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

• 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
• 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

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 化生乳腺癌（MPBC）是一个罕见的子集，占所有乳腺癌的5％。 MPBC是重要的 健康挑战率显示出所有乳腺癌亚型的最惨淡的预后，比非MPBC差 三阴性乳腺癌（TNBC），转移性患者中位生存率为8个月或更少 疾病。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 发表的MPBC还显示了核糖体蛋白L39（RPL39）的功能性致癌突变， 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。 在最近发表的针对这种一氧化氮合酶（NOS）途径的临床试验中 NG-甲基-L-精氨酸（L-NMMA）表明了化学浪费性TNBC患者的高效率。 此外，进行的体内研究表明，肿瘤生长显着降低，与 Alpelisib/L-NMMA组合方案后的凋亡显着增加。因此，我们假设 NOS和PI3K信号通路可能会协同执行其致癌反应 促进侵袭性肿瘤生长。为了检验这一假设，具体目标1试图证明 MPBC Pre-pre-pre-pre-pre-pre-pre-pre-pre-pre-pre-pre-pre-pre-pre-pre the pre the pre hos-pre-pre-pre-pre the的治疗效率 原发性肿瘤生长和转移的临床模型。特定目标2将研究全球和RPL39-- 针对MPBC中的NOS/PI3K抑制作用的特定核糖体翻译景观。在特定的目标3中，细胞 - 肿瘤细胞，髓样细胞，淋巴样细胞和基质细胞之间的细胞相互作用 微环境及其在支撑癌症群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，细胞成像系统和多模式数据分析 模型。因此，这项研究提出了组合靶向方法的机械投资 MPBC中的两个关键途径，标识细胞 - 细胞相互作用，并开发出独特的串扰模型 有效地预测结果和治疗反应和完成我们最近资助的U01临床试验 MPBC患者。