Proteolysis-targeting chimera against BCL-XL inhibits breast cancer metastasis

针对 BCL-XL 的蛋白水解靶向嵌合体抑制乳腺癌转移

基本信息

批准号：
10390383
负责人：
DAOHONG ZHOU
金额：
$ 49.36万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10390383
关键词：
Abscopal effect Anoikis Antigens Apoptosis Apoptotic Autoimmunity BCL-2 Protein BCL2L1 gene Bioinformatics Blood Circulation Blood Platelets Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast cancer metastasis CD27 Antigens CD8-Positive T-Lymphocytes CD8B1 gene Cancer Model Cell Death Cells Cessation of life Chemotherapy-Oncologic Procedure Clinic Clinical Colon Carcinoma Cross Presentation Data Death Rate Dendritic Cells Development Diagnosis Disseminated Malignant Neoplasm Distal Dose-Limiting Equilibrium Estrogen receptor positive Exhibits Genetic Goals Harvest Human Immune Immune system Immunocompetent Immunodeficient Mouse Immunohistochemistry Immunotherapy In Vitro Knock-out Lead MCL1 gene Malignant Neoplasms Mediating Metastatic breast cancer Modeling Molecular Target Mus Neoplasm Circulating Cells Neoplasm Metastasis Organ Outcome Pathway interactions Patients Pharmacology Play Primary Neoplasm Protac Protein Analysis Recurrence Regulatory T-Lymphocyte Renal Cell Carcinoma Reporting Research Role Signal Transduction Specimen Systemic Therapy T-Cell Activation T-Lymphocyte Techniques Technology Testing Therapeutic Time Toxic effect Translating Translational Research Tumor Antigens Tumor Cell Invasion Tumor Immunity Tumor Suppression Tumor-infiltrating immune cells Ubiquitination Woman Work anti-cancer bcl-xlong protein cancer cell cancer therapy cell killing cell type circulating cancer cell cytotoxicity experience hormone therapy immunoregulation improved in vivo in vivo Model inhibitor malignant breast neoplasm multidisciplinary neoantigens new therapeutic target novel prevent protein expression side effect targeted treatment therapeutic target treatment strategy tumor tumor growth tumor-immune system interactions ubiquitin-protein ligase

项目摘要

Project Summary-Abstract Metastasis is the major cause of BrCa death. Most women with metastatic BrCa (stage IV) are treated mainly with systemic therapy such as hormone therapy (for estrogen receptor-positive BrCa), chemotherapy, targeted therapy, and some combinations. Current treatments are very unlikely to cure metastatic BrCa, with more than 70% death rate within 5 years of diagnosis. Therapeutic targeting BrCa metastasis is largely lacking. Here we are aiming to develop a single agent with dual targeting capability: 1) to kill metastatic cancer cells directly; 2) to kill cancer specific regulatory T cells (Tregs) hence inducing anti-cancer immunity. With an effort to search the potential molecular target, we decided to inhibit BCL-XL using an emerging novel PROTAC technology. With two lead PROTAC compounds (BCL-XL-Ps) we have recently developed, we found that both compounds can efficiently lead to the degradation of BCL-XL in vitro and in vivo. Interestingly, it appears that the BCL-XL-Ps work in all syngeneic cancer models we have tested with the strongest suppressive efficacy in breast cancer metastasis. Using multidisciplinary techniques, we believe BCL-XL-Ps kill metastatic cancer cells and Tregs simultaneously as we initially expected. The current project will define the lineage-specific role of BCL-XL in cancer cells and in Tregs. Even though the direct cancer cell killing may not be sufficient to eradicate metastatic tumor growth as shown in the preliminary data, a portion of dead cancer cells may provide sufficient auto- or neo-antigens for T cell activation. In addition, BCL-XL depletion in cancer cells sensitizes them to CD8-T cell mediated killing. The BCL-XL-Ps-mediated Treg depletion and direct activation of T cells elicits a strong anti- cancer immunity that can be harvested for cancer therapy. Simultaneous depletion of BCL-XL by BCL-XL-Ps in cancer cells further sensitize them to CD8-T cell mediated killing. Here we will study the lineage-specific roles of BCL-XL in cancer. The translational research is also strongly supported by clinical observations that BCL-XL protein expression predicts shorter patient survival in breast cancer patients. Our long-term goal is to develop the lead compound into clinic for dual targeting of cancer cells and Tregs in treating metastatic breast cancers.

项目摘要提取转移是BRCA死亡的主要原因。大多数转移性BRCA（IV阶段）的女性主要接受与全身治疗（例如激素疗法）（用于雌激素受体阳性BRCA），化学疗法有针对性治疗和一些组合。当前的治疗极不可能治愈转移性BRCA，超过诊断后5年内的死亡率为70％。靶向BRCA转移的治疗性靶向很大程度上是缺乏的。我们在这里旨在开发具有双重靶向能力的单一药物：1）直接杀死转移性癌细胞； 2）到杀死癌症特异性调节性T细胞（Tregs），因此诱导抗癌免疫力。为了搜索潜在的分子靶标，我们决定使用新兴的新型Protac技术抑制BCL-XL。有两个我们最近开发的铅Protac化合物（BCl-XL-PS），我们发现两种化合物都可以有效地导致Bcl-XL体外和体内降解。有趣的是，BCL-XL-PS似乎有效在所有合成癌模型中，我们都以乳腺癌最强的抑制功效进行了测试转移。使用多学科技术，我们认为BCL-XL-PS杀死转移性癌细胞和Tregs 正如我们最初预期的那样。当前的项目将定义BCL-XL的谱系特定作用癌细胞和Tregs。即使直接癌细胞杀死可能不足以消除转移性肿瘤生长如初步数据所示，一部分死癌细胞可能会提供足够的自动或新抗原用于T细胞活化。此外，癌细胞中的BCl-XL耗竭将其敏感到CD8-T细胞介导的杀戮。 Bcl-XL-PS介导的Treg耗竭和T细胞的直接激活引起了强抗可以收获癌症治疗的癌症免疫力。 Bcl-XL-PS同时耗尽BCl-XL 癌细胞将它们进一步敏感到CD8-T细胞介导的杀戮。在这里，我们将研究谱系特定的角色癌症中的BCl-XL。 BCL-XL的临床观察结果也得到了转化研究的强烈支持蛋白质表达预测乳腺癌患者的患者生存率较短。我们的长期目标是发展铅化合物进入诊所，以双重靶向癌细胞和TREG治疗转移性乳腺癌。