Tumor DNA in CSF and novel modeling decode breast cancer - brain metastases

脑脊液中的肿瘤 DNA 和新颖的模型解码乳腺癌 - 脑转移

基本信息

批准号：
9899331
负责人：
Melanie Hayden Gephart
金额：
$ 18.56万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899331
关键词：
Acute Advisory Committees Animal Model Animals Area Basic Science Biological Biopsy Blood - brain barrier anatomy Brain Brain Neoplasms Breast Cancer Cell Breast Cancer Model Breast Cancer therapy Breast cancer metastasis Caring Cell Culture Techniques Cell Line Cells Central Nervous System Neoplasms Cerebrospinal Fluid Characteristics Clinic Clinical Research Culture Techniques DNA Sequence Alteration Data Department chair Detection Development Diagnostic Disease Disease Progression Disseminated Malignant Neoplasm Drug Screening ERBB2 gene Education Epidermal Growth Factor Receptor Epigenetic Process FDA approved Fingerprint Functional disorder Funding Genes Genetic Genetic Fingerprintings Human Implant Knowledge Laboratories Malignant Neoplasms Mammary Neoplasms Medical Mentored Research Scientist Development Award Mentors Metastatic Neoplasm to the Central Nervous System Metastatic Neoplasm to the Leptomeninges Metastatic breast cancer Metastatic malignant neoplasm to brain Metastatic to Methods Microfluidic Microchips Modeling Mus Mutate Mutation Neoplasm Metastasis Neuraxis Neurosurgeon Operating Rooms Operative Surgical Procedures Patient Care Patients Pharmaceutical Preparations Phase Preclinical Testing Primary Cell Cultures Primary Neoplasm Quality of life Research Sampling Scientist Serum Solid Solid Neoplasm Structure Techniques Technology Testing Therapeutic Time Tissues Training Translating Transplantation Tumor Biology Validation Variant Xenograft Model Xenograft procedure advanced breast cancer anticancer research base blood-brain tumor barrier cancer therapy career cell free DNA clinical application clinical practice clinically relevant commercialization design established cell line exome sequencing experience genetic profiling human disease improved individualized medicine innovation insight malignant breast neoplasm mutant nerve stem cell neuro-oncology next generation sequencing novel novel therapeutics personalized medicine pre-clinical public health relevance response targeted treatment therapeutic evaluation therapy development tool translational study tumor tumor DNA tumor progression

