Tuesday, June 11, 2013
Esophagogastric adenocarcinoma is a heterogeneous disease. Even for patients with localized tumors, we remain ill-equipped to predict which will remain disease-free after surgery or which will suffer recurrence and ultimately succumb to the disease.
A better understanding of the genomics of the different subtypes of esophagogastric adenocarcinoma should result in better prevention, earlier diagnosis, and improved treatment strategies. (1)
Based on cancer epidemiology, pathologic characteristics, tumor location, and emerging molecular signatures, esophagogastric adenocarcinoma can be understood as three distinct malignancies arising in one organ. This is similar to what is seen in other cancers, including breast cancer and lung adenocarcinoma.
There are three types of esophagogastric adenocarcinoma:
- Lauren’s diffuse/signet ring type gastric cancer. In some patients this is caused by a mutation or epigenetic silencing of the CDH1 gene.
- Nondiffuse distal gastric cancer – intestinal type. This type is linked to precursor lesions arising from atrophic gastritis and chronic inflammation related to Helicobacter pylori (H. pylori).
- Proximal nondiffuse cancers of the stomach cardia and gastroesophageal junction. This type is rapidly increasing in incidence in the western hemisphere and is related to lifestyle factors, obesity, and chronic gastric acid reflux.
Many preclinical animal models of esophagogastric cancer fail to accurately predict the clinical efficacy of novel anticancer agents, due in large part to their inability to reflect the complexity and heterogeneity of human tumors. Progress in drug development has been hampered in part by a lack of preclinical models that reliably predict clinical activity of novel compounds in patients.
In an effort to address these shortcomings, a group of investigators at Memorial Sloan Kettering led by me and surgeon Vivian E. Strong are developing patient-derived tumor xenografts.
Fresh specimens are obtained under aseptic conditions from resected primary tumors or biopsy specimens of metastatic tumors from patients who have consented to Memorial Sloan Kettering’s Institutional Review Board–approved protocol. (2)
To create the PDX, approximately 1 gram of tumor is injected subcutaneously into flanks or orthotopically into the gastric wall of NOD SCID mice. Xenografts are established after five passages and maintained by serial transplantation into new mice. Cell cultures are established after five in vitro passages.
Numerous tumor-specific PDTX models have been established and are currently being used to study gene-expression patterns, mutational status, metastatic potential, and drug responsiveness of esophagogastric cancer. This work has been supported by funding provided to me from the American Society of Clinical Oncology, a Memorial Sloan Kettering Cancer Center Translational/Integrative Medicine Research Fund Award, and a Society of MSKCC Research Grant Award.
In collaboration with investigators at the Sloan Kettering Institute, The Rockefeller University, and Weill Cornell Medical Center, I am now implementing these PDXs to help understand the biological drivers of different subsets of esophagogastric cancer and aid rational drug development for this disease.