DATA SCIENCE FOR MOLECULAR GENETICS AND COMMUNICATION IN THE NATURAL SCIENCES

Ph.D

Endovascular Image-Guided Sampling of Tumor-Draining Veins Provides an Enriched Source of Oncological Biomarkers

Introduction: Circulating tumor-derived biomarkers can potentially impact cancer management throughout the continuum of care. This small exploratory study aimed to assess the relative levels of such biomarkers in the tumor-draining vascular beds in patients with solid tumors compared to levels in their peripheral veins. Methods: Using an endovascular image-guided approach, we obtained blood samples from peripheral veins and other vascular compartments–including the most proximal venous drainage from solid tumors–from a set of nine oncology patients with various primary and metastatic malignancies. We then interrogated these samples for a panel of oncological biomarkers, including circulating tumor cells (CTCs), exosome-derived microRNAs (miRNAs), circulating tumor DNA (ctDNA) mutations, and certain cancer-related proteins/biochemical markers. Results: We found substantially higher levels of CTCs, certain miRNAs, and specific ctDNA mutations in samples from vascular beds closer to the tumor compared with those from peripheral veins and also noted that some of these signals were altered by treatment procedures. Discussion: Our results indicate that tumor-proximal venous samples are highly enriched for some oncological biomarkers and may allow for more robust molecular analysis than peripheral vein samples

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers\u27 tissue of origin