项目摘要

DESCRIPTION (provided by applicant): Tumor DNA in CSF and novel modeling decode breast cancer brain metastases Project Summary DESCRIPTION: Advances in the treatment of cancer metastatic to the central nervous system (CNS) require paradigm shifts in diagnostic and scientific tools, with faithful models recapitulating the human disease. I am developing an innovative, less invasive method to identify brain tumor mutations and track how the genetic spectrum of tumors metastatic to the CNS changes over time and with therapy. Tumor cellular and cell-free DNA (cfDNA) acts as a fingerprint, allowing detection of genetic alterations that mark the variation and progression of disease. Tumor DNA in cerebral spinal fluid (CSF) will suggest targeted therapies based on the mutations contained in solid and leptomeningeal (LM) breast cancer metastases within the brain. Newly identified tumor mutations in CSF will detail how brain metastases acquire advantageous mutations in response to therapy. Mutations consistent with LM spread of disease will unveil the underlying pathophysiology of this brain metastasis subtype, and suggest effective, targeted therapies. Solid and LM metastases to the brain from breast cancer are woefully understudied, in part due to a lack of cell culture and animal xenograft models that reliably reflect the human disease. I will create a novel, translatable, xenograft model, involving the intracerebral transplantation of primary cultures of breast cancer cells derived directly from human brain metastases. These primary, human brain metastases-specific tools will allow for novel drug screens and validation of genetic targets identified through sequencing of tumor DNA in CSF. Specific Aim 1: To create a method of identifying and characterizing brain tumor-specific mutations in the CSF of patients with solid and LM breast cancer brain metastases, in CSF I will: a) sequence tumor cellular and cfDNA for known mutations in the primary breast tumor, and determine the mutant fraction, b) apply whole exome sequencing to brain tumor DNA to identify additional mutated genes, and c) develop a cancer sequencing panel consisting of known, targetable mutations in breast cancer. Specific Aim 2: To determine how breast cancer primary tumors, solid brain tumor metastases, and leptomeningeal metastases differ in tumor biology and response to medical therapy, I will utilize novel primary cell culture and intracranial xenograft models from breast cancer CNS metastases to validate tumor mutations identified in CSF and screen therapeutics. Summary: The proposed aims are complimentary yet not reliant on each other, and if successful in combination have substantial potential to exponentially advance our understanding of one of the most common cancers to metastasize to the CNS. Our findings would propose potential therapeutic avenues to improve treatment for these patients. Identifying and following the brain tumor DNA fingerprint in patient CSF will ultimately enable more sophisticated, personalized, and targeted therapies. Our translational study will revolutionize the recognition and treatment of solid and LM metastases, and deepen our understanding of metastatic cancer progression. Testing hypotheses of novel therapeutics for brain metastases requires more specific, rapid, and translatable cell culture and animal models. By developing cell lines and implanting mouse xenograft models intracranial with human breast cancer brain tumors we can test therapeutics and advance our understanding of solid and LM CNS tumors. I am a practicing neurosurgeon, in the early stage of my career, with a clinical practice focused on the surgical treatment of patients with brain tumors. My laboratory focuses on the basic science of neuro-oncology, with a project focus to directly impact patient care and unveil new areas of study in brain tumor biology. I care for brain tumor patients in the operating room and in the clinic, striving in the laboratory to understand the genetic and epigenetic mechanisms that drive tumor genesis in the CNS. This mentored training award is crucial to protect my research time and allow me to further develop my laboratory focus on cellular and cfDNA in CSF, and to advance a working model for established intracranial metastases. My department chair has provided me with 50% protected research time, and I am fully committed to this project.

描述（由申请人提供）：脑脊液中的肿瘤 DNA 和新颖的模型解码乳腺癌脑转移项目摘要描述：转移至中枢神经系统 (CNS) 的癌症治疗的进展需要诊断和科学工具的范式转变，以及可靠的模型我正在开发一种创新的、侵入性较小的方法来识别脑肿瘤突变，并跟踪转移到中枢神经系统的肿瘤的基因谱如何随着时间和肿瘤细胞和治疗的变化而变化。游离DNA（cfDNA）作为指纹，可以检测到标志着疾病变异和进展的基因改变。脑脊液（CSF）中的肿瘤DNA将根据实体脑膜和软脑膜（LM）中包含的突变提出靶向治疗。新发现的脑脊液中的乳腺癌转移将详细说明脑转移如何获得有利的突变以响应治疗，与 LM 疾病传播一致的突变将揭示该大脑的潜在病理生理学。令人遗憾的是，乳腺癌脑转移的实体瘤和 LM 转移的研究还很不足，部分原因是缺乏可靠反映人类疾病的细胞培养和动物异种移植模型。可翻译的异种移植模型，直接来自人脑转移的乳腺癌细胞的原代培养物的脑内移植，这些原代的、人脑转移特异性的工具将允许新的工具。药物筛选和通过脑脊液中肿瘤 DNA 测序确定的遗传靶点的验证具体目标 1：创建一种在脑脊液 I 中识别和表征实体瘤和 LM 乳腺癌脑转移患者脑脊液中脑肿瘤特异性突变的方法。将：a) 对原发性乳腺肿瘤中已知突变的肿瘤细胞和 cfDNA 进行测序，并确定突变分数，b) 对脑肿瘤 DNA 应用全外显子组测序，以识别其他突变基因，以及 c) 开发一个癌症测序小组，其中包括已知的、可瞄准的具体目标 2：为了确定乳腺癌原发肿瘤、实体脑肿瘤转移和软脑膜转移在肿瘤生物学和对药物治疗的反应方面的差异，我将利用乳腺癌中枢神经系统的新型原代细胞培养和颅内异种移植模型。摘要：所提出的目标是互补的，但并不相互依赖，如果成功地结合起来，将有巨大的潜力以指数方式增进我们对治疗的理解。脑脊液中最常见的癌症之一，我们的研究结果将为改善这些患者的治疗提出潜在的治疗途径，最终将实现更复杂、个性化和有针对性的治疗。研究结果转化研究将彻底改变实体瘤和LM转移瘤的识别和治疗，并加深我们对转移性癌症进展的理解，测试脑转移新疗法的假设需要更特异、快速和可转化的细胞培养和动物模型。通过开发细胞系并在颅内植入人类乳腺癌脑肿瘤的小鼠异种移植模型，我们可以测试治疗方法并增进我们对实体瘤和LM中枢神经系统肿瘤的理解。我是一名执业神经外科医生，处于职业生涯的早期阶段，专注于临床实践。我的实验室专注于神经肿瘤学的基础科学，其项目重点是直接影响患者护理并揭示脑肿瘤生物学的新研究领域。手术室在临床中，努力在实验室中了解驱动中枢神经系统肿瘤发生的遗传和表观遗传机制。这项指导培训奖对于保护我的研究时间至关重要，并让我能够进一步发展我的实验室重点关注脑脊液中的细胞和 cfDNA。，并推进已确定的颅内转移的工作模型，我的系主任为我提供了 50% 受保护的研究时间，我完全致力于这个项目。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The "Liquid Biopsy": the Role of Circulating DNA and RNA in Central Nervous System Tumors.

