A Novel Symbiotic Approach for Ovarian Cancer

治疗卵巢癌的新共生方法

基本信息

批准号：
10621319
负责人：
Jogender Tushir-Singh
金额：
$ 38.08万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10621319
关键词：
AKT inhibition Activator Appliances Adaptive Immune System Affect Affinity Agonist Animals Antibodies Antibody Specificity Antibody Therapy Apoptosis Apoptotic Beds Binding Biological Response Modifier Therapy Blood Caliber Cancer Death Rates Cancer Model Cancer Patient Cell Death Cell Death Induction Cells Cessation of life Chemoresistance Clinical Clinical Data Clinical Trials Complex Cytotoxic T-Lymphocytes Data Dimerization Disease Progression Eating Effector Cell Engineering FDA approved FOLR1 gene Female Genital Diseases Folic Acid Antagonists Goals Hematopoietic Neoplasms Home Immune Immune response Immune system Immunocompetent Individual Induction of Apoptosis Infiltration Malignant Neoplasms Malignant neoplasm of ovary Mediating Membrane Membrane Microdomains Modeling Mus Output Pathway interactions Patients Penetration Phagocytes Phagocytosis Platinum Progression-Free Survivals Property Proteins Proto-Oncogene Proteins c-akt Receptor Activation Receptor Signaling Recurrence Regulation Resistance Role Safety Signal Induction Signal Transduction Solid Solid Neoplasm Specificity Surface Surface Antigens T-Cell Depletion TNFRSF10B gene TP53 gene Testing Therapeutic Therapeutic antibodies Tissues antiangiogenesis therapy bevacizumab calreticulin cancer cell cancer immunotherapy caveolin 1 cell type chemotherapy combinatorial cross reactivity cytotoxicity effective therapy efficacious treatment feasibility testing immunogenic cell death immunogenicity improved in vivo individualized medicine loss of function mutation melanoma mouse model neoplastic cell novel ovarian neoplasm patient derived xenograft model receptor recruit resistance mechanism response success therapeutically effective treatment strategy tumor tumor microenvironment

项目摘要

The overall cancer death rates are down ~20% in past 25 years, however they remained unchanged for late stage ovarian cancer (OvCa) patients, making it the deadliest gynecological disease. Cancer immunotherapy makes use of antibody-based approaches to activate immune cells against the cancer cells and have proven effective in blood cancers and melanomas. Despite short-term positive responses, most OvCa specific antibodies have largely failed in clinical trials. This is attributed to limited infiltration of activated immune effector cells into the solid tumor bed. Therefore, it is highly important to generate efficacious therapies that have inbuilt capacity to turn OvCa against itself by exploiting inherent cancer properties. The proposed studies aim to investigate a novel and rationally combined dual-specificity antibody-based approach (called BaCa) that makes use of OvCa enriched surface antigen (FOLR1) and cancer inducible cell-death activator (DR5 or TRAIL-R2). Therapeutic antibodies individually against FOLR1 and DR5 have failed in clinical trials due to lack of efficacy. The BaCa approach combines these two targets in a single agent antibody with combined strength in the activity and selectivity. FOLR1 acts as an anchor to selectivity recruit, retain, and maintain anti-DR5 affinity in the ovarian tumor microenvironment. This results into a high level of DR5 receptor clustering, signaling and activation. As a consequence a highly superior cell death and cytotoxicity is instigated against ovarian tumors. We have already tested the feasibility of BaCa strategy in both ex vivo and in vivo OvCa models. Current application supported with comprehensive preliminary data aims to test the unique ability of BaCa strategy to engage host immune response for long-term immunogenicity against OvCa. If proved accurate and successful in vivo, this path has the inherent “moon-shot” potential to selectively eliminate HGSOC cells, in a similar or improved fashion over FDA approved dual-specificity antibody called blinatumomab. Unlike chemotherapy, proposed biological therapy is safe and will significantly change the landscape of disease progression free survival of OvCa patients. Finally, this strategy has a great potential to be applicable for other solid cancer targeting.

在过去25年中，总体癌症死亡率下降了约20％，但是迟到卵巢癌（OVCA）患者，使其成为最致命的妇科疾病。癌症免疫疗法利用基于抗体的方法激活针对癌细胞的免疫细胞并已证明有效的血液癌和黑色素瘤。尽管有短期积极的反应，但大多数OVCA特定于在临床试验中，抗体在很大程度上失败了。这归因于激活免疫的浸润有限效应细胞进入实体肿瘤床。因此，生成有效的疗法非常重要通过利用继承癌症的特性，内置了将OVCA反对自己的能力。提出的研究旨在研究一种基于双特异性抗体的方法（称为BACA），以研究一种新颖和理性组合利用OVCA富集的表面抗原（FOLR1）和癌症可诱导的细胞死亡激活剂（DR5或 TRAIL-R2）。由于缺乏，针对FOLR1和DR5单独针对FOLR1和DR5的治疗抗体失败了轻松。 BACA方法将这两个靶标结合在单剂抗体中在活动和选择性中。 FOLR1充当选择性招募，保留和维护抗DR5的锚点卵巢肿瘤微环境中的亲和力。这导致高水平的DR5受体聚类，信号传导和激活。结果，高度优势的细胞死亡和细胞毒性被激发卵巢肿瘤。我们已经测试了BACA策略在离体和体内OVCA中的可行性型号。由全面的初步数据支持的当前应用程序旨在测试 BACA策略使宿主免疫响应具有针对OVCA的长期免疫原性。如果提供该路径在体内准确而成功，具有选择性消除的继承“月球射击”潜力与FDA认可的双特异性抗体相似或改进的HGSOC细胞称为 blinatumomab。与化学疗法不同，拟议的生物学疗法是安全的，将大大改变 OVCA患者的疾病进展无生存的景观。最后，该策略具有很大的潜力适用于其他固体癌症靶向。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Feasible Alternative Strategy Targeting Furin Disrupts SARS-CoV-2 Infection Cycle.

DOI：
10.1128/spectrum.02364-21
发表时间：
2022-02-23
期刊：
Microbiology spectrum
影响因子：
3.7
作者：
Mondal T;Shivange G;Habieb A;Tushir-Singh J
通讯作者：
Tushir-Singh J

Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody.

分析靶抗原特异性治疗抗体的肿瘤和组织分布。

DOI：
10.3791/60727
发表时间：
2020
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Shivange,Gururaj;Mondal,Tanmoy;Lyerly,Evan;Gatesman,Jeremy;Tushir-Singh,Jogender
通讯作者：
Tushir-Singh,Jogender

Arming "old guards" with "new dual-targeting weapons".

用“新型双目标武器”武装“老卫士”。

DOI：
10.1016/j.ccell.2021.04.010
发表时间：
2021
期刊：
Cancer cell
影响因子：
50.3
作者：
Lum,LawrenceG;Tushir-Singh,Jogender
通讯作者：
Tushir-Singh,Jogender

Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer.

DOI：
10.1038/s41418-023-01229-7
发表时间：
2023-11
期刊：
CELL DEATH AND DIFFERENTIATION
影响因子：
12.4
作者：
Mondal, Tanmoy;Gaur, Himanshu;Wamba, Brice E. N.;Michalak, Abby Grace;Stout, Camryn;Watson, Matthew R.;Aleixo, Sophia L.;Singh, Arjun;Condello, Salvatore;Faller, Roland;Leiserowitz, Gary Scott;Bhatnagar, Sanchita;Tushir-Singh, Jogender
通讯作者：
Tushir-Singh, Jogender