; Apoptosis; Arginine; Automobile Driving; Blood; Breast Cancer Patient; Breast Cancer cell line; Cancer Center; Cell Communication; Cell Maintenance; Cells; Characteristics; Chemoresistance; Clinical Trials; Core Biopsy; Cytotoxic agent; Data; Data Analyses; Development; Disease; Disease Progression; Dose; Drug resistance; Ecosystem; Endocrine; Enrollment; Environment; Epidermal Growth Factor Receptor; Epithelium; Estrogen Receptors; Exhibits; Fulvestrant; Growth; Health; Human; Immunofluorescence Immunologic; Investigation; Lead; Ligands; Lymphoid Cell; Malignant Neoplasms; Mediating; Mesenchymal; Metaplastic carcinoma of the breast; Metastatic Neoplasm to the Lung; Methodist Church; Modeling; Molecular; Multi-Institutional Clinical Trial; Multicenter Trials; Mutate; Mutation; Myeloid Cells; NOS2A gene; National Cancer Institute; Nature; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthetase Inhibitor; Oncogenic; Outcome; PIK3CA gene; PTEN gene; Paclitaxel; Pathway interactions; Patient-derived xenograft models of breast cancer; Patients; Pattern; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phosphatidylinositols; Phosphotransferases; Postmenopause; Process; Production; Progesterone Receptors; Prognosis; Progression-Free Survivals; Proto-Oncogene Proteins c-akt; Publishing; Radiation therapy; Refractory; Regimen; Research; Resistance; Resources; Ribosomal Proteins; Role; Signal Pathway; Signal Transduction; Specimen; Stromal Cells; Survival Rate; System; TdT-Mediated dUTP Nick End Labeling Assay; Testing; Therapeutic; Tissues; Translating; Treatment Efficacy; Treatment Protocols; United States National Institutes of Health; University of Texas M D Anderson Cancer Center; Yam - dietary; alpelisib; biomarker identification; cancer stem cell; cell growth; chemotherapy; clinical center; combinatorial; drug resistance development; druggable target; effective therapy; efficacy evaluation; efficacy testing; gain of function; hormone receptor-positive; hormone therapy; imaging system; inhibitor; intercellular communication; malignant breast neoplasm; multimodal data; neoplastic cell; objective response rate; omega-N-Methylarginine; phase 2 study; pre-clinical; rare cancer; receptor; response; secondary outcome; small molecule; stem cell population; stem cell self renewal; taxane; therapeutically effective; therapy resistant; transcriptomics; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumorigenesis

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 化生乳腺癌（MPBC）是一个罕见的子集，占所有乳腺癌的1％。但是，MPBC是 一个重大的健康挑战，因为它表现出所有乳腺癌最令人沮丧的预后，甚至比 三阴性乳腺癌（TNBC），转移性疾病患者的存活率为8个月或更少。 由于缺乏可吸毒的靶标，转移性MPBC的主要治疗选择仍然是全身的 化学疗法，对大多数细胞毒性药物具有所需的已知耐药性。 MPBC中一种常见的分子改变是 磷酸肌醇3-激酶和蛋白激酶B（PI3K/AKT）途径的过度激活。另外，我们 最近发布的MPBC显示了核糖体蛋白L39（RPL39）， 负责治疗耐药性，干细胞自我更新和肺转移。机械 RPL39的功能是通过诱导的一氧化氮合酶（Inos）介导的一氧化氮产生来介导的。 此外，我们在一项完整的临床试验中证明了这种一氧化氮合酶（NOS）途径 使用PAN-NOS抑制剂NG-甲基-L-精氨酸乙酸（L-NMMA）可能代表一种高效的治疗 TNBC患者的选择。因此，我们假设一种组合靶向抑制的方法 在MPBC（PI3K/AKT和NOS）中实现的两种主要致癌途径将导致显着 肿瘤回归。为了检验这一假设，该U01应用程序汇集了休斯顿的研究团队 卫理公会癌症中心（HMCC），德克萨斯大学医学博士安德森癌症中心和国家 癌症研究所（NCI）。特定目标1旨在定义使用Alpelisib对PI3K/AKT的双重抑制 使用L-NMMA与NAB-PACLITAXEL合并的NOS抑制作用将提高客观响应率和存活率 在转移性MPBC患者中。在特定的目标2中，使用试验中收集的血液和核心活检组织，我们将 确定对治疗反应的机制，以确定靶向PI3K/AKT和NOS的效率 途径抑制方法。此外，肿瘤细胞，髓样细胞，淋巴机之间的细胞细胞相互作用 细胞和肿瘤微环境内的基质细胞及其在支撑癌症干细胞中的作用 将评估治疗过程中的种群和耐药细胞发育。独特的细胞的影响 肿瘤生态系统中的定位模式在癌症干细胞维持和调节过程中， 以及耐药性的发展，将在单细胞水平上使用空间进行分析 转录组学，免疫荧光，细胞成像系统和多模式数据分析模型。这 因此，研究提出了组合靶向方法针对这两个关键的机械投资 MPBC中的途径，开发独特的串扰模型，并识别抗性和细胞细胞的生物标志物 使用来自MPBC患者的标本的相互作用。

项目成果

Targeting Nitric Oxide: Say NO to Metastasis.

• DOI: 10.1158/1078-0432.ccr-22-2791
• 发表时间: 2023-05-15
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Reddy, Tejaswini P.;Glynn, Sharon A.;Billiar, Timothy R.;Wink, David A.;Chang, Jenny C.
• 通讯作者: Chang, Jenny C.