HER1-3 and Death Receptor protein folding as therapeutic vulnerabilities

HER1-3 和死亡受体蛋白折叠作为治疗漏洞

• 批准号: 10721930
• 负责人: Brian K. Law
• 金额: $ 20.96万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721930
• 关键词: AGR2 gene; Active Sites; Advanced Malignant Neoplasm; Adverse effects; Affect; African American; Agonist; American; Animal Model; Animals; Antineoplastic Agents; Apoptosis; Apoptotic; Autopsy; Binding; Biological Markers; Blood Cell Count; Breast; Breast Cancer Cell; Breast Cancer Patient; CASP8 gene; Cell Death; Cell surface; Cessation of life; Chemicals; Client; Clinical; Clinical Trials; Dependence; Disseminated Malignant Neoplasm; Disulfides; Dose; Down-Regulation; Drug Kinetics; Drug resistance; ERBB2 gene; ERBB3 gene; Epidermal Growth Factor Receptor; Ethnic Population; Exhibits; Family; Formulation; Future; Health; Heterodimerization; Histologic; Human; IGF1R gene; Induction of Apoptosis; Kidney; Knock-out; Ligands; Link; Liver; Malignant Neoplasms; Mediating; Medicine; Metabolism; Modeling; Monitor; Mus; Muscle; Needle biopsy procedure; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Oncogenic; Oncoproteins; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma; Preparation; Primary Neoplasm; Property; Protein Disulfide Isomerase; Protein Inhibition; Proteins; Publishing; Receptor Protein-Tyrosine Kinases; Refractory; Resistance; Role; Route; Safety; Sampling; Signal Transduction; Structure; TNFRSF10A gene; TNFRSF10B gene; Therapeutic; Toxic effect; Tumor Escape; Tumor Necrosis Factor Receptor; Tumor Necrosis Factors; Up-Regulation; Woman; Work; advanced breast cancer; anti-cancer; biomarker validation; breast cancer survival; cancer cell; cancer subtypes; cancer survival; carcinogenesis; clinically relevant; disulfide bond; dosage; improved; in vivo; inhibitor; malignant breast neoplasm; mortality; overexpression; patient stratification; pharmacokinetics and pharmacodynamics; pharmacologic; preclinical efficacy; preclinical study; predictive marker; prevent; protein folding; receptor; refractory cancer; response; targeted agent; therapeutically effective; therapy resistant; treatment effect; triple-negative invasive breast carcinoma; tumor

Breast cancer remains a major killer of women due to the ineffectiveness of current drugs against metastatic and drug-resistant cancers. Additionally, African American (AA) women suffer disproportionately from breast cancer mortality in part because they develop the aggressive Triple- Negative Breast Cancer (TNBC) subtype more frequently than other ethnic groups. Thus, agents effective against drug-resistant and metastatic cancers and TNBCs may improve the survival of breast cancer patients. These aggressive cancers evade cell death through a variety of mechanisms including overactivation of the pro-survival HER-family of Receptor Tyrosine Kinases (RTKs), including EGFR/HER1, HER2, and HER3 (HER1-3), and inactivation of pro-apoptotic signaling. Tumors expressing HER1-3 are difficult to treat due to the partial redundancy among these receptors, their oncogenic signaling as heterodimers, and their ability to aberrantly heterodimerize with non-HER RTKs such as MET and IGF1R. Thus, resistance to current HER-targeted agents is a significant clinical problem. Defective cancer cell apoptosis can result from inactivation of the TNF Receptor Apoptosis Inducing Ligand (TRAIL)/Death Receptor 4/5 (DR4/5) pathway, which selectively kills cancer cells, while not affecting normal cells. Tumor resistance to TRAIL and other DR4/5 agonists results primarily from poor pharmacological properties of the agonists and the ability of cancer cells to downregulate DR4/5. Consequently, agents that could inactivate the EGFR/HER2/HER3 signaling axis and upregulate and activate DR4/5 independently of the TRAIL ligand may be efficacious against breast cancers unresponsive to current medicines. Disulfide bond Disrupting Agents (DDAs) are a new class of anti-cancer agents that induce regression of primary tumors and metastatic lesions of drug-resistant patient-derived tumors in animal models. In addition to the structural uniqueness of DDAs, recent studies indicate that DDAs are the first identified active site inhibitors of the Protein Disulfide Isomerases (PDIs) ERp44 and AGR2. Further, DDA inhibition of the PDIs ERp44, AGR2, and PDIA1 alters the disulfide bonding of HER1-3 and DR4/5, resulting in HER1-3 downregulation, DR5 upregulation, and disulfide bond-mediated oligomerization and activation of DR4/5. The objective of the current project is to move DDAs toward clinical trials. The two Specific Aims proposed to achieve this objective are to 1) optimize DDA pharmacological properties and dosing for future IND-enabling studies, and 2) validate biomarkers to predict tumor sensitivity to DDAs and to monitor target engagement, and thoroughly evaluate any adverse effects of DDAs on normal tissues or animal health. Based on their unique mechanisms of action and preclinical efficacy, we expect DDAs to benefit breast cancer patients with treatment-refractory breast cancers.

