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：
10653814
负责人：
DAOHONG ZHOU
金额：
$ 49.76万
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/10653814
关键词：
Abscopal effect Anoikis Antigens Apoptosis Apoptotic Autoimmunity BCL-2 Protein BCL2L1 gene Bioinformatics 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 Cell Survival Cells Cessation of life Circulation 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 Infiltration Knock-out Lead MCL1 gene Malignant Neoplasms Mediating Metastatic breast cancer Metastatic/Recurrent Modeling Molecular Target Mus Neoplasm Circulating Cells Neoplasm Metastasis Organ Outcome Pathway interactions Patients Play Primary Neoplasm Protac Regulatory T-Lymphocyte Renal Cell Carcinoma Reporting Research Role Signal Transduction Specimen Systemic Therapy T-Cell Activation T-Cell Depletion 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 carcinogenesis cell killing cell type chemotherapy circulating cancer cell cytotoxicity experience hormone therapy immunoregulation improved in vivo in vivo Model inhibitor malignant breast neoplasm multidisciplinary neoantigens new therapeutic target novel pharmacologic 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.

项目概要-摘要转移是 BrCa 死亡的主要原因。大多数患有转移性 BrCa（IV 期）的女性主要接受治疗全身治疗，例如激素治疗（针对雌激素受体阳性 BrCa）、化疗、靶向治疗疗法，以及一些组合。目前的治疗方法不太可能治愈转移性 BrCa，超过诊断后5年内死亡率高达70%。很大程度上缺乏针对 BrCa 转移的治疗。在这里我们目标是开发一种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 (Treg)，从而诱导抗癌免疫。努力寻找潜在的分子靶标，我们决定使用新兴的新型 PROTAC 技术来抑制 BCL-XL。与两个我们最近开发了先导 PROTAC 化合物（BCL-XL-Ps），我们发现这两种化合物都可以有效导致 BCL-XL 在体外和体内的降解。有趣的是，BCL-XL-P 似乎有效在所有同基因癌症模型中，我们测试了对乳腺癌的最强抑制功效转移。使用多学科技术，我们相信 BCL-XL-P 可以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 在癌细胞和 Tregs 中。尽管直接杀死癌细胞可能不足以根除转移性癌细胞如初步数据所示，肿瘤生长，一部分死亡的癌细胞可能提供足够的自体或用于 T 细胞激活的新抗原。此外，癌细胞中 BCL-XL 的缺失使它们对 CD8-T 细胞敏感介导杀戮。 BCL-XL-Ps 介导的 Treg 耗竭和 T 细胞的直接激活引发了强烈的抗- 可以收获用于癌症治疗的癌症免疫力。 BCL-XL-Ps 同时耗尽 BCL-XL 癌细胞进一步使其对 CD8-T 细胞介导的杀伤变得敏感。在这里，我们将研究血统特定的角色 BCL-XL 在癌症中的应用。 BCL-XL 的临床观察结果也有力支持了转化研究蛋白质表达预测乳腺癌患者的生存期较短。我们的长期目标是发展进入临床的先导化合物，用于双重靶向癌细胞和 Tregs 来治疗转移性乳腺癌。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Diagnostic Performance of Early Sjögren's Syndrome Autoantibodies in Juvenile Sjögren's Syndrome: The University of Florida Pediatric Cohort Study.

DOI：
10.3389/fimmu.2021.704193
发表时间：
2021
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Thatayatikom A;Jun I;Bhattacharyya I;Berg K;Lee YJ;Kim Y;Adewumi A;Zhang W;Thatayatikom S;Shah A;Beal C;Modica R;Elder ME;Cha S
通讯作者：
Cha S

Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma.

DOI：
10.3390/cancers13225856
发表时间：
2021-11-22
期刊：
Cancers
影响因子：
5.2
作者：
Kim MC;Jin Z;Kolb R;Borcherding N;Chatzkel JA;Falzarano SM;Zhang W
通讯作者：
Zhang W

Breast Cancer Stem Cells: Signaling Pathways, Cellular Interactions, and Therapeutic Implications.

DOI：
10.3390/cancers14133287
发表时间：
2022-07-05
期刊：
Cancers
影响因子：
5.2
作者：
通讯作者：

Patent landscape of inhibitors and PROTACs of the anti-apoptotic BCL-2 family proteins.

抗凋亡 BCL-2 家族蛋白抑制剂和 PROTAC 的专利情况。

DOI：
10.1080/13543776.2022.2116311
发表时间：
2022-09
期刊：
EXPERT OPINION ON THERAPEUTIC PATENTS
影响因子：
6.6
作者：
Pal, Pratik;Zhang, Peiyi;Poddar, Saikat K.;Zheng, Guangrong
通讯作者：
Zheng, Guangrong

Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity.

DOI：
10.1038/s41467-021-27210-x
发表时间：
2021-11-25
期刊：
Nature communications
影响因子：
16.6
作者：
Lv D;Pal P;Liu X;Jia Y;Thummuri D;Zhang P;Hu W;Pei J;Zhang Q;Zhou S;Khan S;Zhang X;Hua N;Yang Q;Arango S;Zhang W;Nayak D;Olsen SK;Weintraub ST;Hromas R;Konopleva M;Yuan Y;Zheng G;Zhou D
通讯作者：
Zhou D