Precision Medicine of Cancer

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Project 1A: The microbiome is one of the key facets of the precision medicine of human cancer. We are building on our previous discoveries of the microbiome associated with human lung cancer (Greathouse KL et al., Genome Biol. 19:123-31, 2018). Actovorax was more abundant in squamous cell carcinoma greater than in adenocarcinoma in tobacco smokers and TP53 mutant cancers. These results generated several hypotheses that we are investigating. First, is Acidovorax a passenger or contributor to lung carcinogenesis. We are testing this hypothesis in an animal model of human lung cancer (Jin C et al., Cell 176:998-1013, 2019). Our data are consistent with it being a contributor in that the lung cancers occur earlier and are larger in the animal model and using in vitro cellular models. Because inflammation is frequently associated with many types of human cancer including lung cancer, we are investigating the immune cell dysregulate; on caused by Acidovorax. In addition, the nasal co-injection of Acidovorax and anti-inflammatory bacteria such as Lactobacillus and Bifidobacterium is being investigated. FACS analysis showed an increase in gamma-delta immune cells producing IL17 and neutrophils that may function by producing free radicals and/or by their extracellular traps (Chaim HR et al. Annu Rev Cell Dev Bio July 14, 2020). We are currently investigating other hypotheses e.g., Acidovorax, used to metabolize polycyclic aromatic hydrocarbons in biomediation of oil spills, metabolizing chemical carcinogens found in tobacco smoke and reprogramming lung cancer cells to produce CD47 that prevents macrophages from engulfing them. We are also determining the microbiome of esophageal carcinoma in patients with or without Barrett's esophagus that is a cancer-prone chronic inflammatory disease. This microbiome study continues our long history including 24 reports of investigating the molecular and cellular pathogenesis of esophageal cancer. Project 1B: We are focusing on the mechanism(s) by which histological preneoplastic lesions in the bronchus transition to stage 1 carcinoma. Identifying these transition mechanisms may provide interception therapies to prevent lung cancer. These studies are examining: HOXA9 methylation and expression using the methodology established from our previous studies (Lissa D. et al., Lung Cancer 122:151-59, 2018; Robles et al., J Thoracic Oncology 10:1037-48, 2015); creatine riboside expression (Project 1C) using MALDI imaging analysis; RNA scope of bacteria(EUB expression) and Acidovorax using specific probes, single cell RNA seq, spatial transcriptomics, quantitation of CD8+ T cells and M1 and M2 macrophages. These results of preneoplastic bronchial lesions will be compared to our previous studies of stage one lung cancer. In addition, we are currently investigating the proteome in both discovery and validation cohorts of stage one adenocarcinoma and squamous cell carcinoma of the lung in collaboration with Roger Reddel (Children Research Foundation Institute) and Ken Aldape (NCI) and Eytan Ruppin (NCI). This study also includes the RNA seq, DNA methylation, whole exome genome sequencing and the metabolome descripted in Project 1D. Project 1C. As previously detailed in the 2019 annual report, we are using liquid biopsy of urine, serum and plasma to quantitatively measure four biomarkers (creatine riboside(CR), N-acetylneuminic acid(NANA), cortisol sulfate(CS) , and 27alpha-nor-5beta-cholestane-3aplpha, 7alpha, 12alpha 24alpha, 25alpha Pentol glucuronide(NCPG) of lung cancer by mass spectrometry (Mathe E et al., Cancer Res. 74:3259-70, 014; Haznadar, M et al., Cancer Epidemiol. Biomarker Prev. 25:978-86, 2016). We are investigating multiple cohorts: National Cancer Institute and University of Maryland Hospital (NCI-MD); Detection of Early Cancer among Military Personnel (DECAMP1) in collaboration with Avi Spira, Lung Cancer Biomarker Research Network (LCBRN); Vanderbilt Hospital in collaboration with Pierre Masson; and th National Lung Screening Trial (NLST) to determine the utility of the biomarkers: to predict the prognosis of stage 1 and 2 lung cancer that are frequently cured by surgery. However, 25% recur during the next 5 years and could benefit from adjunct chemotherapy and/or immunotherapy; identify benign indeterminate nodules from cancer: and to prioritize candidates for lung cancer screening by low dose CT. We are also developing a CLIA-based clinical test using liquid biopsy of these four biomarkers. We and our collaborators have synthesized heavy labelled creatine riboside and are currently synthesizing heavy labelled NCPG. These will be useful for rapid mass spectrometry analysis in the commercial clinical setting. Project 1D: We have discovered that the novel tumor-derived biomarker creatine riboside is the product of dysregulated urea cycle and pentose phosphate pathway that is commonly found in major lethal types of human cancer being investigated in the Laboratory of Human Carcinogenesis including lung, breast, prostate, liver and esophageal carcinoma. This is another example of ongoing collaboration with our colleagues Brid Ryan, Perwez Hussain, Stefan Ambs and Xin Wang in our Laboratory. We have unpublished data that human mesothelioma produces high levels of creatine riboside. We also have a long history of investigating the etiology by asbestos and the genetic and molecular basis of mesothelioma (e.g., Gabrielson, EW et al., Carcinogenesis13: 1359-64, 1992; Marrogi A et al, Cancer Res 60:3696-700, 2000). Therefore, creatine riboside may be a companion diagnostic biomarker to both target these cancers and select specific arginine depleting therapy by arginase or arginine deaminase and immunotherapy. These therapies are in clinical trials that including mesothelioma. We have initiated collaborations with Raffit Hassan (NCI) and Peter Zlosarek, Bart Center, Cancer Research, UK to investigate mesothelioma that are frequently arginine auxotrophic. We will investigate both previous and ongoing trials. We will follow these patients from the initiation and throughout their therapy. This will provide information on the "proof of principle" clinical value of creatine riboside in the diagnosis and therapy in four cohorts mesothelioma.