Developing targeted therapies for triple-negative breast cancer

开发三阴性乳腺癌的靶向治疗

• 批准号: 8884558
• 负责人: GEN SHENG WU
• 金额: $ 31.54万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8884558
• 关键词: Affect; African American; Apoptosis; Aromatase Inhibitors; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Catalytic Domain; Cell Cycle Arrest; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Clinical; Clinical Treatment; Clinical Trials; Complex; Data; Defense Mechanisms; Disease; Drug resistance; Estrogen Receptors; FDA approved; Growth; Immune; In Vitro; Induction of Apoptosis; Ligands; Malignant Neoplasms; Mediating; Mesenchymal; Molecular; Mus; Oncologist; Paclitaxel; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphoric Monoester Hydrolases; Progesterone Receptors; Protein Phosphatase 2A Regulatory Subunit PR53; Protein Serine/Threonine Phosphatase; Public Health; Regulation; Relapse; Research; Resistance; Role; Signal Transduction; TNFSF10 gene; Tamoxifen; Testing; Therapeutic; Trastuzumab; Treatment Efficacy; Treatment Protocols; Tumor Necrosis Factor-alpha; Ubiquitination; Woman; Xenograft procedure; anticancer activity; base; cancer type; chemotherapeutic agent; citrate carrier; cullin-3; effective therapy; hormone therapy; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; novel; outcome forecast; overexpression; phase I trial; public health relevance; small molecule; targeted treatment; treatment effect; triple-negative invasive breast carcinoma; tumor; tumor growth; ubiquitin-protein ligase; young woman

DESCRIPTION (provided by applicant): Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR) and Her2. TNBC can be classified into at least six subtypes including mesenchymal-like and basal-like with the majority of TNBC categorized as mesenchymal-like. TNBC makes up approximately 15-20% of all breast cancer cases and most commonly affects younger women and African-American women. Patients with TNBC generally have a poor prognosis and short-term survival. This aggressive disease does not respond to widely used targeted therapies such as trastuzumab or endocrine therapies, such as tamoxifen or aromatase inhibitors. Although women with metastatic TNBC can initially respond to conventional chemotherapeutic agents, relapse is inevitable, and oncologists have little to offer other than additional non-cross reactive systemic chemotherapy regimens. Therefore, the challenge is to develop a more effective treatment regimen for women with metastatic TNBC. We find that serine-threonine phosphatase PP2A is a rate-limiting factor (bottleneck) that regulates drug-resistance in TNBC cells. We show that PP2A inhibitors can sensitize both sensitive and resistant mesenchymal-like TNBC cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. TRAIL-based drugs are currently being tested for the treatment of several cancer types in clinical trials. Therefore, these considerations suggest that mesenchymal-like TNBC may be likely to benefit from TRAIL therapy or in combination with PP2A inhibitor therapy. Although mesenchymal-like TNBC cells are highly sensitive to TRAIL-induced apoptosis, basal-like TNBC cells are resistant to TRAIL. We find that the PP2A inhibitor LB100, a small molecule that has recently been approved to enter phase I clinical trials for the treatment of several cancers, increases conventional chemotherapeutic agent-induced anticancer activity in basal-like TNBC cells in vitro and effectively inhibits tumor growth of basal-like TNBC in vivo. This consideration suggests that LB100 alone or in combination with clinically used chemotherapeutic agents could be an efficacious therapy for basal-like TNBC. In addition, our preliminary data show that TRAIL treatment causes the degradation of PP2A/C, a catalytic subunit of PP2A, in TNBC cells. Mechanistically, TRAIL treatment leads to the recruitment of PP2A/C to the death-inducing signaling complex (DISC) where a Cullin-3-based E3 ligase targets PP2A/C for ubiquitination and subsequent degradation. Importantly, in TNBC cells that have developed acquired TRAIL resistance, PP2A/C protein is resistant to TRAIL-induced degradation. In this proposal, we will test the hypotheses that TRAIL alone or in combination with inhibition of PP2A-mediated survival signals or clinically used chemotherapeutic agents sufficiently causes apoptosis in mesenchymal-like TNBC cells and that inhibition of PP2A survival signals alone or in combination with conventional chemotherapeutic agents effectively inhibits the growth of basal-like TNBC. We are proposing to test these hypotheses with the following three specific aims: 1) To evaluate the therapeutic efficacy of TRAIL as a single agent, in combination with LB100, or paclitaxel in mesenchymal-like TNBC cell lines and xenografts; 2) To define the molecular mechanism of PP2A/C ubiquitination in TRAIL-induced apoptosis; and 3) To determine the therapeutic efficacy of LB100 as a single agent or in combination with paclitaxel in basal-like TNBC cell lines and xenografts. This application will determine the efficacy of using TRAIL, a targeted therapy alone, in combination with LB100 (newly approved by the FDA to enter phase I clinical trials for the treatment of several types of cancer), or in combination with clinically usd chemotherapeutic agents to treat mesenchymal-like TNBC and LB100 alone or its combination with clinically used chemotherapeutic agents to treat basal-like TNBC.

