Integrative subtyping to improve therapeutic options for metastatic hormone receptor-positive breast cancer

项目摘要/摘要 这是向Jennifer Caswell-jin博士申请K08奖的申请书，Jennifer Caswell-jin博士是哈佛大学的讲师和乳腺肿瘤学家 斯坦福大学在翻译乳腺癌基因组研究方面建立了自己的事业。该奖项将 通过提供临床试验、生物标记物开发等方面的培训，支持她的职业发展 在克里斯蒂娜·柯蒂斯博士的专家指导下对多组数据进行生物信息学分析，计算和 癌症系统生物学家乔治·斯莱奇博士，乳腺癌临床试验和翻译研究员。 拟议的研究集中在转移性乳腺癌的主要公共卫生问题上，估计 在美国，每年有150,000多名妇女受到影响，造成40,000多人死亡。荷尔蒙 受体阳性(HR+)乳腺癌是最常见的亚型。HR+乳房的八种“综合”亚型 癌症的识别是基于全基因组拷贝数和表达信息的整合 在早期乳房肿瘤中。四个综合亚型，加在一起占所有HR+早期的四分之一 乳腺癌，表现出很高的远处转移风险；这些亚型中的每一种都具有 基因组的不同区域，表现出伴随的拷贝数增加和过度表达。中的研究 这项建议将首次研究整合亚型在转移后的表现，以及驱动 他们可能从个性化治疗方法中受益的假设。目标1是调查 转移性HR+乳腺癌的生物学特性及其综合亚型的影响我们将开发新的方法 评估整合亚型，并将了解它们是否在转移过程中发生变化，是否 与转移的时间相关，以及它们对标准的反应时间长短是否不同 治疗。目的2是评估一种新的靶向治疗组合在两种综合治疗中的效果 转移性乳腺癌的亚型。我们将进行一项临床试验，测试一种靶向治疗方法 在被归类为四种高危综合亚型之一的肿瘤中。因为这两个子类型是 由涉及成纤维细胞生长因子受体配体(FGF3； 整合亚型2)或成纤维细胞生长因子受体(FGFR1；整合亚型6)，我们假设 这些肿瘤可能受益于抑制FGFR。这项试验的参与者将接受标准的内分泌 联合抑制CDK4/6的治疗，以及抑制成纤维细胞的研究药物 生长因子受体途径。我们还将在治疗前和治疗期间进行肿瘤活检，以评估 对于这种联合靶向治疗方法所发生的变化。圆满完成 拟议的研究将为继续努力开发精确的肿瘤学方法奠定基础 转移性HR+乳腺癌，下一步将在R01拨款申请中提出， K08奖。

Project Summary/Abstract This is an application for a K08 Award to Dr Jennifer Caswell-Jin, an Instructor and breast oncologist at Stanford University establishing a career in translational breast cancer genomic research. The Award will support her career development by providing training in clinical trials, biomarker development, and bioinformatic analysis of multi-omic data under the expert mentorship of Dr Christina Curtis, computational and cancer systems biologist, and Dr George Sledge, breast cancer clinical trialist and translational researcher. The proposed research focuses on the major public health problem of metastatic breast cancer, estimated to affect over 150,000 women and to cause over 40,000 deaths each year in the United States. Hormone receptor-positive (HR+) breast cancer is the most common subtype. Eight “integrative” subtypes of HR+ breast cancer have been identified based on the integration of genome-wide copy number and expression information in early-stage breast tumors. Four integrative subtypes, together comprising one-quarter of all HR+ early-stage breast cancers, exhibit a very high risk of distant metastasis; each of these subtypes is characterized by a distinct area of the genome that exhibits concomitant copy number gain and overexpression. The studies in this proposal will examine for the first time how integrative subtypes behave after metastasis, with the driving hypothesis that they may derive benefit from personalized therapeutic approaches. Aim 1 is to investigate the biology and impact of integrative subtypes in metastatic HR+ breast cancer. We will develop novel approaches to assess integrative subtypes and will learn whether they change across metastasis, whether they are associated with timing of metastasis, and whether they have differential lengths of response to standard therapies. Aim 2 is to evaluate the effects of a novel combination of targeted therapy in two integrative subtypes of metastatic breast cancer. We will perform a clinical trial that tests a targeted therapeutic approach in tumors classifying as one of two of the four high-risk integrative subtypes. Because these two subtypes are defined by focal areas of genomic alteration involving either the fibroblast growth factor receptor ligand (FGF3; integrative subtype 2) or the fibroblast growth factor receptor (FGFR1; integrative subtype 6), we hypothesize that these tumors may benefit from FGFR inhibition. Participants in this trial will receive standard endocrine therapy in combination with CDK4/6 inhibition, as well as an investigational agent that inhibits the fibroblast growth factor receptor pathway. We will also perform tumor biopsies before and during treatment to evaluate for changes that occur with this combination targeted therapy approach. Successful completion of the proposed studies will lay the groundwork for continued efforts to develop a precision oncology approach for metastatic HR+ breast cancer, with next steps to be proposed in an R01 grant application before the end of the K08 Award.