“液体活检”：循环 DNA 和 RNA 在中枢神经系统肿瘤中的作用。

DOI：
发表时间：
2016-03
期刊：
影响因子：
0
作者：
Connolly, Ian D;Li, Yingmei;Gephart, Melanie Hayden;Nagpal, Seema
通讯作者：
Nagpal, Seema

Molecular and Genetic Predictors of Breast-to-Brain Metastasis: Review and Case Presentation.

乳腺至脑转移的分子和遗传预测因素：回顾和病例介绍。

DOI：
发表时间：
2015-01
期刊：
影响因子：
0
作者：
Medress, Zachary;Hayden Gephart, Melanie
通讯作者：
Hayden Gephart, Melanie

Nodular Leptomeningeal Disease-A Distinct Pattern of Recurrence After Postresection Stereotactic Radiosurgery for Brain Metastases: A Multi-institutional Study of Interobserver Reliability.

结节性软脑膜疾病 - 脑转移瘤切除后立体定向放射外科手术后复发的独特模式：观察者间可靠性的多机构研究。

DOI：
发表时间：
2020-03-01
期刊：
影响因子：
0
作者：
Turner, Brandon E.;Prabhu, Roshan S.;Burri, Stuart H.;Brown, Paul D.;Pollom, Erqi L.;Milano, Michael T.;Weiss, Stephanie E.;Iv, Michael;Fischbein, Nancy;Soliman, Hany;Lo, Simon S.;Chao, Samuel T.;Cox, Brett W.;Murphy, James D.;Li, Gordon;Gephart, Melanie Hayden;Nagpal, Seema;Atalar, Banu;Azoulay, Melissa;Thomas, Reena;Tillman, Gayle;Durkee, Ben Y.;Shah, Jennifer L.;Soltys, Scott G.
通讯作者：
Soltys, Scott G.

Epidermal Growth Factor Receptor Mutation Status Confers Survival Benefit in Patients with Non-Small-Cell Lung Cancer Undergoing Surgical Resection of Brain Metastases: A Retrospective Cohort Study.

表皮生长因子受体突变状态为接受脑转移手术切除的非小细胞肺癌患者带来生存获益：一项回顾性队列研究。

DOI：
发表时间：
2019
期刊：
影响因子：
2
作者：
Huang, Yuhao;Chow, Kevin K H;Aredo, Jacqueline V;Padda, Sukhmani K;Han, Summer S;Kakusa, Bina W;Hayden Gephart, Melanie
通讯作者：
Hayden Gephart, Melanie

Leptomeningeal Carcinomatosis: Molecular Landscape, Current Management, and Emerging Therapies.

软脑膜癌：分子景观、当前治疗和新兴疗法。