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.

项目总结/摘要：乳腺癌（BC）是最常见和第二大致死性疾病 女性的恶性肿瘤开发治疗耐药BCa（TR-1）患者的新型有效疗法 BC）和三阴性BCa（TNBC）仍然是改善生存结局的最高未满足需求。脯氨酸-， 谷氨酸和富含亮氨酸的蛋白1（PELP 1）是一种原癌基因，在多个核细胞中起关键作用。 受体（NR）功能导致BC进展。PELP 1表达在BCa中上调，促进 通过组蛋白修饰的表观遗传变化，是BCa生存不良的预后指标， 药物治疗抵抗和转移。我的F31论文研究的重点是开发一个先进的， 类小分子抑制剂靶向致癌PELP 1（SMIPs），并阐明其作为一种先进的 BC疗法。我假设PELP 1将NR与表观遗传修饰剂偶联，并以SMIP靶向该轴 将在治疗TR-BC和TNBC方面具有治疗效用。我的初步数据显示铅化合物， SMIP 34抑制一组已建立的BCa细胞系的增殖，IC 50在3-10μM之间。结果 表明SMIP 34具有阻断PELP 1致癌功能能力，包括降低细胞活力， 侵袭性和促进细胞凋亡。目标1将定义SMIP 34作为 PELP 1抑制剂。我将使用多种生物物理学方法来证实SMIP 34与PELP 1的直接相互作用。 我将使用PELP 1的条件性CRISPR敲除进一步确认特异性。我将评估 SMIP 34抑制PELP 1致癌相互作用组并评估下游信号通路的调节 使用全基因组方法，包括ChIP-Seq和质谱分析。SMIP 34治疗的效果 将通过RNA-Seq测定基因表达，并进一步分析，以确定潜在的相关性 生物标志物。目的2将评估SMIP 34在使用临床前和临床试验治疗晚期乳腺癌中的效用。 PDX模型。免疫活性的CD 1小鼠模型将用于研究毒性并确定 SMIP 34的最大耐受剂量。将使用患者来源的外植体（PDEX）模型来表征 SMIP 34对人BC肿瘤外植体生长的离体作用。TR-BC和TNBC同基因模型， 除了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。我会用免疫组化技术分析肿瘤组织 以确认作用机制和功效。我的长期职业目标是阐明 乳腺癌和妇科癌症中的致癌信号传导，以开发靶向 治疗最终，F31奖学金将提供多种机会来发展我的职业生涯， 一个独立的研究者，专注于女性癌症的新的转化进展 治疗学