Dual targeting of PI3K and NOS pathways in Metaplastic BreastCancer (MBC)

化生性乳腺癌 (MBC) 中 PI3K 和 NOS 通路的双重靶向

基本信息

批准号：
10739097
负责人：
JENNY C-N CHANG
金额：
$ 64.42万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-08 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739097
关键词：
3-Phosphoinositide Dependent Protein Kinase-1 Accounting Acetates Adhesions Aftercare Apoptosis Arginine Automobile Driving Biopsy Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Catalytic Domain Cell Communication Cell Line Cells Chemoresistance Clinical Trials Combined Modality Therapy Complement Cytotoxic agent Data Data Analyses Detection Development Disease Drug resistance Environment Event Exhibits Funding Genes Growth Health Image Immunocompetent Immunofluorescence Immunologic Invaded Investigation Lymphoid Cell Macrophage Malignant Neoplasms Mediating Metaplastic carcinoma of the breast Metastatic Neoplasm to the Lung Modeling Molecular Mus Mutate Mutation Myeloid Cells NOS2A gene Neoplasm Metastasis Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthetase Inhibitor Oncogenic PIK3CA gene PTEN gene Pathway interactions Patient-derived xenograft models of breast cancer Patients Pharmaceutical Preparations Phosphatidylinositols Phosphotransferases Population Pre-Clinical Model Primary Neoplasm Production Prognosis Prognostic Factor Property Protein Isoforms Proto-Oncogene Proteins c-akt Publishing RNA RNA-Protein Interaction Radiation therapy Refractory Regimen Resistance Resolution Ribosomal Proteins Ribosomes Role SUM-159 Breast Cancer Cell Line Signal Pathway Specimen Stromal Cells Surveys Survival Rate TP53 gene Testing Therapeutic Translations Treatment Efficacy alpelisib cancer subtypes cell growth cell motility cell type chemotherapy clinical prognosis combinatorial druggable target efficacy evaluation gain of function hormone therapy imaging system in vivo inhibitor intercellular communication malignant breast neoplasm mouse model multimodal data neoplastic cell omega-N-Methylarginine outcome prediction participant enrollment patient derived xenograft model pre-clinical response ribosome profiling stem cell self renewal taxane therapeutically effective therapy resistant transcriptome sequencing transcriptomics treatment response triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

ABSTRACT Metaplastic breast cancer (MpBC) is a rare subset accounting for <5% of all breast cancers. MpBC is a significant health challenge as it exhibits the most dismal prognosis of all breast cancer subtypes, worse than non-MpBC triple-negative breast cancer (TNBC), with median 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 published that MpBC also 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 a recently published clinical trial targeting this nitric oxide synthase (NOS) pathway with a pan-NOS inhibitor NG-methyl-L-arginine acetate (L-NMMA), high efficacy in chemorefractory TNBC patients was demonstrated. Furthermore, in vivo studies performed showed a significant reduction in tumor growth, associated with a significant increase in apoptosis after the alpelisib/L-NMMA combinatorial regimen. Therefore, we hypothesize that the NOS and PI3K signaling pathways may exert their oncogenic responses synergistically to promote aggressive tumor growth. To test this hypothesis, Specific Aim 1 seeks to demonstrate the therapeutic efficacy of simultaneous inhibition of NOS and PI3K pathways with chemotherapy in MpBC pre- clinical models on primary tumor growth and metastasis. Specific Aim 2 will investigate the global and RPL39- specific ribosome translation landscape in response to NOS/PI3K inhibition in MpBC. In Specific Aim 3, the cell- cell interactions among tumor cells, myeloid cells, lymphoid cells, and stromal cells within the tumor microenvironment and their role in supporting cancer niche populations will be evaluated 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, identifies cell–cell interactions, and develops unique crosstalk models that will effectively predict outcome and treatment response and complement our recently funded U01 clinical trial on 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<5%，是一种重要的乳腺癌。健康挑战，因为它在所有乳腺癌亚型中表现出最糟糕的预后，比非 MpBC 更糟糕三阴性乳腺癌（TNBC），转移性患者的中位生存率为 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。发表 MpBC 还在核糖体蛋白 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。在最近发表的一项利用泛 NOS 抑制剂针对一氧化氮合酶 (NOS) 途径的临床试验中 NG-甲基-L-精氨酸乙酸酯 (L-NMMA) 在化疗难治性 TNBC 患者中显示出高效能。此外，进行的体内研究显示肿瘤生长显着减少，这与 alpelisib/L-NMMA 组合方案后细胞凋亡显着增加。 NOS 和 PI3K 信号通路可能协同发挥其致癌反应为了检验这一假设，具体目标 1 试图证明化疗同时抑制 NOS 和 PI3K 通路对 MpBC 前期的治疗效果具体目标 2 将研究原发性肿瘤生长和转移的临床模型和 RPL39-。在 MpBC 中，特定核糖体翻译景观响应 NOS/PI3K 抑制。肿瘤内肿瘤细胞、骨髓细胞、淋巴细胞和基质细胞之间的细胞相互作用微环境及其在支持癌症生态位群体中的作用将在单细胞水平上进行评估使用空间转录组学、免疫荧光、CyTOF 成像系统和多模式数据分析因此，本研究提出了针对组合目标方法的机制研究。 MpBC 中的两条关键通路，识别细胞间相互作用，并开发独特的串扰模型，该模型将有效预测结果和治疗反应，并补充我们最近资助的 U01 临床试验 MpBC 患者。