Bone Marrow Micrometastatic Disease in Ewing Sarcoma

描述(申请人提供)：这份K23奖项的申请书包含两个互补的部分：职业发展计划和研究计划。职业发展计划将支持候选人史蒂文·杜博伊斯博士的关键额外培训，他是加州大学旧金山分校(UCSF)的儿科肿瘤学家。杜博伊斯博士利用他之前的培训，开发了一个新兴的发展疗法研究项目，专注于儿科实体肿瘤。鉴于生物标记物在早期临床研究中的作用越来越大，DuBois博士现在需要在生物标记物的开发和验证方面进行专门的培训。他将使用他的尤文肉瘤患者骨髓微转移疾病的基于流式细胞术的标记物作为平台，在此平台上获得关于流式细胞术和磷酸流式细胞术的额外教学和实践培训。他还将完成专注于检测微转移疾病的其他技术、肿瘤学分子标记物和药物基因组学的专门培训。杜博伊斯博士组建了一支由多学科导师组成的优秀团队，为他的培训和研究提供便利。在儿科实体肿瘤的临床和翻译研究方面的国际专家凯瑟琳·马泰博士将担任主要导师。她将监督整个培训和研究计划，提供她在该领域的丰富经验。Mignon Loh博士将提供她在使用磷酸流式细胞术研究癌细胞细胞内信号方面的专业知识。伊丽莎白·辛克莱博士将提供她在使用流式细胞术检测稀有细胞群方面的专业知识。该研究计划的重点是一种基于流式细胞术的技术，用于检测尤文肉瘤患者骨髓中的隐匿性肿瘤细胞。杜博伊斯博士开发了这项技术，他的初步研究表明，尽管不同患者的肿瘤细胞数量差异很大，但骨髓微转移疾病在尤文肉瘤患者中几乎是普遍存在的。在这项应用的目标1中，他建议评估未经治疗的尤文肉瘤患者的无进展生存期和基线骨髓肿瘤细胞之间的关联程度。在目标2中，他将测定尤文肉瘤患者骨髓肿瘤细胞的流式细胞仪检测的清除率。在目标3中，他将评估流式细胞术在隐匿的骨髓尤文肉瘤细胞中询问胰岛素样生长因子-1受体(IGF-1R)信号通路的能力。将这种分析方法整合到他目前的流式细胞仪分析中，将允许在骨髓肿瘤细胞中研究与临床相关的信号通路。拟议的研究将提供额外的数据，以支持R01申请，研究骨髓微转移疾病，作为尤文肉瘤国家III期临床试验中风险分层的工具。

DESCRIPTION (provided by applicant): This application for a K23 award contains two complementary components: a career development plan and a research plan. The career development plan will support critical additional training for the candidate, Dr. Steven DuBois, a pediatric oncologist at the University of California, San Francisco (UCSF). Dr. DuBois has used his previous training to develop a burgeoning developmental therapeutics research program focused on pediatric solid tumors. Given the increasing role of biomarkers in early phase clinical studies, Dr. DuBois now requires specific training in biomarker development and validation. He will use his flow cytometry-based marker of bone marrow micrometastatic disease in patients with Ewing sarcoma as a platform on which to obtain additional didactic and hands-on training in flow cytometry and phospho-flow cytometry. He will also complete dedicated training focused on other techniques for detecting micrometastatic disease, molecular markers in oncology, and pharmacogenomics. Dr. DuBois has assembled an outstanding team of multidisciplinary mentors to facilitate his training and research. Dr. Katherine Matthay, an international expert in clinical and translational studies in pediatric solid tumors, will serve as primary mentor. She will oversee the overall training and research plans, providing her wealth of experience in this field. Dr. Mignon Loh will provide her expertise on the use of phospho-flow cytometry to study intracellular signaling in cancer cells. Dr. Elizabeth Sinclair will provide her expertise in the use of flow cytometry to detect rare populations of cells. The research plan focuses on a flow cytometry-based technique for detecting occult tumor cells in the bone marrow of patients with Ewing sarcoma. Dr. DuBois developed this technique and his preliminary studies demonstrate that bone marrow micrometastatic disease is nearly universal in patients with Ewing sarcoma, though the number of tumor cells varies widely between patients. In Aim 1 of this application, he proposes to assess the magnitude of the association between progression-free survival and baseline bone marrow tumor cells in untreated patients with Ewing sarcoma. In Aim 2, he will determine the clearance rate of bone marrow tumor cells detected by flow cytometry in patients with Ewing sarcoma. In Aim 3, he will evaluate the ability of flow cytometry to interrogate insulin-like growth factor-1 receptor (IGF-1R) signaling pathways in occult bone marrow Ewing sarcoma cells. Incorporation of this assay into his current flow cytometry assay will allow a clinically-relevant signaling pathway to be studied in bone marrow tumor cells. The proposed studies will provide additional data needed to support an R01 application to study bone marrow micrometastatic disease as a tool for risk-stratification in a national phase III clinical trial for Ewing sarcoma.