Development of Small Molecule Inhibitor of PELP1 for Treating Advanced Breast Cancer

开发治疗晚期乳腺癌的 PELP1 小分子抑制剂

• 批准号: 10362545
• 负责人: Kristin Ann Altwegg
• 金额: $ 1.62万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10362545
• 关键词: Affect; Aggressive Clinical Course; Apoptosis; Aromatase Inhibitors; Biogenesis; Biological Assay; Biological Markers; Breast Cancer Patient; Breast Cancer therapy; Cancer Intervention; Cell Line; Cell Survival; ChIP-seq; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Couples; Data; Development; Diagnosis; Disease; Disease Progression; ERBB2 gene; Endocrinology; Engineering; Enzymes; Epigenetic Process; Estrogen Antagonists; Estrogen Receptors; Estrogen receptor positive; Extramural Activities; Fellowship; Female; Foundations; Funding; Gene Expression; Glutamic Acid; Goals; Growth; Growth Factor; HDAC2 gene; Histones; Human; Immunocompetent; Knock-out; Knowledge; Lead; Leucine; MAP Kinase Gene; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Modeling; Neoplasm Metastasis; Nuclear Receptors; Oncogenic; Outcome; Patients; Pharmacotherapy; Play; Pre-Clinical Model; Proline; Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogenes; Public Health; Research; Research Personnel; Research Proposals; Resistance; Ribosomes; Role; SETDB1 gene; Signal Pathway; Signal Transduction; Small Interfering RNA; Specificity; Technology; Testing; Therapeutic; Toxic effect; Training; Tumor Tissue; Tumor Volume; Woman; Xenograft Model; advanced breast cancer; anticancer research; biophysical techniques; breast cancer progression; career; coactivator-associated arginine methyltransferase 1; effective therapy; efficacy evaluation; genome-wide; histone modification; hormonal signals; hormone therapy; improved; in vivo; inhibitor; innovation; knock-down; malignant breast neoplasm; molecular subtypes; mouse model; novel; patient derived xenograft model; peptidomimetics; prognostic indicator; receptor function; small molecular inhibitor; small molecule inhibitor; survival outcome; survivorship; targeted treatment; therapy resistant; transcriptome sequencing; treatment effect; treatment strategy; tumor; tumor growth; tumor xenograft

PROJECT SUMMARY/ABSTRACT: Breast cancer (BC) is the most prevalent and second most lethal malignancy in females. Development of novel effective therapies for patients with therapy-resistant BCa (TR- BC) and triple negative BCa (TNBC) remains the highest unmet need in improving survival outcomes. Proline-, glutamic acid, and leucine-rich protein 1 (PELP1), is a proto-oncogene that plays a critical role in multiple nuclear receptor (NR) functions leading to BC progression. PELP1 expression is upregulated in BCa, promotes epigenetic changes through histone modification, is a prognostic indicator of poor BCa survival, and contributes to drug therapy-resistance and metastases. The focus of my F31 dissertation research is to develop a First-in- Class small molecule inhibitor targeting oncogenic PELP1 (SMIPs) and elucidate the efficacy as an advanced BC therapy. I hypothesize that PELP1 couples NRs with epigenetic modifiers and targeting this axis with SMIPs will have therapeutic utility in treating both TR-BC and TNBC. My preliminary data indicates lead compound, SMIP34, inhibits proliferation in an established panel of BCa cell lines with an IC50 between 3-10μM. Results indicate that SMIP34 has ability to block PELP1 oncogenic functions including reduction of cell viability and invasiveness and promotion of apoptosis. Aim 1 will define the mechanisms by which SMIP34 functions as a PELP1 inhibitor. I will use multiple biophysical methods to confirm the direct interaction of SMIP34 with PELP1. I will further confirm specificity using conditional CRISPR knockout of PELP1. I will evaluate the ability of SMIP34 to inhibit the PELP1 oncogenic interactome and assess modulation of downstream signaling pathways using genome wide approaches including ChIP-Seq and Mass Spec analyses. The effects of SMIP34 treatment on gene expression will be determined by RNA-Seq and further analyzed in order to identify potential correlative biomarkers. Aim 2 will evaluate the utility of SMIP 34 in treating advanced breast cancer using preclinical and PDX models. Immuno-competent CD1 mouse models will be used to study toxicity and to determine the maximum tolerated dose of SMIP34. Patient derived explant (PDEX) models will be utilized to characterize the ex vivo effects of SMIP34 on growth of human BC tumor explants. Both TR-BC and TNBC syngenic models, in addition to PDX orthotopic xenograft models, will be utilized to test the effects of treatment on tumor volume, disease progression, maximum tolerated dose, and observable toxicity. I will use IHC analyses of tumor tissues to confirm mechanism of action and efficacy. My long-term career objective is elucidating the mechanistic contributions oncogenic signaling in breast and gynecological cancers for the purpose of developing targeted therapies. Ultimately, the F31 Fellowship will provide multiple opportunities to develop my career as an independent extramurally funded investigator focused on novel translational advances in women's cancer therapeutics.

项目摘要/摘要：乳腺癌（BC）是最普遍，第二大致命的 女性的恶性肿瘤。开发耐治疗BCA患者的新型有效疗法（TR- BC）和三阴性BCA（TNBC）仍然是改善生存结果的最高未满足需求。脯氨酸 - 谷氨酸和富含亮氨酸的蛋白1（PELP1）是一种原始癌基因，在多重核中起关键作用 受体（NR）功能导致BC进展。 PELP1表达式在BCA中进行了更新，促进 通过组蛋白修饰的表观遗传变化是BCA存活不良的预后指标，并有助于 进行药物疗法的抗性和转移。我的F31论文研究的重点是开发第一台 类小分子抑制剂靶向致癌PELP1（SMIPS），并阐明效率为先进 卑诗省治疗。我假设PELP1与表观遗传学修饰符NRS NRS并用SMIPS靶向该轴 将具有治疗型TR-BC和TNBC的治疗效用。我的初步数据表明铅化合物， SMIP34，抑制在3-10μm之间IC50的已建立的BCA细胞系中的增殖。结果 表明SMIP34具有阻断PELP1致癌功能的能力，包括降低细胞活力和 侵入性和凋亡的促进。 AIM 1将定义SMIP34用作一个机制 PELP1抑制剂。我将使用多种生物物理方法来确认SMIP34与PELP1的直接相互作用。 我将使用PELP1的条件CRIS敲除进一步确认特异性。我将评估 SMIP34抑制PELP1致癌相互作用组和下游信号通路的评估调制 使用基因组范围的方法，包括CHIP-seq和Mass Spec分析。 SMIP34处理的影响 基因表达将通过RNA-Seq确定并进一步分析以识别潜在的相关性 生物标志物。 AIM 2将评估SMIP 34使用临床前和临床前治疗晚期乳腺癌的实用性 PDX型号。免疫能力的CD1小鼠模型将用于研究毒性并确定 最大耐受剂量的SMIP34。患者衍生的外植体（PDEX）模型将用于表征 SMIP34对人BC肿瘤外植体生长的离体影响。 TR-BC和TNBC合成模型， 除PDX原位异种移植模型外，还将用于测试治疗对肿瘤体积的影响， 疾病进展，最大耐受剂量和可观察到的毒性。我将使用肿瘤组织的IHC分析 确认作用和效率机制。我的长期职业目标是阐明机制 乳腺癌和妇科癌中的致癌信号传导，目的 疗法。最终，F31奖学金将为发展我的职业提供多种机会 独立的外部资助研究者，重点关注妇女癌症的新转化进展 疗法。