Human Breast Cancer Stem Cell Surrogates

人类乳腺癌干细胞替代物

• 批准号: 8135371
• 负责人: Massimo Cristofanilli
• 金额: $ 44.62万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135371
• 关键词: Address; Aftercare; Aldehydes; Animal Model; Biopsy; Blood; Blood Tests; Bone Marrow; Breast; Breast Cancer Treatment; CD44 gene; Cancer Biology; Cancer Patient; Cell Line; Cells; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Collaborations; Commit; Core Biopsy; Cytokeratin; Data; Detection; Diagnosis; Disease; Distant; Distant Metastasis; Doctor of Philosophy; ERBB2 gene; Early Diagnosis; Ensure; Exhibits; FDA approved; Failure; Flow Cytometry; Fresh Tissue; Goals; Growth; Hematopathology; Human; Immunocompromised Host; Immunology; In Vitro; Institutional Review Boards; Interdisciplinary Study; Lead; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Measures; Mediating; Mediator of activation protein; Medical Oncology; Methods; Microscopic; Molecular; Mus; Neoadjuvant Therapy; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pattern; Phenotype; Primary Neoplasm; Principal Investigator; Property; Protocols documentation; Radiation; Radiation Oncology; Radiation therapy; Radiation-Sensitizing Agents; Recurrence; Resistance; Role; Signal Pathway; Signal Transduction; Site; Staging; Staining method; Stains; Stem cells; Technology; Testing; Therapeutic; Tissues; Transplantation; Tumor Angiogenesis; Tumor Biology; Tumor Markers; Tumor Stem Cells; Undifferentiated; Work; aldehyde dehydrogenase 1; base; cancer cell; cancer stem cell; chemotherapy; design; genetic inhibitor; improved; in vivo; lapatinib; lymph nodes; malignant breast neoplasm; minimally invasive; neoplastic cell; notch protein; novel; outcome forecast; patient population; pre-clinical; preclinical study; prognostic; radiation resistance; randomized trial; research study; resistance mechanism; response; stem cell therapy; treatment response; tumor; tumor xenograft

DESCRIPTION (provided by applicant): It has been suggested that the small fraction of tumor cells capable of initiating local or distant recurrence exhibit properties of stem cells, and that identification and molecular characterization of putative cancer stem cells will lead to better outcomes through targeted cancer stem cell therapies in appropriately selected patients. Clinical studies examining the predictive and prognostic significance of these cells have been limited by several factors, including variable methods for isolating single cells from tissues, the need for multiple markers to distinguish committed from undifferentiated cells, and the availability of fresh tissue from patients for study. Originating from the primary tumor, circulating tumor cells (in the blood) and disseminated tumor cells (in the bone marrow) are attractive cancer stem cell candidates, and practical clinical surrogates for cancer stem cell study because they exist as single cells, and can be quantified using available FDA approved technology. Therefore, we propose a translational strategy to examine primary, circulating, and disseminated tumor cells from breast cancer patients to test our central hypothesis that circulating and disseminated tumor cells present in the blood and bone marrow of non-metastatic breast cancer patients represent cancer stem cells which are precursors to distant metastases and potential targets for novel treatment. Our hypothesis is based on preliminary data from an ongoing IRB-approved clinical protocol that demonstrates disseminated tumor cells in the bone marrow of patients with non-metastatic breast cancer are positive for the expression of cancer stem cell markers of tumor initiating capacity; CD44+CD24- and aldehyde dehydrogenase-1 (ALDH1). Translational aims are based on three IRB protocols and tailored to the material collected, treatment approach, and patient population in each trial. The translational work represents an established multidisciplinary collaboration between Massimo Cristofanilli, MD Breast Medical Oncology, James Reuben, PhD, Hematopathology, and Wendy Woodward, MD-PhD, Clinical and Experimental Breast Radiation Oncology. The goals are 1) Measure CTCs and DTCs in patients without metastatic disease, assess these cells for stem cell features and correlate these to outcome and ALDH1 staining in the primary; 2) Measure CTCs and primary tumor stem cells in patients receiving neoadjuvant chemotherapy and correlate response to therapy between these measures as well as transplant and culture primary biopsy material for molecular studies; 3) Determine key mediators of ¿-catenin and Notch-1 crosstalk in radioresistance of cancer stem cells, and test inhibition of these pathways as radiosensitizers. In these studies we hope to demonstrate that CTCs/DTCs are prognostic and predictive surrogates for cancer stem cells that are easily accessible for examination on the single cell level. This approach could be used to select patients for individualized therapy using targeted sensitizing agents based on the proposed preclinical studies.

描述（由申请人提供）：已经表明，能够引发局部或远处复发的小部分肿瘤细胞表现出干细胞的特性，并且推定的癌症干细胞的鉴定和分子表征将通过在适当选择的患者中进行靶向癌症干细胞治疗而导致更好的结果。检查这些细胞的预测和预后意义的临床研究受到几个因素的限制，包括从组织中分离单细胞的不同方法、需要多种标记物来区分定向细胞和未分化细胞以及来自患者的新鲜组织的可用性用于研究。源自原发性肿瘤的循环肿瘤细胞（血液中）和播散性肿瘤细胞（骨髓中）是有吸引力的癌症干细胞候选物，并且是癌症干细胞研究的实际临床替代物，因为它们作为单细胞存在，并且可以使用可用的FDA批准的技术进行定量。因此，我们提出了一种翻译策略来检查乳腺癌患者的原发性、循环和播散性肿瘤细胞，以检验我们的中心假设，即非转移性乳腺癌患者血液和骨髓中存在的循环和播散性肿瘤细胞代表癌症干细胞，这些细胞是远处转移的前体和新治疗的潜在靶点。我们的假设是基于正在进行的IRB批准的临床方案的初步数据，该方案证明非转移性乳腺癌患者骨髓中的播散性肿瘤细胞表达肿瘤起始能力的癌症干细胞标志物; CD 44 + CD 24-和醛脱氢酶-1（ALDH 1）。转化目标基于三个IRB方案，并针对每项试验中收集的材料、治疗方法和患者人群进行定制。翻译工作代表了Massimo Cristofanilli，MD乳腺医学肿瘤学，James Reuben，PhD，血液病理学和Wendy Woodward，MD-PhD，临床和实验乳腺放射肿瘤学之间建立的多学科合作。目标是1）测量没有转移性疾病的患者中的CTC和DTC，评估这些细胞的干细胞特征并将其与原发性中的结果和ALDH 1染色相关联; 2）测量接受新辅助化疗的患者中的CTC和原发性肿瘤干细胞，并将这些测量以及移植和培养原发性活检材料之间的治疗反应相关联以用于分子研究; 3）确定在癌症干细胞的辐射抗性中的连环蛋白和Notch-1串扰的关键介质，并测试作为辐射增敏剂的这些途径的抑制。在这些研究中，我们希望证明CTC/DTC是癌症干细胞的预后和预测替代物，这些干细胞很容易在单细胞水平上进行检查。这种方法可用于选择患者进行个体化治疗，使用靶向增敏剂的基础上提出的临床前研究。