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Activating Cell Death Pathways in Breast Cancer Cells

激活乳腺癌细胞的细胞死亡途径

基本信息

批准号：
10926572
负责人：
Stanley Lipkowitz
金额：
$ 104.58万
依托单位：
DIVISION OF CLINICAL SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10926572
关键词：
Agonist Animals Antibodies Apoptosis Binding Proteins Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line Caspase Cell Death Cell Death Induction Cells Cessation of life Clinical Trials Collaborations Combined Modality Therapy Credentialing Data Drug Synergism Drug usage Endometrial Carcinoma Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epigenetic Process Family Genes Genetic Induction of Apoptosis Ligands Mediating Mitochondria National Center for Advancing Translational Sciences Necrosis Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Phase II Clinical Trials Protein Tyrosine Kinase Proteins Resistance TNF gene TNFRSF10A gene TNFRSF10B gene TNFRSF1A gene Toxic effect Trastuzumab Tumor Necrosis Factor Ligand Superfamily Member 6 Tumor Necrosis Factor Receptor Work cancer cell cancer subtypes cell killing chemotherapeutic agent functional genomics immunogenicity malignant breast neoplasm member novel novel drug class pre-clinical preclinical study receptor recruit targeted agent targeted treatment tumor initiation

项目摘要

Cancer cells avoid apoptosis by a variety of genetic and epigenetic mechanisms. TNF family death receptors (e.g., TNFR, Fas, DR3, TRAIL Receptor 1, and TRAIL Receptor 2) induce apoptosis in cells by recruiting and activating caspases upon activation by their respective ligands (e.g., TNF, Fas Ligand, and TRAIL). We are investigating the expression and function of TRAIL death receptors (members of the TNFR family) and their ligands (e.g., TRAIL and agonistic antibodies) in breast cancer cells in order to selectively trigger apoptosis in the cancer cells. In our early work, we found that most breast cancer cell lines are resistant to the induction of apoptosis by TRAIL. We have demonstrated that a subset of breast cancer cells, those with triple-negative/basal-like features are very sensitive to TRAIL-induced apoptosis while other breast cancer subtypes are relatively resistant to TRAIL-induced apoptosis. This subset of breast cancers is particularly aggressive and most in need of targeted therapies. Further, we found that TRAIL Receptor 2, and not TRAIL Receptor 1, is required for TRAIL induced apoptosis in the sensitive breast cancer cells. This latter finding will help in the selection of TRAIL agonists for eventual clinical trials in breast cancer patients. In addition, we have found that resistance to TRAIL-induced apoptosis can be overcome by co-incubation of the cells with chemotherapeutic agents, targeted agents such as trastuzumab, and EGFR inhibitors. More recently, we have demonstrated that inhibition or loss of the G2/M checkpoint tyrosine kinase Wee1 enhances TRAIL-mediated apoptosis in basal-like breast cancer cells. Together these studies are beginning to provide clear preclinical rationales for studies of TRAIL ligands alone or in combination with other drugs in patients with breast cancer. Ongoing work is: 1) using functional genomics to identify and characterize the genes and proteins that regulate apoptosis induced by TRAIL receptor agonists in breast cancer cells. 2) characterizing novel TRAIL receptor agonists in breast cancer cells, 3) evaluating the effects on the immunogenecity of breast cancer cells. In a spin off projject we are characterizing the mechanism of action of ClpP agonists. The latter drug was described to work via the TRAIL pathway. However, our data suggest that it works independent of the TRAIL pathway to kill breast cancer and other cancer cells. Our ongoing work includes 1) characterizing the mchanism of death induced by ClpP agonists on breast cancer cells; 2) in collaboration with NCATS we conducted a screen to identify drugs that synergize with ClpP agonists in breast cancer cells and are validating hits from that screen to credential combination therapies that will be useful with ClpP agonists. 3) investigating the effects of ClpP agonists on breast cancer tumor initiating cells.

癌细胞通过多种遗传和表观遗传机制避免凋亡。 TNF 家族死亡受体（例如 TNFR、Fas、DR3、TRAIL 受体 1 和 TRAIL 受体 2）在被各自配体（例如 TNF、Fas 配体和 TRAIL）激活后，通过募集和激活半胱天冬酶来诱导细胞凋亡。我们正在研究乳腺癌细胞中 TRAIL 死亡受体（TNFR 家族成员）及其配体（例如 TRAIL 和激动性抗体）的表达和功能，以选择性触发癌细胞凋亡。在我们的早期工作中，我们发现大多数乳腺癌细胞系对 TRAIL 诱导的细胞凋亡具有抵抗力。我们已经证明，具有三阴性/基底细胞样特征的乳腺癌细胞子集对 TRAIL 诱导的细胞凋亡非常敏感，而其他乳腺癌亚型对 TRAIL 诱导的细胞凋亡相对抵抗。这部分乳腺癌特别具有侵袭性，最需要靶向治疗。此外，我们发现 TRAIL 受体 2，而不是 TRAIL 受体 1，是 TRAIL 诱导敏感乳腺癌细胞凋亡所必需的。后一项发现将有助于选择 TRAIL 激动剂用于乳腺癌患者的最终临床试验。此外，我们还发现，通过将细胞与化疗药物、曲妥珠单抗等靶向药物和 EGFR 抑制剂共孵育，可以克服对 TRAIL 诱导的细胞凋亡的抵抗。最近，我们已经证明，G2/M 检查点酪氨酸激酶 Wee1 的抑制或缺失会增强 TRAIL 介导的基底样乳腺癌细胞的细胞凋亡。这些研究共同开始为乳腺癌患者单独或与其他药物联合使用 TRAIL 配体的研究提供明确的临床前原理。正在进行的工作是：1) 使用功能基因组学来鉴定和表征调节乳腺癌细胞中 TRAIL 受体激动剂诱导的细胞凋亡的基因和蛋白质。 2) 表征乳腺癌细胞中新型 TRAIL 受体激动剂，3) 评估对乳腺癌细胞免疫原性的影响。在一个衍生项目中，我们正在表征 ClpP 激动剂的作用机制。后一种药物被描述为通过 TRAIL 途径发挥作用。然而，我们的数据表明它的作用独立于 TRAIL 通路来杀死乳腺癌和其他癌细胞。我们正在进行的工作包括 1) 描述 ClpP 激动剂对乳腺癌细胞诱导死亡的机制； 2) 我们与 NCATS 合作进行了筛选，以确定在乳腺癌细胞中与 ClpP 激动剂协同作用的药物，并正在验证该筛选的命中结果，以验证可与 ClpP 激动剂一起使用的联合疗法。 3)研究ClpP激动剂对乳腺癌肿瘤起始细胞的影响。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer.

DOI：
10.3390/cancers15071936
发表时间：
2023-03-23
期刊：
Cancers
影响因子：
5.2
作者：
通讯作者：

Identification of WEE1 as a potential molecular target in cancer cells by RNAi screening of the human tyrosine kinome.

DOI：
10.1007/s10549-009-0571-2
发表时间：
2010-07
期刊：
BREAST CANCER RESEARCH AND TREATMENT
影响因子：
3.8
作者：
Murrow, Lyndsay M.;Garimella, Sireesha V.;Jones, Tamara L.;Caplen, Natasha J.;Lipkowitz, Stanley
通讯作者：
Lipkowitz, Stanley

Targeting TRAIL Death Receptors in Triple-Negative Breast Cancers: Challenges and Strategies for Cancer Therapy.