Abstract A44: Establishment of patient-derived Hispanic gastric cancer xenografts to test targeted therapeutics
Authors: Jean F. Ruiz-Calderon, Marcia Cruz-Correa, George A. Calin, Suranganie Dharmawardhane
Journal: Cancer Research (2018)

Abstract Gastric cancer is a health disparity with 2.3 times higher incidence rates in Hispanics than in non-Hispanic Whites (NHWs). Very few studies have been conducted to characterize this health disparity in Hispanics; however, studies from East Asian patients, in whom gastric cancer is also a health disparity, have revealed that p21-activated kinases (PAKs 1,2 and 4), which are known to regulate cancer metastasis, are biomarkers for gastric cancer. Even though inhibition of PAKs impedes gastric cancer progression, current PAK inhibitors have failed to successfully complete clinical trials. Thus, we hypothesize that the inhibition of upstream effectors of PAK, the Rho GTPases Rac and Cdc42, is a rational treatment for gastric cancers with high PAK expression. The purpose of this study is to identify the Rac/Cdc42/PAK pathway as novel biomarkers for Hispanic gastric cancer and to test targeted therapeutics in patient-derived gastric cancer xenografts (PDGCXs). To achieve this aim, gastric cancer tissues and normal gastric mucosa from biopsies and/or surgery are being collected for expression profiling with customized qRT-PCR arrays for mRNA and Agilent arrays for noncoding RNAs (ncRNAs), and Western blotting. Using immunodeficient mice, xenografts have been established from the NCI-N87 gastric cancer cell line (from ATCC) and a tumor from a 58-year-old Hispanic (Puerto Rican) female (San Juan Oncology Hospital). As demonstrated by Western blotting, compared to the AGS nonmetastatic gastric cancer cell line, the NCI-N87 metastatic gastric cancer cells express more PAK isoforms and phospho (active)-PAK. We have also shown that our recently developed Rac/Cdc42 inhibitor MBQ-167 reduces the viability of the NCI-N87 cell line (Humphries-Bickley et al., Mol Cancer Therap 2017;16:805-18). Therefore, we are currently testing the effect of MBQ-167 in SCID mice with NCI-N87 xenografts. Gene expression profiling of the gastric cancer tissue from the Hispanic patient revealed that 13 genes were overexpressed (&amp;gt;1.5-fold change) in gastric cancer tissue in comparison to the normal gastric mucosa, including Rac1, PAK1, STAT3, KDR (VEGFR2), CXCR4, IGF1, VEGFA, and IL-6, all of which are associated with Rac/Cdc42/Pak signaling. Differential profiling using a custom-made Agilent array for ncRNAs demonstrated upregulation of a number of procancer microRNAs (miRNAs) such as miR-106b and downregulation of tumor suppressors such as let-7a and miR-145, as well as upregulation of the long ncRNA CCAT2, which we have shown to be important for colon cancer malignancy. Overall, our data show that a number of unique and established biomarkers are present in Hispanic gastric cancer, including elevated Rac/Cdc42/PAK signaling. Therefore, treatment with drugs targeting the Rac/Cdc42/PAK pathway represents a novel therapeutic option for such gastric cancers. In conclusion, modeling gastric cancer in PDGCXs is expected to enable the testing and design of targeted and individualized treatments for Puerto Rican patients. Citation Format: Jean F. Ruiz-Calderon, Marcia Cruz-Correa, George A. Calin, Suranganie Dharmawardhane. Establishment of patient-derived Hispanic gastric cancer xenografts to test targeted therapeutics [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A44.