Development of a new class of BLVRB-targeted redox therapeutics in breast cancer

开发一类新型 BLVRB 靶向乳腺癌氧化还原疗法

基本信息

批准号：
10759653
负责人：
Natalia Marchenko
金额：
$ 28.52万
依托单位：
BLOOD CELL TECHNOLOGIES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-14 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10759653
关键词：
Ablation Acceleration Address Animals Antioxidants Biliverdine Biochemical Biochemistry Biological Assay Biological Availability Blood Cells Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Breast Cancer therapy Cancer Biology Cell Death Cell Survival Cell model Characteristics Chemoresistance Chronic Coupled Coupling Cytoprotection Data Dependence Development Enzymes Equilibrium Feasibility Studies Generations Genetic Genetic Models Genetic study Goals Heme Human Human Genetics In Vitro Infrastructure Inhibition of Cancer Cell Growth Intellectual Property Intervention Laboratories Lead Lipid Peroxidation Malignant Neoplasms Metabolic Mitochondria Modeling Mus Names Normal Cell Oral Outcome Oxidation-Reduction Oxidative Stress Oxidoreductase Pathway interactions Pharmaceutical Chemistry Phase Phenotype Pre-Clinical Model Proliferating Radiation therapy Reactive Oxygen Species Reagent Reproducibility Research Design Research Support Resistance Structure Technology Therapeutic Time Tissues Toxic effect Translational Research Treatment Efficacy Validation Work anti-cancer therapeutic antioxidant enzyme cancer cell cellular targeting chemotherapy clinically relevant commercialization conventional therapy gene complementation human model implantation in vitro Assay in vivo in vivo Model inhibitor innovation malignant breast neoplasm mouse model novel orthotopic breast cancer oxidative damage pharmacologic pre-clinical preclinical development preclinical efficacy protoporphyrin IX standard of care tumor growth

项目摘要

SUMMARY Enhanced metabolic and mitochondrial activity inherent in actively proliferating cancer cells generates an excessive amount of reactive oxygen species (ROS), associated with intracellular redox imbalance that impacts cellular viability.To survive chronic oxidative stress, cancer cells evolve to activate scavenging/anti-oxidant enzymes to restore redox balance. This differential activation of antioxidant pathways compared to normal cells provides a therapeutic window for novel cellular targets. Moreover, the effects of chemo- and radiotherapy (in part) are attributed to oxidative stress that causes irreversible oxidative damage and cell death, and activation of redox-regulating pathways is thought to promote resistance to such therapies. The obligatory dependence of cancer cells on antioxidant defense pathways as a fundamental pro-survival mechanism suggests the broad translational utility of their targeting in breast cancer. Modulation of redox-adaptation mechanisms represents a feasible strategy to eradicate cancer cells and/or restore chemosensitivity to conventional therapies. For the first time, we identified the heme (Fe2+-protoporphyrin IX) catabolic enzyme BLVRB (biliverdin IXβ reductase) as a new cellular target in breast cancer. We demonstrated the requisite and non-redundant pro- survival antioxidant function of BLVRB in breast cancer cells, coupled with therapy resistance and poor outcomes in breast cancer patients. The primary hypothesis of this application is that BLVRB functions in a redox- regulated pathway of antioxidant handling and cytoprotection in breast cancer cells. The secondary hypothesis is that BLVRB-selective inhibitor(s) may be developed as a novel and potentially non-toxic strategy for breast cancer treatment with minimal predicted off-target effects in normal cells. Using (1) BLVRB/inhibitor co-crystal structures, (2) computational RMSD matrices for SARs, and (3) extensive ADME/T and PK studies, we identified two lead compounds with excellent bioavailability and oral PK characteristics that selectively block BLVRB redox coupling. The objectives of this proposal are (1) to extend initial proof-of-principle studies for BLVRB pre-clinical target validation using in vivo breast cancer models, and (2) to characterize first-in-class BLVRB-selective inhibitors for in vitro and in vivo efficacy. Study Design: We will apply in vivo genetic models for target validation, simultaneously addressing redox-dependent mechanisms by gene complementation studies using BLVRB+/+ and BLVRB-/- breast cancer isogenic lines: (1) to confirm requisite functions in tumor growth and metastatic burden; (2) to establish redox-dependent phenotype (Aim 1). Aim 2 will validate the pre-clinical efficacy of lead compounds using well-established phenotypic read-outs in vitro and in orthotopic breast cancer implantation models. We will also address synthetic lethality BLVRB inhibitors with standard-of-care chemotherapy in vivo. Impact: If successful, the proposed work would be first-in-class pre-clinical validation of redox inhibitors in breast cancer, representing a potential paradigm shift for cancer therapeutics.

概括积极增殖的癌细胞固有的代谢和线粒体活性增强过量的活性氧（ROS），与影响的细胞内氧化还原不平衡有关为了生存慢性氧化物应激，癌细胞演变为激活清除/抗氧化剂酶以恢复氧化还原平衡。与正常细胞相比，这种抗氧化途径的差异激活为新型细胞靶标提供了一个治疗窗口。此外，化学和放疗的作用（在部分）归因于氧化应激，会导致不可逆的氧化损伤和细胞死亡以及激活氧化还原调节途径被认为可以促进对这种疗法的抗性。强制性依赖性抗氧化剂防御途径上的癌细胞作为基本的促生物学机制表明了广泛的它们在乳腺癌中的靶向效用。氧化还原适应机制的调节代表可行的放射性癌细胞和/或恢复对常规疗法的化学敏感性的策略。我们第一次确定了血红素（Fe2+ - 甲状腺素IX）分解代谢酶BLVRB（biliverdin IXβ减少了）作为乳腺癌中的新细胞靶标。我们证明了必要的和非冗余的亲 BLVRB在乳腺癌细胞中的生存抗氧化功能，再加上耐药性和不良预后在乳腺癌患者中。该应用的主要假设是BLVRB在氧化还原中的功能乳腺癌细胞中抗氧化剂处理和细胞保护的调节途径。次要假设是BLVRB选择性抑制剂可以作为一种新型且潜在的无毒策略而开发癌症治疗最少会预测正常细胞的脱靶效应。使用（1）BLVRB/抑制剂共晶结构，（2）SARS的计算RMSD矩阵，以及（3）广泛的ADME/T和PK研究，我们确定了具有出色的生物利用度和口服PK特性的两种铅化合物，它们有选择地阻止BLVRB氧化还原耦合。该提案的目标是（1）扩展BLVRB前临床前目标的初始原则研究使用体内乳腺癌模型的验证，（2）表征一流的BLVRB选择性抑制剂的验证体外和体内效率。研究设计：我们将应用体内遗传模型进行目标验证，同样，使用BlvRB+/+和 blvrb - / - 乳腺癌等源性线：（1）确认肿瘤生长和转移性灼伤的必要功能；（2）建立依赖氧化还原的表型（AIM 1）。 AIM 2将验证铅的临床前效率在体外和原位乳腺癌植入中使用完善的表型读出的化合物型号。我们还将通过体内使用标准化学疗法来解决合成的杀伤力BLVRB抑制剂。影响：如果成功的话，拟议的工作将是对乳房中氧化还原抑制剂的第一类临床前验证癌症，代表癌症治疗的潜在范式转移。