Mouse model project using forward genetics (2012)

David Tuveson, MD, PhD

Year: 2012
Institution: Cold Spring Harbor Laboratory
Country: United States
State: NY
Award Type: NETRF GRANTS 2005-2017
NET Type: Gastrointestinal
Science Type: Basic

In recent years, much progress has been made in improving our therapies for patients with advanced pancreatic neuroendocrine tumors (panNETs). The recent approval of targeted drugs demonstrated that a better understanding of the genetic basis of panNETs may offer insights into precision medicine for our patients. In an effort to further our knowledge, our group has completed next-generation sequencing (NGS) in the tumor tissue of 81 patients with panNETs (95 tumor samples sequenced in total); 10 patients underwent NGS of their tumor tissue at multiple time-points. Our preliminary findings are novel and striking. We have built on prior findings and demonstrated that tumor grade and differentiation can be characterized through NGS, and in patients who had multiple tumor samples sequenced, we identified progression in tumor grade and the acquisition of new mutations (some, possible resistance mechanisms) in almost all patients. Working closely with our laboratory colleagues, we are currently investigating potential resistance mechanisms, particularly in relation to therapy with the targeted drug therapy. Furthermore, in many patients, we identified actionable genetic changes that could guide use of an approved or experimental therapy.
Our results, performed in tumor tissue, demonstrate the potential of NGS to characterize the genetic landscape of panNETs. The detection of tumor-derived cell-free (cf) DNA circulating in the blood provides the opportunity to conduct similar investigation in a safer, easier, and non-invasive manner. In this pilot study of 10 patients, we propose two specific aims to evaluate a role for sequenced cfDNA in patients with panNETs. Our first aim is to detect and quantify cfDNA in blood samples collected from these patients. Our second aim is to determine the concordance rate between the genomic spectrums of panNETs identified by NGS, performed on tumor tissue specimens and cfDNA. For tumor tissue specimens, archived samples will be used if sufficient tissue is available, and if this tissue was obtained within one year of blood sample collection for quantification of cfDNA. Patients with heavy tumor burden will be enrolled in this pilot study, as prior investigation in other tumor types has demonstrated an improved ability to detect cfDNA in this setting. To perform NGS, we are using novel technology developed at our institution, the Memorial Sloan Kettering-Integrated Mutation Profiling for Actionable Cancer Targets (MSK-IMPACT). This will be the first study to investigate a role for cfDNA in panNETs. We hope our work will validate a safe, non-invasive method, and future research efforts will be directed towards using this modern sequencing technology in cfDNA to investigate genetic changes over time and through therapy, in order to personalize our treatments for patients with this cancer.

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