Welcome to the laboratory of Ron Bose, MD, PhD,
at Washington University School of Medicine in St. Louis, MO.
We are hiring! See our Post-doctoral Fellowship ad in Nature Careers!
Three years ago, we moved into the Brand New research building, the Debra and George W. Couch III Biomedical Research Building, located at 4515 McKinley Avenue on the Washington University School of Medicine campus.
For the past two years, we have been using Organoid culture methods to study oncogenic mutations.
With the new Marvel Superhero movies this Spring, we had fun making this poster.
Cancer Genomics and HER2 Activating Mutations
Breast Cancer Organoids
HER2 receptor tyrosine kinase signaling in human cancers
Background: HER2 is a proto-oncogene and a receptor tyrosine kinase belonging to the EGFR family. It has an extracellular half that is involved in receptor dimerization and an intracellular half that has the tyrosine kinase domain and a C-terminal tail with multiple autophosphorylation sites. Phosphorylation of these sites initiates a signaling cascade that activates the Ras-MAPK, PI3-kinase/Akt, and the JAK-STAT pathways. HER2 gene amplification is found in about 20% of human breast cancer patients. Herceptin (trastuzumab) was the first FDA-approved drug to inhibit HER2 and there are now 5 FDA-approved HER2 inhibitors that are used in the treatment of breast and other human cancers.
Project Area 1: HER2 Activating Mutations in Breast and Colon Cancer.
We were the first to identify HER2 activating mutations in breast cancers that were diagnosed as “HER2 negative.” This is a very important finding because these patients can benefit from HER2 targeted drugs, but are not offered them because their cancers are diagnosed as negative for HER2 gene amplification by routine pathology testing. Next-generation DNA sequencing test can readily identify these mutations. We have carefully studied these mutations in the lab, and identified how they activate HER2, what their drug sensitivity is, and exploring their role broadly in tumorigenesis. We identified a potent inhibitor for these mutations, neratinib, and launched the first clinical trial to prospectively treat metastatic breast cancer patients with HER2 mutations in their cancer. This trial was successful and published in Clinical Cancer Research in 2017. We additionally found HER2 activating mutations in other solid tumors, including colon cancer, and we continue to study these mutations to understand how they interact with other oncogenes and tumor suppressor genes in the cancer and how to maximize drug treatment for patients. We will presenting our latest work at the AACR Annual Meeting on April 2, 2019 – click here for details.
Project Area 2: Breast Cancer Organoids.
Organoids are a novel, 3-dimensional cell culture system that can grow primary human cancer cells with high efficiency and success rates. Organoid technology was first developed by Prof. Hans Clevers and colleagues in the Netherlands as a system to grow adult, intestinal stem cells and in the past 4 years, it has been demonstrated to be a powerful tool for cancer research. See review articles in Nature Reviews Cancer and the New England Journal of Medicine. Organoid culture methods represent a fundamental change in tissue culture, because it uses a defined set of growth factors, niche factors, and small molecule inhibitors to support the growth of cancer or stem cells. Organoids are a way to rapidly (weeks) grow primary patient samples and to test or study them in the laboratory. Further, organoids have enabled us to accelerate the study of HER2 mutations and we can perform drug testing on organoids in 96 and 384-well plates.
We have been working with organoids for the past 2 years and will present results on this at AACR Annual Meeting on April 2, 2019 – click here for details.
Please come talk to me to get more details about this research. I am very interested in having new post-doctoral fellows, graduate students, and undergraduates come to the lab.
Updated March 21, 2019.