描述（由申请人提供）：三阴性乳腺癌（TNBC）缺乏雌激素受体（ER）、孕激素受体（PR）和Her 2的表达。TNBC可以分为至少六种亚型，包括间充质样和基底样，其中大多数TNBC被分类为间充质样。TNBC约占所有乳腺癌病例的15-20%，最常影响年轻女性和非洲裔美国女性。TNBC患者的预后一般较差，生存期短。这种侵袭性疾病对广泛使用的靶向治疗（如曲妥珠单抗）或内分泌治疗（如他莫昔芬或芳香酶抑制剂）无反应。虽然患有转移性TNBC的女性最初可以对常规化疗药物有反应，但复发是不可避免的，肿瘤学家除了提供额外的非交叉反应性全身化疗方案外几乎没有什么可提供的。因此，挑战是为患有转移性TNBC的女性开发更有效的治疗方案。我们发现丝氨酸-苏氨酸磷酸酶PP 2A是调节TNBC细胞耐药性的限速因子（瓶颈）。我们发现PP 2A抑制剂可以使敏感和耐药间充质样TNBC细胞对肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的凋亡敏感。基于TRAIL的药物目前正在临床试验中测试用于治疗几种癌症类型。因此，这些考虑表明间充质样TNBC可能受益于TRAIL疗法或与PP 2A抑制剂疗法组合。虽然间充质样TNBC细胞对TRAIL诱导的细胞凋亡高度敏感，但基底样TNBC细胞对TRAIL具有抗性。我们发现，PP 2A抑制剂LB 100，一种最近被批准进入I期临床试验用于治疗几种癌症的小分子，在体外增加了基底样TNBC细胞中常规化疗剂诱导的抗癌活性，并在体内有效抑制基底样TNBC的肿瘤生长。这种考虑表明，单独的LB 100或与临床使用的化疗剂组合可以是基底样TNBC的有效疗法。此外，我们的初步数据显示，TRAIL处理导致TNBC细胞中PP 2A的催化亚基PP 2A/C的降解。从机制上讲，TRAIL处理导致PP 2A/C募集到死亡诱导信号复合物（DISC），其中基于Cullin-3的E3连接酶靶向PP 2A/C进行泛素化和随后的降解。重要的是，在已经产生获得性TRAIL抗性的TNBC细胞中，PP 2A/C蛋白对TRAIL诱导的降解具有抗性。在该提议中，我们将测试以下假设：单独的TRAIL或与PP 2A介导的存活信号的抑制或临床使用的化疗剂的组合足以引起间充质样TNBC细胞的凋亡，并且单独的PP 2A存活信号的抑制或与常规化疗剂的组合有效地抑制基底样TNBC的生长。我们提出用以下三个具体目标来检验这些假设：1）评估TRAIL作为单一药剂、与LB 100或紫杉醇组合在间充质样TNBC细胞系和异种移植物中的治疗功效; 2）确定PP 2A/C泛素化在TRAIL诱导的细胞凋亡中的分子机制;和3）确定LB 100作为单一药剂或与紫杉醇组合在基底样TNBC细胞系和异种移植物中的治疗功效。本申请将确定单独使用TRAIL（一种靶向疗法）、与LB 100（FDA新批准进入用于治疗几种类型癌症的I期临床试验）组合或与临床上使用的化疗剂组合来治疗间充质样TNBC和单独使用LB 100或其与临床上使用的化疗剂组合来治疗基底样TNBC的功效。