Marker-Based Targeting of Chemoresistant Subtype of Gastric Cancer Discovered by Proteomics
Abstract
Our study aims to develop marker-based treatment strategy for patients with stomach cancer, which is one of Fiscal Year 2016 Peer Reviewed Cancer Research Program Topic Areas (stomach cancer). Stomach cancer is highly relevant to our military troops and their families because many of them have served in regions that have higher risk of exposure to hazardous ionizing radiation (during World War II in Japan), infection of Helicobacter pylori (in Japan/Korea/Taiwan), and exposure to Agent Orange (in Korea and Vietnam). These are all well-known risk factors for development of stomach cancer. Stomach cancer is one of the most virulent cancers in the world. Each year over 950,000 of people are diagnosed with stomach cancer and over 700,000 patients die worldwide (third leading cause of death). Although the incidence of stomach cancer in lower stomach has significantly declined over the past 40 years, the incidence of stomach cancer near esophagus (upper stomach) in the USA has increased at a rate substantially exceeding that of prostate cancer, brain cancer, and melanoma. This increase is not associated with the diagnosis of cases in a relatively early stage; therefore, the number of deaths has also increased. Surgical resection is the only curative treatment for stomach cancer. The 5-year survival rate after surgical resection is only around 40%, and many patients succumb to this malignant disease due to recurrence after treatment. However, there are no reliable methods (or predictive markers) that can identify patients with high risk of recurrence after treatment and therapeutic strategies to prevent recurrence yet. Molecular heterogeneity of gastric cancer has been shown through previous studies on analysis of gene expression, copy number alterations, DNA methylation, and somatic mutations data. While some studies uncovered interesting association of genetic alterations with clinical outcomes, many of these findings have not been translated into clinics yet. This is partially because the analyses were limited to genomic level and thus missed some informative features such as proteins and post-translational changes. To overcome current limitations, we analyzed proteomic profiling data from stomach tumors and aim to uncover proteomic subtypes and potential driver proteins (as well as therapeutic targets) associated with molecularly and clinically distinct subtypes. Analysis of proteomic data revealed four distinct proteomic subtypes of stomach cancer and also demonstrated significant association of one of subtypes (subtype A) with poor prognosis and resistance to chemotherapy. Further analysis of data revealed that key transcription regulators and other potential regulators that are significantly upregulated in subtype A stomach cancer. Therefore, we hypothesize that these genes might be accountable for development and progression of stomach cancer with poor prognosis and resistance to chemotherapy. In the proposed study, we aim to (1) find and validate robust genetic markers that can easily identify patients with chemoresistant tumors, (2) test if subtype A is chemoresistant in patient-derived xenograft models, and (3) determine molecular mechanisms of chemoresistance. If successful, this will open up new opportunity for marker-based treatment of patients with chemoresistant stomach tumors by identifying them in prior to treatments, leading to personalized medicine for patients with stomach cancer. Success of our study will lead to marker-based clinical trials for stomach cancer in 3 to 5 years. The Department of Veterans Affairs considers stomach cancer to be a Service-connected malignancy from exposure to hazardous to ionizing radiation. Some 195,000 Soldiers were exposed to radiation during World War II in Japan after the atom bombs were dropped. Additionally, US Soldiers living under field conditions are likely to be at greater risk of H. pylori infections, and H. pylori is classified as a class I
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710300
Entities
People
- Ju-Seog Lee
Organizations
- United States Army
- University of Texas at Austin