89Zr-Trastuzumab-PET, Rapid Autopsies, and Patient-Derived Xenografts to Determine the Extent of Clonal Evolution in Treatment-Refractory HER2+ Gastric Cancer
Abstract
Military Relevance: Cancers of esophagus and stomach are the most rapidly increasing cancer in the United States, particularly in young males ages 25-39, so it is of high impact to the military and Veteran population. Helicobacter pylori (H. pylori) is a bacteria that can be found in water and is considered a Group 1 carcinogen per the World Health Organization, as H. pylori infection can lead to stomach cancer. Research studies have shown that U.S. Service members and family living abroad or under field conditions may be at greater risk for H. pylori infection, substantially increasing their risk for developing gastric cancers. The proposed research will benefit active duty Service members, their families, and/or other military beneficiaries by (1) developing a better understanding of why cancers stop responding to treatment, (2) developing new treatments for this cancer, and (3) developing a new imaging technique that may help aid in early detection and diagnosis. Objective and Rationale: Doctors and scientists from two premier research institutions in New York -- Rockefeller University and Memorial Sloan Kettering Cancer Center (MSK) have joined forces and organized a formidable team of experts in cancer biology, tumor genomics, tumor models, and functional imaging with the ultimate goal of developing new treatments for patients with cancers of the stomach and esophagus. Research Goals: Worldwide, 200,000 persons each year develop HER2-positive cancers of esophagus and stomach. A large clinical trial demonstrated that these individuals experience improved tumor shrinkage and survival when trastuzumab (Herceptin) is combined with chemotherapy. Unfortunately, despite initial dramatic response to trastuzumab, most patients with cancers of esophagus and stomach develop cancer growth and progression; this phenomenon is called "trastuzumab resistance." Trastuzumab resistance is an important clinical issue, and, until now, no other HER2-directed treatment has produced a benefit in these patients. Afatinib is a new drug currently used in treatment of lung cancer. Laboratory experiments in mouse models of HER2-positive esophagus and stomach cancer performed at MSK show that all, 10 of 10, mice treated with afatinib experienced near complete resolution of their tumors. Based on these results, MSK doctors developed a clinical trial of afatinib for patients with HER2-positive esophagus or stomach cancer. Based on promising early activity and benefit seen on this trial, the study has been expanded to accrue 46 patients. Patients are assessed for cancer stabilization and shrinkage with computed tomography (CT) scans. The doctors believe that positron emission tomography (PET) for cancer imaging can help image the cancer, and help understand why patients may or may not respond to afatinib. We developed 89Zr-trastuzumab PET to specifically image HER2-positive tumors and to give insight as to how afatinib affects tumors. On the study, 89Zr-trastuzumab PET scans and tumor biopsies and testing are performed to understand which abnormalities drive the growth and resistance of HER2-positive cancer. The results of these studies will provide resources for future laboratory and clinical investigation for HER2-positive cancers of esophagus and stomach patients. Synergy between basic research skills and clinical expertise of the collaborating groups is a distinguishing feature of this proposal aimed to improve treatment options for patients with cancer of esophagus and stomach.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610343
Entities
People
- Jason S. Lewis
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army