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: 10393358
• 负责人: JENNY C-N CHANG
• 金额: $ 44.89万
• 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/10393358
• 关键词: Accounting; Acetates; Apoptosis; Arginine; Automobile Driving; Biological Markers; 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; Dose; Drug resistance; Ecosystem; Endocrine; Enrollment; Environment; Epidermal Growth Factor Receptor; Epithelial; 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; PI3K/AKT; 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; 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; base; cancer stem cell; cell growth; chemotherapy; clinical center; combinatorial; drug development; druggable target; effective therapy; 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.

摘要