Abstract
Treatment of metastatic gastric cancer typically involves chemotherapy and monoclonal antibodies targeting HER2 (ERBB2) and VEGFR2 (KDR). However, reliable methods to identify patients who would benefit most from a combination of treatment modalities targeting the tumor stroma, including new
immunotherapy approaches, are still lacking. Therefore, we integrated a mouse model of stromal activation and gastric cancer genomic information to identify gene expression signatures that may inform treatment strategies. We generated a mouse model in which VEGF-A is expressed via adenovirus, enabling a stromal response marked by immune infiltration and angiogenesis at the injection site, and identified distinct stromal gene expression signatures. With these data, we designed multiplexed IHC assays that were applied to human primary gastric tumors and classified each tumor to a dominant stromal phenotype representative of the vascular and immune diversity found in gastric cancer. We also refined the stromal gene signatures and explored their relation to the dominant patient phenotypes identified by recent large-scale studies of gastric cancer genomics (The Cancer Genome Atlas and Asian Cancer Research Group), revealing four distinct stromal phenotypes. Collectively, these findings suggest that a genomicsbased systems approach focused on the tumor stroma can be used to discover putative predictive biomarkers of treatment response, especially to antiangiogenesis agents and immunotherapy, thus offering an opportunity to improve patient stratification.
Introduction
Gastric cancer is the second leading cause of cancer-related death worldwide, with the highest prevalence in Asia (1, 2). Therapy for metastatic gastric cancer includes a combination of chemotherapies and targeted therapies for Her2 (ERBB2) and VEGFR2 (KDR) as monoclonal antibodies. The prevalence of
Her2 overexpression is only 15% to 20%; thus, the majority of patients are dependent on chemotherapy and antiangiogenesis. Although cancer immunotherapy is in the early phases of development for gastric cancer, there are trials under way to explore this modality both as monotherapy and in combination
with the anti-VEGFR2 antibody ramucirumab (www.clinicaltrials. gov and refs. 3 and 4). Both stromal therapies, antiangiogenesis and immunotherapy, are in need of reliable means to identify those patients that will receive optimal therapeutic benefit, and to spare unnecessary side effects for those where the
chance of clinical benefit is low. One of the goals of the human genome project is to characterize
the genetic and epigenetic variation of cancers, enabling their use to generate new therapeutic hypotheses. In gastric cancer, there have been several large efforts published in recent years. The two largest come from The Cancer Genome Atlas (TCGA; ref. 5) and Asian Cancer Research Group (ACRG;
ref. 6). Both have published RNA profile analyses that divide patients into 4 subgroups. In the present study, we generated stromal-specific RNA and IHC-based signatures that represent different stages of stromal activation in cancer. We then interrogated how this stromal approach compares with the prior tumor-centric approaches to come to a theoretical classification system to separate which patients might benefit most from antiangiogenesis and cancer immunotherapy.
1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. 2Lilly Research Laboratories, Eli Lilly and Company, New York,
New York. 3General Electric Global Research Center, Niskayuna, NewYork. 4Department of Pathology,Wood Hudson Medical Center, Covington,
Kentucky. 5Department of Hematology-Oncology, Samsung Medical Center, Seoul, Seoul Korea. 6Department of Pathology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
M.T. Uhlik and J. Liu contributed equally to this article.
Corresponding Author: Laura E. Benjamin, Eli Lilly and Company, 450 East 29th
Street, 11th Floor, New York, NY 10016. Phone: 908-400-1544; E-mail: lbenjami@mac.com
doi: 10.1158/0008-5472.CAN-16-0022
2016 American Association for Cancer Research.
Downloaded from cancerres.aacrjournals.org on November 5, 2019. © 2016 American Association for Cancer Research.