由于目前的药物对乳腺癌无效，乳腺癌仍然是女性的主要杀手 转移性和耐药性癌症。此外，非裔美国 (AA) 女性也遭受痛苦 乳腺癌死亡率不成比例，部分原因是它们发展出侵袭性三重 阴性乳腺癌 (TNBC) 亚型比其他种族群体更常见。因此，代理商 有效对抗耐药性和转移性癌症以及 TNBC 可能会提高患者的生存率 乳腺癌患者。这些侵袭性癌症通过多种机制逃避细胞死亡 包括受体酪氨酸激酶 (RTK) 的促生存 HER 家族的过度激活， 包括 EGFR/HER1、HER2 和 HER3 (HER1-3)，以及促凋亡信号传导失活。 由于这些受体之间的部分冗余，表达 HER1-3 的肿瘤难以治疗， 它们作为异二聚体的致癌信号传导，以及它们与非 HER 异常异二聚化的能力 RTK，例如 MET 和 IGF1R。因此，对当前 HER 靶向药物的耐药性是一个重要的问题。 临床问题。 TNF 受体失活可能导致癌细胞凋亡缺陷 细胞凋亡诱导配体 (TRAIL)/死亡受体 4/5 (DR4/5) 途径，选择性杀死 癌细胞，同时不影响正常细胞。肿瘤对 TRAIL 和其他 DR4/5 激动剂的耐药性 主要是由于激动剂的药理学特性较差以及癌细胞的能力所致 下调 DR4/5。因此，可以灭活 EGFR/HER2/HER3 信号传导的药物 轴并独立于 TRAIL 配体上调和激活 DR4/5 可能有效对抗 对当前药物无反应的乳腺癌。二硫键破坏剂（DDA）是一种 诱导原发性肿瘤和转移性病变消退的新型抗癌药物 动物模型中的耐药患者源性肿瘤。除了结构的独特性 DDA，最近的研究表明，DDA 是第一个确定的蛋白质活性位点抑制剂 二硫键异构酶 (PDI) ERp44 和 AGR2。此外，DDA 抑制 PDIs ERp44、AGR2、 PDIA1 改变 HER1-3 和 DR4/5 的二硫键，导致 HER1-3 下调， DR5 上调，以及二硫键介导的寡聚化和 DR4/5 激活。这 当前项目的目标是将 DDA 推向临床试验。提出的两个具体目标 为了实现这一目标，1) 优化 DDA 药理学特性和未来剂量 支持 IND 的研究，2) 验证生物标志物以预测肿瘤对 DDA 的敏感性并监测 目标参与，并彻底评估 DDA 对正常组织或 动物健康。基于其独特的作用机制和临床前功效，我们预计 DDA 使患有难治性乳腺癌的乳腺癌患者受益。