Molecular features of patient-derived luminal breast cancer xenotransplant models

描述(申请人提供)：尽管多年来学术、政府和制药机构投入了巨大的资金和努力，但大多数在小鼠身上显示出希望的乳腺癌药物无法治愈患者的乳腺癌。这种低效是极其昂贵的，并且阻碍了新的有效的乳腺癌药物的识别。这种差异表明，对于正确预测人类乳腺癌的药物反应，小鼠不是一个可靠的模型。尽管如此，在针对乳腺癌的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具有良好的效果。我们已经发现并纠正了小鼠的一个关键荷尔蒙缺陷，使普通小鼠不适合雌激素受体阳性的人类乳腺癌的建模和药物测试。我们创造了基因工程小鼠，恢复了缺失的荷尔蒙成分--垂体人催乳素，并确定催乳素人源化的小鼠是雌激素受体阳性患者来源的乳腺癌组织的优秀接受者。有趣的是，我们已经建立了两个雌激素受体阳性患者的来源系，它们是从原位乳房植入部位自发转移到肺的。这些模型将首次允许我们探索新的治疗策略，以提高抗雌激素在转移环境中的疗效。这一点很重要，因为乳腺癌的辅助治疗是在原发肿瘤手术切除后进行的，乳腺癌患者死于转移而不是原发肿瘤。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和原发肿瘤的平行分子图谱来实现，以确定替代候选药物靶点。这个探索性的R21项目的新概念得到了坚实的科学理论和以前无法获得的实验模型的支持。潜在的影响是强烈的，有可能发现转移性ER阳性乳腺癌的改进治疗策略，可能在非常短的时间内使患者受益。这个项目意义重大，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，新的荷尔蒙改进的小鼠模型可以作为一种培养容器来确定患者肿瘤对一组现有药物的敏感性，从而立即使患者个体受益。结果可能是转移性乳腺癌的挽救生命的量身定做的治疗。

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.