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.

乳腺癌仍然是妇女的主要杀手，由于目前的药物无效， 转移性和耐药性癌症。此外，非洲裔美国人（AA）妇女遭受 不成比例的乳腺癌死亡率，部分原因是他们发展了积极的三重- 阴性乳腺癌（TNBC）亚型比其他种族更常见。因此，代理 有效对抗耐药性和转移性癌症和TNBC可能会改善患者的生存期。 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）的促存活HER家族的过度活化， 包括EGFR/HER 1、HER 2和HER 3（HER 1 -3），以及促凋亡信号传导的失活。 表达HER 1 -3的肿瘤由于这些受体之间的部分冗余而难以治疗， 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，如MET和IGF 1 R。因此，对当前HER靶向剂的抗性是一个显著的不利因素。 临床问题肿瘤坏死因子受体失活可导致癌细胞凋亡缺陷 凋亡诱导配体（TRAIL）/死亡受体4/5（DR 4/5）途径，选择性杀死 癌细胞，而不影响正常细胞。肿瘤对TRAIL和其他DR 4/5激动剂的耐药性 这主要是由于激动剂的药理学性质差以及癌细胞 下调DR 4/5。因此，可以抑制EGFR/HER 2/HER 3信号传导的药物 轴和上调和激活DR 4/5独立的TRAIL配体可能是有效的， 乳腺癌对现有药物无反应。二硫键破坏剂（DDAs） 诱导原发性肿瘤和转移性病灶消退的一类新的抗癌剂， 在动物模型中的耐药患者来源的肿瘤。除了结构上的独特性， DDAs，最近的研究表明，DDAs是第一个确定的蛋白质活性位点抑制剂 二硫化物异构酶（PDI）ERp 44和AGR 2。此外，DDA抑制PDIs ERp 44，AGR 2， PDIA 1改变HER 1 -3和DR 4/5的二硫键，导致HER 1 -3下调， DR 5上调和二硫键介导的DR 4/5寡聚化和活化。的 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的药理学性质和未来的剂量， IND使能研究，和2）验证生物标志物，以预测肿瘤对DDA的敏感性，并监测 靶向接合，并彻底评估DDA对正常组织的任何不良影响， 动物健康基于其独特的作用机制和临床前疗效，我们预计 以使患有难治性乳腺癌的乳腺癌患者受益。