Posted November 10, 2020

Military Health and Cancer

The Peer Reviewed Cancer Research Program (PRCRP), established through a Congressional appropriation in Fiscal Year 2009 (FY09), has funded $429.8 Million (M) in basic and translational cancer research relevant to the health and well-being of the military community, including Service members, their families, and Veterans. To aid in military mission readiness, among the topics the PRCRP supports are awards focused on studying environmental factors that pose a risk for developing cancer and examining knowledge gaps in cancer research that may impact mission readiness. The awards summarized below are examples of cutting-edge, high-impact research supported by PRCRP in its goal to improve the welfare of Service members, their families, Veterans, and the American public affected by cancer. Links to the public and technical abstracts written by the Principal Investigator appear below each highlight.

Environmental/Exposure Risk Factors Associated with Cancer
Military Exposure-Related Pleural Mesothelioma: An Innovative Translational Approach to Inform Novel Molecular-Targeted Treatment Development

David Harpole, M.D., Duke University
Raphael Bueno, M.D., Brigham and Women�s Hospital

Malignant pleural mesothelioma (MPM) is an aggressive form of cancer that develops in the pleural lining of the lungs and is caused by inhalation of asbestos fibers. Service members and Veterans are at risk for mesothelioma due to asbestos exposure at deployment locations in the developing world and older military facilities and naval vessels. Funded by a FY16 Translational Team Science Award, Drs. David Harpole and Raphael Bueno are working to better define the genetic differences between military- and civilian-related MPM. Mesothelioma tumor samples are being collected from diverse patient populations at Duke Cancer Institute, Brigham and Women’s Hospital, University of California, San Diego Cancer Center, and VA Medical Centers in Boston, Durham, and San Diego. The investigators are sequencing tumor samples from Veteran and non-Veteran patients for genetic characterization. To date, the investigators have assembled the largest and most comprehensive collection of mesothelioma samples with linked military service and clinical data in North America. Their examination of the mutational landscape of MPM led to four defined mutational clusters. Based on the mutations identified, genetically engineered mouse models and patient-derived xenografts are being created and will be used to study MPM tumorigenesis and metastasis. Currently, efforts are underway to identify novel therapeutics by conducting a high throughput screen of small molecule inhibitors and FDA approved drugs on normal and oncogenic mesothelial cells in vitro. The insight gained from this award may directly benefit the thousands of Veterans and their dependents who were exposed to asbestos during their service. 

Link:
Public and Technical Abstracts: Military Exposure-Related Pleural Mesothelioma: An Innovative Translational Approach to Inform Novel Molecular-Targeted Treatment Development

Analysis of Gastric Adenocarcinoma Data in a Pan-GI Context to Reveal Genes, Pathways, and Interactions that Yield Novel Therapeutic Advantages

Rehan Akbani, Ph.D., University of Texas M.D. Anderson Cancer Center

Military members deployed in regions in Asia (Japan/Korea/Taiwan) are susceptible to region-specific risk factors for gastric adenocarcinoma (GAC) such as Helicobacter pylori infection. In FY15, Dr. Rehan Akbani was awarded a Career Development Award to perform a multi-dimensional bioinformatics analysis on gastric adenocarcinoma data and other gastrointestinal-related diseases, to better understand the associated molecular pathways in gastric cancer pathogenesis. With the belief that every patient’s cancer is molecularly distinct and the need for personalized cancer therapy, the proposed research aimed to identify new biomarkers and pathways as potential targets for a customized therapy program. Major findings from this project include identification of numerous pathways and genes that are dysregulated in gastric cancer. Abnormal pathways include TGF-beta pathway, the PI3/AKT/mTOR pathway, DNA damage pathway, mismatch repair pathway, and homology-dependent repair pathway. Each of these pathways are potential targets for therapeutic intervention. Dr. Akbani also identified altered expression of KRAS, HRAS, NRAS and high immune activity in some subtypes of gastric cancer compared to other gastrointestinal-related diseases. RAS-targeting drugs and immunotherapy are also potential therapeutic avenues. The results of this project have been reported in 12 publications and 3 conference presentations. Collectively, these studies will provide insight into novel pathways and gene interactions in gastric cancers and lead to improved therapeutic regimens for military members and their families.

