Cancer is a major cause of mortality in Lebanon and worldwide. There is a paucity of advances in the treatment of end-stage or advanced-stage cancer leading to the supposition that "prevention is the cure". Yet, biomarkers and strategies for early detection and prevention of cancer are scarce. Limiting these advances is our poor understanding of the earliest events that drive cancer development and would thus constitute markers/targets for early detection and intervention. It is widely appreciated that genomic changes provide tumors with the ability to grow and expand. Yet, very little is known about molecular changes that lead to the onset of cancer. My research interests focus on filling these voids; first by understanding genomic aberrations in cancer pathogenesis in order to better comprehend the biology of malignant neoplasms and second by devising genomics-driven molecular strategies for early detection, prevention and prognosis of cancer. To accomplish these goals, we survey specific cancer prototypes, such as lung cancer, with characterized sequential histopathological stages that offer a window of opportunity to delineate molecular events preceding the onset of malignant/invasive lesions. Below are different projects that our laboratory is currently actively pursuing.
- We recently found that mice with knockout of G-protein coupled receptor 5A (Gprc5a-/-), not only developed lung cancers after tobacco carcinogen exposure but also that these lesions harbored somatic Kras mutations, the same variants thought to act as drivers of lung cancer in humans. Using such genetically modified mouse models, molecular profiling and immune phenotyping a central goal of our laboratory is to understand the progression of normal airway epithelium to lung cancer and to identify drugs that impede this process and prevent development of the malignancy.
- Our group is probing the role of an innate immune marker that sequesters iron-laden siderophores (lipocalin 2 /Lcn2). We have recently generated mice with knockout of both Gprc5a and Lcn2 as well as syngeneic models in which we seek to assess the role of Lcn2 in both the tumor epithelial and immune lung microenvironment compartments.
- Using syngeneic mouse models, we are probing the role of the host immune response, particularly immune surveillance and immune checkpoint pathways, in development and progression of lung cancer in vivo.
- Using the Lcn2 knockout mouse, we are also trying to understand the role of the host microbiome in the development and progression of lung cancer
- Our group is also interested to delineate the cell-of-origin of lung malignancy. We aim to use a mouse model of Kras mutant lung cancer to delineate the cell-of-origin of premalignant and malignant Kras mutant lung lesions and, in collaboration with various groups, probe stemness properties of these potential progenitor cells
- We are studying the potential causal cues linking chronic waterpipe (narghile) exposure and lung cancer development in vivo
Genome-wide gene expression changes in the normal-appearing airway during the evolution of smoking-associated lung adenocarcinoma
Kantrowitz J, Sinjab A, Xu L, McDowell TL, Sivakumar S, Lang W, Nunomura-Nakamura S, Fukuoka J, Nemer G, Darwiche N, Chami H, Tfayli A, Wistuba II, Scheet P, Fujimoto J, Spira AE, Kadara H
Cancer Prev Res. 2018 Jan 30. Pii:canprevres.0295.2017
Strategies for identification of somatic variants using the ion torrent deep targeted sequencing platform
Deshpande A, Lang W, McDowell T, Sivakumar S, Zhang J, Wang J, San Lucas FA, Fowler J,
Kadara H*, Scheet P*
BMC Bioinformatics. 2018, Jan 4;19(1):5
Genomic landscape of atypical adenomatous hyperplasia reveals divergent modes to lung adenocarcinoma
Sivakumar S, San Lucas FA, McDowell TL, Lang W, Xu L, Fujimoto F, Zhang J, Futreal PA, Fukuoka J, Yatabe Y, Dubinett SM, Spira AE, Fowler J, Hawk ET, Wistuba II, Scheet P,
Cancer Research. 2017 Nov 15;77(22):6119-6130
Development of Kras mutant lung adenocarcinoma in mice with knockout of the airway lineage-specific gene Gprc5a
Fujimoto J, Nunomura-Nakamura S, Liu Y, Lang W, McDowell T, Jakubek Y, Ezzeddine D, Ochieng JK, Petersen J, Davies G, Fukuoka J, Wistuba II, Ehli E, fowler J, Scheet P,
International Journal of Cancer (featured on the cover). 2017 Oct 15;141(8):1589-1599
Distinct pattern of TP53 mutations in HIV-related head and neck squamous cell carcinoma
Gleber-Netto FO, Zhao M, Trivedi S, Wang J, Jasser S, McDowell C,
Kadara H, Zhang J, Wang J, William WN Jr., Lee JJ, Nguyen ML, Pai SI, Walline HM, Shin DM, Ferris RL, Carey TE, Myers JN, Pickering CR on behalf of the HNC SPORE HIV supplement consortium
Cancer. 2017, Oct 20. 9
- National Cancer Institute (NCI, 1R01CA205608-01A1) Provocative Questions initiative (PQ1), Progression of the airway field of injury to Kras mutant lung cancer, 2016-2020, total direct costs: $1,000,000, role: principal investigator.
- Cancer Prevention and Research Institute of Texas (CPRIT) Individual Investigator Research Award (RP150079), Elucidating the evolution of the premalignant airway genome in space and time, 2015-2018 (with one year no cost extension), direct costs: $886,000, role: principal investigator.
- American University of Beirut Collaborative Research Stimulus Award, Spatiotemporal protein markers of smoking-mediating airway injury and Kras mutant lung cancer, 2017-2019, total direct costs: $40,000, role: principal investigator.
- American University of Beirut Medical Center MPP, Lipocalin 2 in development and growth of Kras mutant lung adenocarcinoma, 2017-2020, total direct costs per year: $32,000, role: principal investigator.
- American University of Beirut Medical Center MPP, TBX2 subfamily in early detection of lung cancer in smokers, 2017-2019, total direct costs per year: $30,000, role: co-principal investigator.
- American University of Beirut Medical Center MPP, TBX2 subfamily in early molecular pathogenesis of lung cancer, 2017-2019, total costs per year: $32,000, role: co-principal investigator.
- National Cancer Institute/Early Detection Research Network, Biomarkers for the early detection of pancreatic cancer, 2014-2016, role: co-investigator.
- American Lung Association Lung Cancer Discovery Award, Dissecting lung tumor promoting profiles in the normal-appearing airway, 2014-2016, direct costs: $200,000, role: principal investigator.
- US Department of Defense (DoD) Lung Cancer Research Program Collaborative Award, Molecular profiles of lung cancer pathogenesis in US veterans, 2010-2014, role: co-investigator.
- LUNGevity Foundation early detection of lung cancer research grant, Identification of biomarkers for the detection of SCLC, 2013-2016, direct costs: $300,000, role: principal investigator.
- American University of Beirut Collaborative Stimulus Research Award, American University of Beirut, Beirut, Lebanon, 2017.
- Cancer Prevention and Research Institute of Texas (CPRIT) Individual Investigator Research Award, Austin, Texas, USA, 2015
- American Lung Association Lung Cancer Discovery Award, USA, 2014.
- Division of Cancer Medicine (DoCM) Excellence in Research Award, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA, 2011
- Jeffrey Lee Cousins Fellowship in Lung Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA, 2010
- AACR-Aflac Scholar-in-training award, American Association for Cancer Research, Philadelphia, USA, 2010
- MD Anderson Cancer Center Trainee Excellence in Research award, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA, 2006