Our continuing research projects utilize an integrative biology, translational and precision medicine strategy, as evidenced by co-authored primary and collaborative studies. They reflect the priorities of the NCI FY17 Cancer Research Initiative and Cancer Moonshot Blue Ribbon Panel.

Project 1:  Precision Medicine of Cancer

Biomarkers are the foundation upon which diagnostic precision is improved and comprise potential therapeutic targets. Our Biomarker program emphasizes the integration of molecular, clinical, and environmental data for single patients to identify lung, esophageal, liver and colon cancer biomarkers and build a molecular taxonomy that will result in improved cancer diagnosis and treatment. We are focused on the earliest stages of cancer; when therapy is most effective but a subset of patients remain at high risk of recurrence. Our strategy is to begin by analyzing resources from our NCI-MD cohort and then validate those findings in multiple clinical cohorts throughout the world, to find associations that are generalizable to cancer populations globally and to uncover biological factors of health disparity. Through rigorous bioinformatics and statistical analyses of molecular data, including mRNA and miRNA, DNA methylation, inflammatory cytokines, tumor microbiome and tumor and urinary metabolites, together with clinical and environmental exposure data for single patients, we develop signatures of cancer risk, diagnosis, prognosis, and therapeutic outcome. The integration of classifiers across different data types within a given disease generates hypothesis, illuminates novel disease mechanisms, and provides actionable information to guide medical decisions for cancer patients. We are also investigating the lung cancer microbiome to determine its value as cancer biomarker and to understand the role of the microbiota in cancer initiation and progression.

Image

References:

1. Vargas AJ, Harris CC. Biomarker development in the precision medicine era: lung cancer as a case study. Nat Rev Cancer. Aug; 16(8): 525-37, 2018. PMID: 27388699

2. Mathe EA, Patterson AD, Haznadar M, Manna SK, Krausz KW, Bowman ED, Shields PG, Idle JR, Smith PB, Kazandjian DG, Hatzakis E, Gonzalez FJ, Harris CC. Noninvasive urinary metabolomic profiling identifies diagnostic and prognostic markers in lung cancer. Cancer Res. Jun 15;74(12):3259-70, 2014. PMID: 24736543

3. Greathouse KL, White JR, Vargas AJ, Bliskovsky VV, Beck JA, von Muhlinen N, Polley EC, Bowman ED, Khan MA, Robles AI, Cooks T, Ryan BM, Padgett N, Dzutsev AH, Trinchieri G, Pineda MA, Bilke S, Meltzer PS, Hokenstad AN, Stickrod M, Walther-Antonio MR, Earl JP, Mell JC, Krol JE, Balashov SV, Bhat AS, Ehrlich GD, Valm A, Deming C, Conlan S, Oh J, Segre JA, Harris CC. Interaction between the microbiome and TP53 in human lung cancer. Genome Biol. Aug 24; 19(1):123. 2018. PMID: 30143034

Project 2:  p53, Aging and Cancer

The p53 network is an intrinsic monitoring and responsive pathway of telomeric attrition and chronic stress involved in cellular aging and senescence. Cellular senescence, in cancer cells, can be a tumor suppressive mechanism that can be activated by p53. We are currently studying the molecular mechanisms of cellular senescence in normal human cells and the role of p53 isoforms in aging and carcinogenesis. Our research focuses on integrative p53 and miRNA networks in tumor suppression and the functional role of p53 isoforms, e.g., “dominant negative” ∆133p53, that also has gain of function as a transactivator of specific DNA repair genes such as RAD51 and “co-transactivator” of wild-type p53, p53β, both as natural regulators of cellular senescence, DNA repair and stem cell biology and are dysregulated in cancer, including damaging side effects of radiation and chemotherapy, and aging diseases, such as Hutchinson-Gilford Progeria Syndrome and Alzheimer’s disease. As a result of molecular evolution, ∆133p53 is specifically present in humans and primates, but not in other organisms, including mice, because of lack of an initiating methionine codon corresponding to the human codon 133 at exon 5 of TP53.

Image