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

基本信息

批准号：
10634540
负责人：
Elinor Karlsson
金额：
$ 57.33万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
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/10634540
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 Credentialing DNA Sequence DNA Sequence Alteration DNA analysis Data Data Correlations 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 Liquid substance 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 TNF receptor-associated factor 3 TP53 gene Techniques Technology Testing Therapeutic Uses Time Transitional Cell Carcinoma Variant Veins Work actionable mutation anticancer treatment cancer care cancer cell cancer genome cancer risk cancer therapy clinical translation diagnostic tool early screening experience improved in silico large cell Diffuse non-Hodgkin&apos s lymphoma model development noninvasive diagnosis novel osteosarcoma outcome prediction patient screening precision medicine prevent prospective screening standard care therapy resistant timeline tool translation to humans translational cancer research treatment planning treatment response treatment strategy tumor tumor DNA tumor progression variant detection

项目摘要

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.

项目摘要最近的技术进步推动了新颖，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”释放垂死的癌细胞具有筛查癌症风险的个体的潜在效用，确定这些患者可能继电后处理后，识别可起作用的突变以计划治疗和表征肿瘤基因组进化。但是，仍然存在一些挑战，包括需要标准化收集和处理过程，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血液收集的静脉之类的因素（中心VS。外围）可能会影响ctDNA的产量和测定的可重复性。而且，同时评估共同可以使用CTDNA（即肺癌中的EGFR突变），肿瘤类型较低的CTDNA轻松进行突变突变伯嫩和/或大型结构变体（缺失/反转）仍然很难表征。最后，人类患者的前瞻性抽样评估血液活检的预测价值需要相关的长时间（年）。虽然这种研究可能是在鼠类癌模型中是理想的疾病的进展很快，血量有限，重复采样可能很困难，这是有问题的准确概括治疗反应和抗性的循环。有趣的是，宠物狗赞助开发癌症，这些癌症紧密反映其人类相对于临床过程，分子失调和基因组改变，因此它们代表了改善血液活检的独特模型性能和应用。因为宠物犬接受标准治疗（化学/放射/免疫疗法）体验压缩疾病时间表，通常可以很快获得关键信息。走向这一结局，我们产生了初步数据，表明ctDNA在癌症的狗中很容易检测到，可以检测到与肿瘤中的遗传变化一致，并且该治疗具有可变对ctDNA水平的影响。该提议的目的是建立在这些发现的资格狗的基础上以癌症作为血液活检进步的相关工具，并使用此模型来优化和进步它应用于人类患者。具体而言，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，并进行纵向研究以跟踪最小残留疾病和可能性复发。为了促进发现结果的快速临床翻译，我们选择了具有基因组景观的犬类癌具有人类等效物：尿路上皮癌（BRAF V595E），肥大细胞肿瘤（盒内串联重复），骨肉瘤（大结构变体），淋巴瘤（MYC扩增，TRAF3突变）和 Hemangiosarcoma（P53，PIK3CA突变）。通过这项工作创建的工具也将具有持续的实用程序随着未来犬类翻译的癌症研究，从而支持该模型系统的持续开发。