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.

项目总结