Monitoring of Therapy or Recurrence in Breast Cancer with Cancer-specific Mutatio

具有癌症特异性突变的乳腺癌的治疗或复发监测

• 批准号: 8004537
• 负责人: STEVE Seev SOMMER
• 金额: $ 35.5万
• 依托单位: MEDOMICS, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8004537
• 关键词: Apoptotic; Biological Assay; Biological Markers; Blood; Blood capillaries; Blood specimen; Breast; Cancer Patient; Cancer Remission; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Colon; DNA; Detection; Detection of Minimal Residual Disease; Development; Diagnosis; Disease remission; Elements; Exons; Feasibility Studies; Genes; Genome; Genomics; Goals; Image; Individual; Intervention; Laboratories; Lead; Malignant Neoplasms; Mammary Neoplasms; Marketing; Measures; Methods; Modality; Molecular; Monitor; Monitoring for Recurrence; Mutate; Mutation; Necrosis; Normal tissue morphology; Nucleic Acids; Oncologist; Outcome; Output; Patient Monitoring; Patients; Phase; Plasma; Positron-Emission Tomography; Process; Recurrence; Recurrent disease; Series; Signs and Symptoms; Solid; Somatic Mutation; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Treatment Failure; Variant; X-Ray Computed Tomography; base; bone imaging; cancer cell; cancer recurrence; cancer therapy; cancer type; capillary; cost; exome; follow-up; improved; malignant breast neoplasm; mortality; next generation; polymerization; public health relevance; research clinical testing; response; single molecule; success; therapeutic effectiveness; tumor; tumor progression

DESCRIPTION (provided by applicant): Personalized methods are urgently needed for monitoring tumor status and assessing recurrence or treatment failure. Conventional means of monitoring include clinical signs, symptoms, laboratory results, and expensive tests such as radiographic imaging (CT scan, bone scan, PET scan). However, more sensitive and, ideally, more quantitative methods would be advantageous. We seek to combine two powerful molecular technologies to monitor tumors in blood by identifying and tracking, a "cancer mutation signature" specific for each individual patient. Four core observations underlie our goal of developing such a test. (1) In several recent studies, the Vogelstein group demonstrated that 100-200 somatic mutations generally occur in the exome of breast, colon, and other cancers. (2) Recent technological advances in massively parallel sequencing allow a vast amount of sequencing over an entire genome (or subset thereof) and would permit the detection of somatic tumor mutations in multiple cancer-related genes within a relatively short time. (3) Previous studies have shown that cancer-specific DNA released from necrotic or apoptotic cancer cells can be detected in plasma. (4) Technical advances in Pyrophosphorolysis-Activated Polymerization (PAP), a highly sensitive and specific method developed by the founder of this company, enables detection of a single copy of DNA harboring such cancer- specific signatures in both the plasma and cellular compartments of blood. The proposed study will develop operational criteria for a "cancer mutation signature" by analyzing tumor and normal DNA, as well as serial blood samples from four breast cancer patients. [What makes this project unique is the fact that we will identify a set of tumor mutations for each patient that (1) specifically defines the individual tumor of that patient and (2) are not present in the patient's matched normal tissue, providing a truly personalized "cancer signature".] Using massively parallel sequencing, about 20 mutations will be detected in the tumor DNA of each patient, confirmed by capillary sequencing, and shown to be absent in the normal DNA. PAP assays will be developed for each of five mutations chosen per patient. Criteria for a reliable "cancer mutation signature" will be determined. It is hypothesized that between two and five somatic mutations will be required per cancer, given the possibility of confounders. With the "cancer mutation signature", blood samples will be tested to monitor the patient at diagnosis and during the subsequent clinical course. Outcomes will be compared to the standard patient monitoring modalities. Success in this Phase I feasibility study will lead to a Phase II clinical study and eventually to a commercial test for individualized personal testing for cancer patients. PUBLIC HEALTH RELEVANCE: For patients with cancer, better methods for monitoring therapy or recurrence could improve outcome while reducing cost. Conventional means of monitoring cancer progression are not sensitive enough to determine the therapeutic effectiveness or to detect recurrence of the tumor in a timely manner. With the power of the revolutionary next-generation sequencing, it becomes possible to identify an individual's unique cancer mutation signature (a method applicable to all cancer types), in which single molecules of the cancer signature can be detected in blood. The monitoring of therapy or recurrence (MOTOR) with a combination of massively parallel sequencing and PAP (Pyrophosphorolysis-Activated Polymerization) has the potential to revolutionize cancer treatment.

描述（由申请人提供）：迫切需要个性化方法来监测肿瘤状态并评估复发或治疗失败。传统的监测手段包括临床体征、症状、实验室结果和昂贵的测试，例如放射成像（CT 扫描、骨扫描、PET 扫描）。然而，更灵敏且理想情况下更定量的方法将是有利的。我们寻求结合两种强大的分子技术，通过识别和跟踪每个患者特有的“癌症突变特征”来监测血液中的肿瘤。我们开发此类测试的目标有四个核心观察结果。 (1) Vogelstein小组在最近的几项研究中证明，乳腺癌、结肠癌和其他癌症的外显子组中通常发生100-200个体细胞突变。 (2) 大规模并行测序的最新技术进步允许对整个基因组（或其子集）进行大量测序，并允许在相对较短的时间内检测多个癌症相关基因的体细胞肿瘤突变。 (3)先前的研究表明，在血浆中可以检测到坏死或凋亡的癌细胞释放的癌症特异性DNA。 (4) 焦磷酸解激活聚合 (PAP) 技术的进步是该公司创始人开发的一种高度灵敏和特异的方法，能够检测到血浆和细胞区室中含有此类癌症特异性特征的 DNA 单拷贝。血。拟议的研究将通过分析肿瘤和正常 DNA 以及四名乳腺癌患者的连续血液样本来制定“癌症突变特征”的操作标准。 [该项目的独特之处在于，我们将为每位患者确定一组肿瘤突变，这些突变（1）具体定义了该患者的个体肿瘤，并且（2）不存在于患者匹配的正常组织中，从而提供了真正的个性化的“癌症特征”。] 使用大规模并行测序，将在每位患者的肿瘤 DNA 中检测到约 20 个突变，并通过毛细管测序进行确认，并显示在正常 DNA 中不存在。将为每位患者选择的五个突变中的每一个开发 PAP 检测。将确定可靠的“癌症突变特征”的标准。考虑到混杂因素的可能性，假设每种癌症需要两到五种体细胞突变。通过“癌症突变特征”，将测试血液样本，以在诊断时和随后的临床过程中监测患者。结果将与标准患者监测方式进行比较。第一阶段可行性研究的成功将导致第二阶段临床研究，并最终进行针对癌症患者的个性化个人测试的商业测试。 公共卫生相关性：对于癌症患者来说，更好的监测治疗或复发的方法可以改善结果，同时降低成本。监测癌症进展的常规方法不够灵敏，无法确定治疗效果或及时检测肿瘤的复发。借助革命性的下一代测序的力量，可以识别个体独特的癌症突变特征（一种适用于所有癌症类型的方法），其中可以在血液中检测到癌症特征的单分子。结合大规模并行测序和 PAP（焦磷酸解激活聚合）来监测治疗或复发 (MOTOR) 有可能彻底改变癌症治疗。