Director: Shunqiang Li, PhD
The mission of the Human and Mouse Linked Evaluation of Tumors (HAMLET) Core is to promote understanding of the biology and genetics of Human Breast Cancer and to provide better preclinical models to validate new treatment and imaging approaches.
Scientific Focus of the HAMLET Core
Breast Cancer is a complex disorder comprised of a spectrum of cancer subtypes with distinct clinical phenotypes, genetic anomalies and therapeutic responsiveness. Preclinical testing of new anticancer drugs and cancer translational studies require model systems that recapitulate the breast cancer spectrum as accurately as possible. While cell line-derived human breast xenografts are frequently used for this purpose, the ability of these systems to predict drug efficacy is limited for the following reasons. First, fundamental issues arise from the fact that the clinical features of the tumors from which these cell lines were derived were not adequately documented, so that it is rarely possible to establish whether any given cell line is a truly valuable model for the therapeutic hypothesis in question. Next, there are concerns regarding artifacts generated by long term in vitro culture. Since the establishment of breast cancer cell lines has been a rare event, we can be certain that the genetic diversity of human breast cancer is not fully represented in the one hundred or so breast cancer cell lines that are currently available.
With this in mind, Drs. Matthew Ellis and Shunqiang Li launched the HAMLET project in 2006 to establish patient-derived xenograft (PDX) models using breast cancer tissue and to compare the similarities between the original tumors and their xenografts. In collaboration with others, Drs. Li and Ellis have established over 45 WHIM (Washington University Human-In-Mouse) tumor lines. Most of the WHIM lines were derived from metastatic diseases that were resistant to multiple treatments. The patient’s clinical outcome, therapeutic history and responsiveness to treatment have been fully documented and are available to researchers. Patients provided documented consent for the use of their tumor tissues, DNA and RNA by researchers. The WHIM lines have been characterized by global gene expression; by array CGH; and in some cases, by complete genome sequencing, reverse phase protein array (RPPA), and kinome profiling. Some estrogen receptor-positive (ER+) WHIM models have been tested for response to estrogen stimulation. Our study found that the WHIM models exhibit remarkable genetic and phenotypic similarities with the human tumor from which they were derived. In essence, they are “live” replicas of the human tumors. 18 ER+ WHIM lines were successfully developed from patients with endocrine therapy resistant disease and our genomic and functional analyses revealed mechanistic insights into resistance that have not been achieved using conventional cell line approaches. Hence, deeply sequenced WHIM models are an important resource for the search for genome-forward treatment options and capture endocrine drug resistance etiologies not observed in standard cell lines. The originating tumor genome provides a bench mark to assess genetic drift and clonal representation after transplantation [featured in our Cell Reports and Nature publications]. Drs. Li and Ellis are continuously expanding this resource.
WHIM tumor related materials have been disseminated to over 30 investigators for use in translational research. WHIM models have been successfully incorporated in multiple funded projects, including:
- The Cancer Proteomics Centers at Washington University in St. Louis; the University of North Carolina, Chapel Hill; and Boise State University (Matthew J. Ellis, et al; NIH grant 5U24A160035)
- Personalized Breast Cancer Vaccines Based on Genome Sequencing (William Gillanders, et al; Komen Foundation, promise grant KG111025)
- Cell Death Activation to Prevent Late Relapse in Breast Cancer (Matthew J. Ellis, et al; Komen Foundation, promise grant PG12220321)
- Preclinical Testing of New Anticancer Compounds (Shunqiang Li; Sponsored by Pfizer and Millennium Pharmaceuticals)
Collaborations Available Through the HAMLET Core
Each published WHIM line has been expanded and the material is distributed on a first-come, first-served basis; subject to availability. WHIM material available includes:
- Live frozen cells
- Live tumor bearing mice
- Protein lysates
- DNA and RNA
- Formalin fixed material
The HAMLET Core also provides:
- Pharma contract research
- Tumor/cell line licensing
- Therapeutic or imaging experiments in collaboration with academic investigator
- Patients' clinical outcomes, therapeutic history and responsiveness to treatment
- Existing genomic and proteomic data (publicly available for each WHIM line once it has been published)
- Pre-publication data (available through project consultation work)
- Establishment of patient-derived xenograft models from other, non-breast, cancer types
Contact Information: sqli@dom.wustl.edu