Link:
Public and Technical Abstracts: Analysis of Gastric Adenocarcinoma Data in a Pan-GI Context to Reveal Genes, Pathways, and Interactions that Yield Novel Therapeutic Advantages

Gaps in Cancer Prevention, Early Detection/Diagnosis, Prognosis, Treatment, and/or Survivorship
Abbreviated Magnetic Resonance Imaging and Biomarker-Based Detection of Early Liver Cancer

Robert Marks, M.D., Naval Medical Center San Diego
Kathryn Fowler, M.D., University of California � San Diego
Claude Sirlin, M.D., University of California, San Diego
Rohit Loomba, M.D., University of California, San Diego

Hepatocellular carcinoma (HCC) is the second leading cause of cancer related death worldwide. HCC’s major risk factors, including alcoholism and hepatitis C and chronic hepatitis B infection, disproportionally affect the military population, beneficiaries, and U.S. Veterans. Recent evidence suggests an increased incidence of HCC among US veterans compared to the civilian population. Current guidelines recommend ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) for screening patients at risk for developing HCC. Ultrasounds have a limited sensitivity in detecting small tumors and MRI scan times are lengthy and expensive. To address these limitations, a FY17 Translational Team Science Award led by Dr. Robert Marks and Drs. Kathryn Fowler, Claude Sirlin, and Rohit Loomba developed a novel scanning method for HCC detection. The newly developed diagnostic tool, Abbreviated MRI (AMRI), is cost-effective and reduces the total scan time, while maintaining high sensitivity for HCC detection compared to conventional ultrasound. The team of researchers are comparing diagnostic accuracy between ultrasound screening and their new AMRI method for 200 patients, military and civilian, with chronic liver disease. This study will also examine the importance of clinical biomarkers in combination with HCC screening. Thus far, 50 patients with cirrhosis and Hepatitis B have enrolled in the study protocol and their imaging data has been analyzed. If successful, the AMRI protocol, in combination with validated biomarkers, could lead to expedited treatment of HCC and decreased mortality for US Veterans and their dependents. 

Link:

Public and Technical Abstracts: Abbreviated Magnetic Resonance Imaging and Biomarker-Based Detection of Early Liver Cancer

References:

1. Bueno R. Multimodality treatments in the management of malignant pleural mesothelioma: An update. Hematology Oncology Clin North America 19:1089-1097, vii. PMID:16325125
2. https://www.veteranstodayarchives.com/2012/02/01/military-veterans-and-cancer/
3. Jackman RP, Schlichting C, Carr W, et al. Prevalence of Helicobacter pylori in United States Navy submarine crews. Epidemiology and Infection 134(3):460-464.
4. Marshall BJ. The 1995 Albert Lasker Medical Research Award. Helicobacter pylori. The etiologic agent for peptic ulcer. Journal of the American Medical Association 274(13):1064-1066.
5. Antonic V, Stojadinovic A, Kester KE, et al. Significance of infectious agents in colorectal cancer. Journal of Cancer 4(3):227-240.
6. Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2012, National Cancer Institute, The Surveillance, Epidemiology, and End Results (SEER) Program of the NCI: Bethesda, MD. Available from: http://seer.cancer.gov/csr/1975_2012/.
7. McGlynn KA, Petrick JL, and London WT. Global epidemiology of hepatocellular carcinoma: An emphasis on demographic and regional variability. Clinics in Liver Disease 19(2):223-238. doi: 10.1016/j.cld.2015.01.001. PubMed PMID: 25921660.
8. Beste LA, Leipertz SL, Green PK, et al. Trends in the burden of cirrhosis and hepatocellular carcinoma by underlying liver disease in US Veterans from 2001-2013. Gastroenterology 149(6):1471-1482. doi: 10.1053/j.gastro.2015.07.056. PubMed PMID: 26255044.
9. Njei B, Rotman Y, Ditah I, et al. Emerging trends in hepatocellular carcinoma incidence and mortality. Hepatology 61(1):191-199. doi: 10.1002/hep.27388. PubMed PMID: 25142309; PMCID: 4823645.
10. Persson E, Quraishi S, Welzel T, et al. Risk of liver cancer among US male veterans with cirrhosis, 1969-1996. British Journal of Cancer 107(1):195-200.
11. S. Department of Veteran Affairs, Management of Hepatocellular Carcinoma (HCC) [September 2015]. Available from: http://www.hepatitis.va.gov/provider/guidelines/2009HCC.asp#S4X.
12. Bruix J, Sherman M, and American Association for the Study of Liver Disease. Management of hepatocellular carcinoma: An update. Hepatology 53(3):1020. doi: 10.1002/hep.24199;10.1002/hep.24199. PubMed PMID: PMID: 21374666.

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