Molecular features of patient-derived luminal breast cancer xenotransplant models

患者来源的腔内乳腺癌异种移植模型的分子特征

• 批准号: 8692105
• 负责人: HALLGEIR RUI
• 金额: $ 20.23万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692105
• 关键词: Adjuvant; Agonist; Antibodies; Antiestrogen Therapy; Antineoplastic Agents; Breast Cancer Model; Breast Cancer Treatment; Bromocriptine; Cancer Patient; Clinical; Clinical Trials; Complement; Data; Development; Diagnosis; Disease; Disease Resistance; Distant; Dopamine Agonists; Drug Targeting; Endocrine; Engineering; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptors; Estrogen receptor positive; Excision; Expenditure; Experimental Models; Gene Delivery; Genetic Engineering; Genetically Engineered Mouse; Government; Heterogeneity; Hormonal; Hormones; Human; Hyperprolactinemia; IL2RA gene; Immunodeficient Mouse; Individual; Institution; Life; Lung; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Maps; Metastatic Neoplasm to the Lung; Metastatic to; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Pituitary Gland; Primary Neoplasm; Prolactin; Prolactin Receptor; Proteins; Receptor Inhibition; Residual state; Resistance; Site; Solid; Specimen; Subgroup; Testing; Therapeutic; Time; Tissues; Transcript; Work; Xenograft Model; Xenograft procedure; breast cancer diagnosis; clinically relevant; congenic; drug candidate; drug testing; expectation; hormone therapy; implantation; improved; malignant breast neoplasm; molecular marker; mouse model; novel; novel therapeutics; pre-clinical; protein profiling; public health relevance; therapeutic target; tumor

DESCRIPTION (provided by applicant): Despite enormous expenditures and efforts by academic, government, and pharmaceutical institutions over many years, most breast cancer drugs that show promise in mice, fail to cure breast cancer in patients. Such inefficiency is enormously costly and hampers identification of new and effective breast cancer drugs. This discrepancy suggests that mice are not a reliable model for correct prediction of drug responsiveness of human breast cancer. Nonetheless, before candidate drugs against breast cancer are allowed into clinical trials, FDA requires promising effects on human breast cancer grown in immunodeficient mice. We have discovered and corrected a key hormonal deficiency of mice that make regular mice suboptimal for modeling and drug testing of estrogen receptor-positive human breast cancer. We have created genetically engineered mice that restore the missing hormone component, pituitary human prolactin, and have determined that the prolactin-humanized mice are excellent recipients for estrogen receptor-positive patient-derived breast cancer tissues. Intriguingly, two of the first estrogen receptor-positive patient derived lines tha we have established spontaneously metastasize to lungs from orthotopic mammary implantation sites. These models will for the first time allow us to explore new therapeutic strategies to improve the efficacy of anti-estrogens in the metastatic setting. This is important because adjuvant treatment for breast cancer is given after surgical resection of primary tumors, and breast cancer patients die from metastases and not from the primary tumor. The objectives will be achieved by exploring combination treatment of antiestrogens with prolactin-pathway suppressive drugs as well as parallel molecular profiling of lung metastases and primary tumors to identify alternative candidate drug targets. The novel concepts of this exploratory R21 project are supported by solid scientific rationale and previously unavailable experimental models. The potential impact is strong, with the possibility of uncovering improved therapeutic strategies to metastatic ER-positive breast cancer that could benefit patients within a very short time frame. This project is significant because the majority of patients who die from breast cancer were initially diagnosed with ER-positive disease. Finally, the new hormonally improved mouse model could benefit individual patients immediately by serving as a culture vessel to determine the sensitivity of a patient's tumor against a panel of existing drugs. Life-saving, tailored therapy fr metastatic breast cancer could be a result.

描述（由申请人提供）：尽管学术界、政府和制药机构多年来付出了巨大的支出和努力，但大多数在小鼠身上显示出前景的乳腺癌药物却无法治愈患者的乳腺癌。这种低效率的成本非常高，并且阻碍了新的有效乳腺癌药物的鉴定。这种差异表明小鼠并不是正确预测人类乳腺癌药物反应的可靠模型。尽管如此，在允许抗乳腺癌候选药物进入临床试验之前，FDA 要求对在免疫缺陷小鼠中生长的人类乳腺癌有良好的效果。我们发现并纠正了小鼠的一个关键激素缺乏症，这种缺乏症导致普通小鼠在雌激素受体阳性人类乳腺癌的建模和药物测试中表现不佳。我们创造了基因工程小鼠，可以恢复缺失的激素成分——垂体人催乳素，并确定催乳素人源化小鼠是雌激素受体阳性的患者来源的乳腺癌组织的优秀受体。有趣的是，我们建立的第一个雌激素受体阳性患者的两个细胞系从原位乳腺植入部位自发转移到肺部。这些模型将首次使我们能够探索新的治疗策略，以提高转移性​​环境中抗雌激素的疗效。这很重要，因为乳腺癌的辅助治疗是在手术切除原发肿瘤后进行的，乳腺癌患者死于转移，而不是死于原发肿瘤。这些目标将通过探索抗雌激素与催乳素途径抑制药物的联合治疗以及肺转移瘤和原发性肿瘤的平行分子分析以确定替代候选药物靶点来实现。这个探索性 R21 项目的新颖概念得到了坚实的科学原理和以前无法获得的实验模型的支持。潜在的影响是巨大的，有可能发现改进的转移性 ER 阳性乳腺癌治疗策略，从而在很短的时间内使患者受益。该项目意义重大，因为大多数死于乳腺癌的患者最初被诊断为 ER 阳性疾病。最后，新的激素改善小鼠模型可以作为培养容器来确定患者肿瘤对一组现有药物的敏感性，从而立即使个体患者受益。结果可能是针对转移性乳腺癌的挽救生命的定制疗法。