Leveraging canine spontaneous cancer to optimize the power of blood biopsy

利用犬自发癌优化血液活检的功效

• 批准号: 10421266
• 负责人: Elinor Karlsson
• 金额: $ 59.08万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-07 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10421266
• 关键词: Address; Affect; Aftercare; Applications Grants; B-Cell Lymphomas; BRAF gene; Benchmarking; Biological Assay; Biological Markers; Biological Models; Biopsy; Blood; Blood Volume; Cancer Model; Cancer Patient; Canis familiaris; Clinical; Collection; DNA; DNA Sequence; DNA Sequence Alteration; Data; Decision Making; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Early Diagnosis; Ensure; Epidermal Growth Factor Receptor; Evaluation; Evolution; Exhibits; Frequencies; Future; Genetic; Genomics; Goals; Grant; Hemangiosarcoma; Hematopoiesis; Human; Immunotherapy; Individual; Longitudinal Studies; Lymphoma; Malignant Neoplasms; Malignant neoplasm of lung; Mast Cell Neoplasm; Methodology; Methods; Modeling; Molecular; Monitor; Mus; Mutation; Oncology; Outcome; PIK3CA gene; Patient-Focused Outcomes; Patients; Performance; Peripheral; Plasma; Predictive Value; Prevention; Procedures; Radiation; Relapse; Reproducibility; Research; Residual Neoplasm; Resistance; Resources; Risk; Sampling; Sensitivity and Specificity; Site; Standardization; Systems Development; TNF receptor-associated factor 3; TP53 gene; Techniques; Technology; Testing; Therapeutic Uses; Time; TimeLine; Transitional Cell Carcinoma; Variant; Veins; Work; actionable mutation; anticancer treatment; base; cancer care; cancer cell; cancer genetics; cancer genome; cancer risk; cancer therapy; clinical translation; diagnostic tool; early screening; experience; improved; in silico; large cell Diffuse non-Hodgkin' s lymphoma; liquid biopsy; model development; noninvasive diagnosis; novel; osteosarcoma; outcome prediction; patient screening; precision medicine; prevent; prospective; screening; standard care; therapy resistant; tool; translation to humans; translational cancer research; treatment planning; treatment response; treatment strategy; tumor; tumor DNA; tumor progression; variant detection

PROJECT SUMMARY Recent technological advances have driven the development of novel, less invasive approaches for assessing the tumor genome. In particular, the “blood biopsy” which leverages circulating tumor DNA (ctDNA) released by dying cancer cells, has potential utility for screening individuals at risk for cancer, determining those patients likely to relapse post treatment, identifying actionable mutations to plan treatment and characterizing tumor genome evolution. However, several challenges remain including the need to standardize collection and processing procedures, optimize sequencing/analysis platforms, and correlate data generated from ctDNA with patient outcomes. For example, factors such as time of day or vein used for blood collection (central vs. peripheral) may influence ctDNA yields and reproducibility of the assay. Moreover, while evaluation for common mutations can readily be performed using ctDNA (i.e., EGFR mutations in lung cancer), tumor types with low mutation burden and/or large structural variants (deletions/inversions) remain more difficult to characterize. Finally, prospective sampling of human patients to assess the predictive value of blood biopsy requires a relatively long timeline (years). While such studies would presumably be ideal in murine cancer models where disease progression is rapid, blood volumes are limited, repeated sampling can be difficult, and it is problematic to accurately recapitulate cycles of treatment response and resistance. Interestingly, pet dogs spontaneously develop cancers that closely mirror their human counterparts with respect to clinical course, molecular dysregulation and genomic alterations, and as such they represent a unique model for improving blood biopsy performance and application. Because pet dogs receive standard treatment (chem/radiation/immunotherapy) yet experience a compressed disease timeline, critical information can typically be obtained quite rapidly. Toward that end, we have generated preliminary data demonstrating that ctDNA is readily detectable in dogs with cancer, that genetic changes concordant with those in the tumor can be detected, and that treatment has a variable impact on ctDNA levels. The purpose of this proposal is to build upon these findings to credential dogs with cancer as a relevant tool for blood biopsy advancement and use this model to optimize and advance its application to human patients. Specifically, we will determine how various factors affect ctDNA yield, assess concordance of tumor and ctDNA sequence data, develop and implement a diagnostic mutation panel for patient screening, and conduct longitudinal studies to track both minimal residual disease and likelihood of relapse. To facilitate rapid clinical translation of findings, we selected canine cancers with genomic landscapes that have human equivalents: urothelial carcinoma (BRAF V595E), mast cell tumor (KIT internal tandem duplication), osteosarcoma (large structural variants), lymphoma (Myc amplification, TRAF3 mutation) and hemangiosarcoma (p53, PIK3CA mutation). Tools created through this work will have utility for ongoing as well as future canine translational cancer research, thereby supporting continued development of this model system.

项目概要 最近的技术进步推动了新型、侵入性较小的评估方法的发展 肿瘤基因组。特别是利用循环肿瘤DNA（ctDNA）的“血液活检” 垂死的癌细胞，对于筛查有癌症风险的个体、确定这些患者具有潜在的用途 治疗后可能复发，识别可操作的突变以计划治疗并描述肿瘤特征 基因组进化。然而，仍然存在一些挑战，包括需要标准化收集和 处理程序，优化测序/分析平台，并将 ctDNA 生成的数据与 患者的结果。例如，诸如一天中的时间或用于采血的静脉（中央与静脉）等因素。 外周血）可能会影响 ctDNA 产量和检测的重现性。此外，在评估常见 使用 ctDNA 可以轻松进行突变（即肺癌中的 EGFR 突变），肿瘤类型具有低 突变负担和/或大型结构变异（缺失/倒位）仍然更难以表征。 最后，对人类患者进行前瞻性采样以评估血液活检的预测价值需要 相对较长的时间线（年）。虽然此类研究在小鼠癌症模型中可能是理想的，其中 疾病进展快，血量有限，重复采样困难，存在问题 准确地再现治疗反应和抵抗的周期。有趣的是，宠物狗自发地 发展出与人类癌症在临床过程、分子水平方面非常相似的癌症 失调和基因组改变，因此它们代表了改善血液活检的独特模型 性能和应用。因为宠物狗尚未接受标准治疗（化学/放射/免疫疗法） 由于疾病时间被压缩，通常可以相当快地获得关键信息。走向 为此，我们生成了初步数据，证明 ctDNA 在患有癌症的狗中很容易检测到， 可以检测到与肿瘤中的基因变化一致的基因变化，并且治疗具有可变性 对 ctDNA 水平的影响。该提案的目的是基于这些发现来验证狗 将癌症作为血液活检进展的相关工具，并使用该模型来优化和推进 它在人类患者中的应用。具体来说，我们将确定各种因素如何影响 ctDNA 产量， 评估肿瘤和 ctDNA 序列数据的一致性，开发和实施诊断突变面板 用于患者筛查，并进行纵向研究以追踪微小残留病和发生疾病的可能性 复发。为了促进研究结果的快速临床转化，我们选择了具有基因组景观的犬类癌症 具有人类等同物：尿路上皮癌 (BRAF V595E)、肥大细胞肿瘤 (KIT 内部串联 重复）、骨肉瘤（大结构变异）、淋巴瘤（Myc 扩增、TRAF3 突变）和 血管肉瘤（p53，PIK3CA 突变）。通过这项工作创建的工具也将具有持续的实用性 作为未来的犬转化癌症研究，从而支持该模型系统的持续开发。