Developing Individualized Medicine Targeting Metastatic Breast Cancer Stem Cells

开发针对转移性乳腺癌干细胞的个体化药物

• 批准号: 9793276
• 负责人: Min Yu
• 金额: $ 14.12万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9793276
• 关键词: Animals; Biological Markers; Biopsy; Blood Circulation; Blood specimen; Breast Cancer Patient; Cells; Cessation of life; Clinical; Complex; Development; Disseminated Malignant Neoplasm; Distant; Face; Future; Genetic; Heterogeneity; Immunodeficient Mouse; In Vitro; Lead; Malignant Neoplasms; Metastatic breast cancer; Methods; Molecular; Neoplasm Circulating Cells; Neoplasm Metastasis; Organ; Patients; Pharmaceutical Preparations; Prediction of Response to Therapy; Predisposition; Primary Neoplasm; Property; Research; Research Proposals; Signal Transduction; Source; Stimulus; Subcategory; Testing; Training; Treatment Efficacy; Treatment Protocols; Tumor Biology; Tumor Cell Biology; Tumor Cell Line; United States; Venipunctures; Woman; Xenograft procedure; base; cancer cell; cancer stem cell; cancer therapy; drug sensitivity; effective therapy; individualized medicine; innovation; liquid biopsy; malignant breast neoplasm; metastatic process; minimally invasive; molecular marker; mortality; neoplastic cell; peripheral blood; personalized medicine; response; specific biomarkers; success; targeted treatment; transcriptomics; treatment strategy; tumor; tumorigenesis

Summary Breast cancer occurs in one in eight women in the United States and leads to 40,000 deaths annually. The leading cause of breast cancer mortality is metastasis — cancer cells spreading and growing in distant organs throughout the body. It is speculated that only a small subset of tumor cells, considered cancer stem cells (CSCs), can initiate metastases. The development of CSC-targeted therapies is crucial in treating metastasis. However, the intricate metastatic process, complex and diverse genetic backgrounds, responses to various treatments and tumor microenvironmental stimuli all lead to the functional heterogeneity of metastatic CSCs, making the identification and treatment of these cells extremely challenging. A potential approach to overcoming this challenge is the development of individualized treatments that rely on the characterization of the unique molecular properties of CSCs from a particular patient, enabling the targeting of specific cancer- promoting signals. The success of this individualized treatment strategy depends heavily on collecting the biopsies that reveal the current tumor biology in a patient. Circulating tumor cells (CTCs), shed from primary or metastatic tumors into the systemic circulation, contain potential metastatic CSCs, and venipuncture offers a feasible, minimally invasive liquid biopsy source for obtaining small quantities of these rare CTCs. Our recently pioneered ex vivo culture method for expanding these rare CTCs has enabled a proof-of-concept study to identify metastatic CSCs from the CTCs and perform drug sensitivity testing. The recent success of using a large panel of tumor cell lines to perform drug sensitivity testing and identify subcategories that predict effective treatments has also validated the concept of individualized medicine. However, a systemic approach using patient-derived metastatic CSCs to establish such biomarkers and therapy predictions has never been done before. To fill this crucial gap, in this proposal, we plan to expand CTCs obtained from metastatic breast cancer patient blood samples in vitro and evaluate their tumorigenesis in immunodeficient mice. This will allow us to functionally identify metastatic CSCs, analyze their unique molecular properties, investigate their interactions with their microenvironments, and examine their susceptibility to clinical-grade drug panels. Results from these analyses will be combined to match metastatic CSC-specific genetic and transcriptomic biomarkers with effective treatment regimens, which will be applied in the future to prescribe therapies targeting metastatic CSCs in breast cancer patients. Our success will advance the field of individualized medicine by identifying effective targeted therapies based upon the unique molecular biomarkers of metastatic CSCs from liquid biopsies. My training in genetics, CTC biology, xenografted animal studies, and drug susceptibility screens uniquely prepared me to face the challenges of this innovative research proposal and move toward the era of personalized medicine.

总结 在美国，每八名妇女中就有一名患有乳腺癌，每年导致4万人死亡。的 乳腺癌死亡的主要原因是转移-癌细胞在远处器官中扩散和生长 在整个身体。据推测，只有一小部分肿瘤细胞，被认为是癌症干细胞， （CSC）可以引发转移。CSC靶向治疗的发展在治疗转移中至关重要。 然而，复杂的转移过程，复杂多样的遗传背景，对各种肿瘤的反应， 治疗和肿瘤微环境刺激都导致转移性CSC的功能异质性， 使得这些细胞的鉴定和治疗极具挑战性。一种潜在的方法， 克服这一挑战是发展个体化治疗， 来自特定患者的CSC的独特分子特性，使其能够靶向特定的癌症- 促进信号。这种个性化治疗策略的成功在很大程度上取决于收集 活组织检查可以揭示患者当前的肿瘤生物学。循环肿瘤细胞（CTC），从原发性或 转移性肿瘤进入体循环，含有潜在的转移性CSC，静脉穿刺提供了一个 可行的，微创的液体活检来源，以获得少量的这些罕见的CTC。我们最近 用于扩增这些罕见CTC的开创性离体培养方法使概念验证研究成为可能， 从CTC中识别转移性CSC并进行药物敏感性测试。最近成功地使用了 大组肿瘤细胞系进行药物敏感性测试，并确定预测有效的亚类 治疗也验证了个体化医疗的概念。然而，一个系统的方法， 用于建立这种生物标志物和治疗预测的患者来源的转移性CSC还从未进行过 以前为了填补这一关键空白，在本提案中，我们计划扩大从转移性乳腺癌中获得的CTC 患者的血液样品在体外，并评估其在免疫缺陷小鼠的肿瘤发生。这将使我们能够 功能性鉴定转移性CSC，分析其独特的分子特性，研究其相互作用 与他们的微环境，并检查他们对临床级药物面板的敏感性。从这些 将结合分析，以匹配转移性CSC特异性遗传和转录组学生物标志物， 有效的治疗方案，这将在未来应用于处方治疗靶向转移 乳腺癌患者中的CSC。我们的成功将通过识别 基于来自液体的转移性CSC的独特分子生物标志物的有效靶向疗法 活组织检查我在遗传学、CTC生物学、异种移植动物研究和药物敏感性筛选方面的培训 独特的准备，我面对这个创新的研究建议的挑战，并走向时代， 个性化医疗

项目成果

Insights into brain metastasis: Recent advances in circulating tumor cell research.

• DOI: 10.1002/cnr2.1239
• 发表时间: 2022-04
• 期刊: CANCER REPORTS
• 影响因子: 1.7
• 作者: Klotz, Remi;Yu, Min
• 通讯作者: Yu, Min

Ectopic Expression of a Truncated Isoform of Hair Keratin 81 in Breast Cancer Alters Biophysical Characteristics to Promote Metastatic Propensity.

• DOI: 10.1002/advs.202300509
• 发表时间: 2024-02
• 期刊: Advanced science (Weinheim, Baden-Wurttemberg, Germany)
• 作者: Kang DS;Moriarty A;Wang YJ;Thomas A;Hao J;Unger BA;Klotz R;Ahmmed S;Amzaleg Y;Martin S;Vanapalli S;Xu K;Smith A;Shen K;Yu M
• 通讯作者: Yu M

Metastasis Stemming from Circulating Tumor Cell Clusters.

• DOI: 10.1016/j.tcb.2019.02.001
• 发表时间: 2019-04
• 期刊: Trends in cell biology
• 影响因子: 19
• 作者: Yu M