HER1-3 and Death Receptor protein folding as therapeutic vulnerabilities

乳腺癌仍然是女性的主要杀手，因为目前治疗乳腺癌的药物无效 转移性和抗药性癌症。此外，非裔美国人(AA)妇女遭受 乳腺癌死亡率不成比例的部分原因是他们患上了侵袭性的三倍- 阴性乳腺癌(TNBC)亚型比其他民族更常见。因此，代理 对耐药和转移性癌症有效，TNBCs可能提高人肺癌的存活率 乳腺癌患者。这些侵袭性的癌症通过各种机制逃避细胞死亡。 包括促进生存的受体酪氨酸激酶(RTK)HER家族的过度激活， 包括EGFR/HER1、HER2和HER3(HER1-3)，以及促凋亡信号的失活。 由于这些受体之间的部分冗余，表达HER1-3的肿瘤很难治疗， 它们作为异源二聚体的致癌信号，以及它们与非HER异常异源二聚体的能力 RTK，如MET和IGF1R。因此，对当前HER靶向药物的耐药性是一个重要的原因。 临床问题。肿瘤坏死因子受体失活可导致有缺陷的癌细胞凋亡 凋亡诱导配体/死亡受体4/5(DR4/5)通路，选择性杀伤 癌细胞，而不影响正常细胞。肿瘤对TRAIL和其他DR4/5激动剂的耐药性 结果主要是由于激动剂的药理特性不佳以及癌细胞对 因此，可以使EGFR/HER2/HER3信号失活的药物 不依赖TRAIL配体上调和激活DR4/5可能有效地对抗 乳腺癌对目前的药物没有反应。二硫键断裂剂(DDA)是一种 诱导原发灶和转移灶消退的新型抗癌药物 耐药患者源性肿瘤动物模型。除了结构上的独特性之外， DDAS，最近的研究表明，DDAS是第一个被鉴定的蛋白质的活性部位抑制物 二硫键异构酶(PDI)ERp44和AGR2。此外，DDA对PDI ERp44，AGR2， 而PDIA1改变了HER1-3和DR4/5的二硫键，导致HER1-3下调， DR5上调，二硫键介导的DR4/5的寡聚和激活。 当前项目的目标是将DDA推向临床试验。提出了两个具体目标 实现这一目标的目标是：1)优化DDA的药理性质和未来的给药剂量 支持IND的研究，以及2)验证生物标记物以预测肿瘤对DDA的敏感性并监测 靶向参与，并彻底评估DDAS对正常组织或 动物健康。基于其独特的作用机制和临床前疗效，我们预计DDAs 使乳腺癌患者受益于治疗难治的乳腺癌。

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.