Molecular Characterization and Personalized Approaches to Non-Hodgkin Lymphoma from Circulating Tumor DNA

循环系统非霍奇金淋巴瘤的分子特征和个体化治疗 肿瘤DNA 患者之间的生物学和临床异质性仍然是改善癌症的固有障碍 结果。这种异质性使得治疗结果和个性化治疗方法的预测 临床肿瘤学的一个主要挑战。弥漫性大B细胞淋巴瘤（DLBCL）就是一例， 成人常见的非霍奇金淋巴瘤。在过去的30年里， 解开这种疾病的患者间异质性，导致基于分子亚型的鉴定 基于临床和影像学因素的细胞来源和风险分层工具。最近，该领域的 基因组学在识别个体中驱动淋巴瘤的特定基因方面取得了额外的进展， 这反过来又导致了个性化医疗的革命。尽管如此，尽管这些 然而，随着治疗技术的进步，目前的个性化治疗方法未能改善DLBCL患者的结局。 在过去的十年中，检测无细胞肿瘤衍生DNA或循环肿瘤DNA的新方法 （ctDNA），已经出现。我们之前应用了深度测序的癌症个性化特征分析（CAPP-1）。 Seq），一种用于ctDNA检测的靶向测序方法，用于DLBCL患者。此外，我们最近 探讨了接受标准治疗的DLBCL患者中ctDNA的反应动力学，定义了稳健的 分子反应标准后，只要21天。因此，ctDNA的检测提供了一个机会， 提高了对肿瘤基因型和表型的理解，包括对治疗的反应， 到个性化的诊断和疾病管理方法。在这个提案中，我将进一步扩展ctDNA 通过CAPP-Seq检测，开发直接从分子水平全面表征DLBCL的方法， 血浆，包括全基因组拷贝数分析和检测相单倍型，一个独特的 B细胞恶性肿瘤实体（Aim 1）。然后，我将改进和验证一个新的框架，称为连续 个体化风险指数（CIRI），整合基因组信息与ctDNA分子反应标准， DLBCL患者的临床有用的个性化风险模型（目的2）。最后，我将运用这些工具进行研究 DLBCL患者接受嵌合抗原受体（CAR）T- 细胞，复发性和难治性DLBCL的新兴疗法，这仍然是临床需要的领域（目的3）。 这项建议将在斯坦福大学医学院进行，导师是 Ash Alizadeh，MD/PhD.通过完成这一计划，我将获得相关的计算经验， 生物学和生物医学数据科学成功地启动了职业生涯作为一个独立的调查员，专注于 为淋巴瘤患者开发和翻译新技术。

Molecular characterization and personalized approaches to non-Hodgkin lymphoma from circulating tumor DNA Biological and clinical heterogeneity between patients remain inherent barriers to improving cancer outcomes. This heterogeneity makes prediction of therapeutic outcomes and personalized treatment approaches a major challenge in clinical oncology. This is exemplified by diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma in adults. Over the last 30 years, significant strides have been made in unraveling the inter-patient heterogeneity of this disease, leading to identification of molecular subtypes based on the cell-of-origin and risk stratification tools based on clinical and radiographic factors. Recently, the field of genomics has made additional strides in identifying the specific genes that drive lymphomas in individual patients, which has in turn led to a revolution in personalized medicine. Nevertheless and despite these advances, current personalized approaches to therapy have failed to improve outcomes for patients with DLBCL. During the last decade, novel methods to detect cell-free tumor-derived DNA, or circulating tumor DNA (ctDNA), have emerged. We previously applied Cancer Personalized Profiling by Deep Sequencing (CAPP- Seq), a targeted sequencing approach for ctDNA detection, to patients with DLBCL. Additionally, we recently explored the response dynamics of ctDNA in DLBCL patients receiving standard therapy, defining robust molecular response criteria after as few as 21 days. Detection of ctDNA therefore provides an opportunity for both improved understanding of tumor genotype and phenotype, including response to therapy, opening the door to personalized approaches to diagnosis and disease management. In this proposal, I will further extend ctDNA detection by CAPP-Seq to develop methods to comprehensively molecularly characterize DLBCL directly from the blood plasma, including genome-wide copy-number profiling and detection of phased haplotypes, a unique entity in B-cell malignancies (Aim 1). I will then refine and validate a novel framework, called the Continuous Individualized Risk Index (CIRI), to integrate genomic information with ctDNA molecular response criteria to build a clinically useful personalized model of risk for DLBCL patients (Aim 2). Finally, I will apply these tools to study the genetics and molecular response dynamics of DLBCL patients receiving chimeric antigen receptor (CAR) T- cells, an emerging therapy for relapsed and refractory DLBCL, which remains an area of clinical need (Aim 3). This proposal will be carried out at the Stanford University School of Medicine, under the mentorship of Ash Alizadeh, MD/PhD. Through completion of this proposal, I will gain the relevant experience in computational biology and biomedical data science to successfully launch a career as an independent investigator focused on developing and translating new technologies for patients with lymphoma.