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.

概括 乳腺癌发生在美国的八名妇女，每年导致40,000人死亡 乳腺癌死亡率的主要原因是转移 - 癌细胞在远处的器官中扩散和生长 在整个身体中，只有一小部分肿瘤细胞癌症干细胞 （CSC），最初的转移可以开发CSC靶向的疗法对于治疗转移至关重要。 但是，复杂的转移过程，复杂而多样的遗传背景，对各种的反应 治疗和肿瘤微环境刺激都导致转移性CSC的功能异质性， 使这些细胞的识别和处理极具挑战性。 克服这种依赖于特征的个性化治疗的挑战 来自特定患者的CSC的独特分子特性，使特定癌症的靶向 促进信号。 活检揭示了患者当前的肿瘤生物学。 转移性肿瘤进入全身循环，包含潜在的转移CSC，静脉穿刺提供 可行的，微创的液体活检源，用于获得少量的稀有CTC 开创性的离体培养方法扩展了这些稀有的CTC 从CTC中识别转移性CSC并进行药物敏感性测试。 大型肿瘤细胞底线进行药物敏感性测试并确定可预测有效的子类别 治疗还验证了个性化医学的概念。 从未做过这种生物标志物和治疗预测的患者衍生的转移性CSC 在填补这一关键差距之前，我们计划扩大从变化的乳腺癌 体外血液样本并评估其在免疫缺陷小鼠中的肿瘤。 在功能上识别转移性CSC，分析其独特的分子特性，研究其相互作用 凭借其微环境，并检查了他们对临床级药物板的感染 分析将合并为匹配匹配匹配匹配匹配csc特异性遗传和三角体生物标志物 Effective Treatment Regimens, Which Will be Applied in The Future to Prescribe TARGETING METASTATATATATATATATATATATATATATATATATATATATATATATATATATATATATATATATATITITITITIT 乳腺癌患者中的CSC。 基于液体转移性CSC的独特分子生物标志物的有效靶向疗法 活检。 独特地准备我面对这项创新研究建议的挑战，并朝着时代发展 个性化医学。

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

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

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