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.

摘要 化生性乳腺癌（MpBC）是一种罕见的亚型，占所有乳腺癌的<5%。MPBC是一个重要的 健康挑战，因为它表现出所有乳腺癌亚型中最令人沮丧的预后，比非MpBC更糟 三阴性乳腺癌（TNBC），转移性乳腺癌患者的中位生存期为8个月或更短 疾病由于缺乏药物靶点，转移性MpBC的主要治疗选择仍然是全身性的 化疗，尽管已知对大多数细胞毒性药物的耐药性。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（PI 3 K/AKT）途径的过度活化。另外我们 发表了MpBC还在核糖体蛋白L39（RPL 39）中显示功能获得性致癌突变， 其负责治疗抗性、干细胞自我更新和肺转移。机械论 RPL 39的功能通过诱导型一氧化氮合酶（iNOS）介导的一氧化氮产生来介导。 在最近发表的一项针对一氧化氮合酶（NOS）通路的泛NOS抑制剂的临床试验中， NG-甲基-L-精氨酸醋酸盐（L-NMMA）已被证明对化疗难治性TNBC患者具有高疗效。 此外，进行的体内研究显示肿瘤生长的显著减少，与肿瘤生长相关。 在alpelisib/L-NMMA组合方案后细胞凋亡显著增加。因此，我们假设 NOS和PI 3 K信号通路可能协同发挥其致癌反应， 促进恶性肿瘤生长。为了验证这一假设，具体目标1试图证明 同时抑制NOS和PI 3 K通路与化疗在MpBC前的治疗效果 原发性肿瘤生长和转移的临床模型。具体目标2将调查全球和RPL 39- MpBC中响应NOS/PI 3 K抑制的特异性核糖体翻译景观。在具体目标3中，细胞- 肿瘤内肿瘤细胞、髓样细胞、淋巴样细胞和基质细胞之间的细胞相互作用 微环境及其在支持癌症小生境人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、CyTOF成像系统和多模式数据分析， 模型因此，本研究提出了一种机制调查的组合有针对性的方法对 MpBC中的两个关键途径，识别细胞间相互作用，并开发出独特的串扰模型， 有效地预测结果和治疗反应，并补充我们最近资助的U 01临床试验， MpBC患者。