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Faculty

Michele Carbone, MD, PhD

Michele Carbone, MD, PhD
  • Full Member
    Cancer Biology Program
    University of Hawaii Cancer Center
  • Director, Thoracic Oncology
    University of Hawaii Cancer Center
    University of Hawaii at Manoa
  • Academic Appointments

  • Researcher (Professor)
    Cancer Biology Program
    University of Hawaii Cancer Center
    University of Hawaii at Manoa
  • Professor
    Department of Pathology
    John A. Burns School of Medicine
    University of Hawaii at Manoa

Degrees

  • 1984 MD, Medical School of Rome "La Sapienza", Italy
  • 1993 PhD, Medical School of Rome "La Sapienza", Italy
  • Medical Board Certifications in Anatomic Pathology:
    • 1988 University of Rome, Italy
    • 1999 University of Chicago, USA

Honors

  • National Institutes of Health Fogarty Fellowship, 1986-1994
  • Knight of the Republic of Italy (Cavaliere della Repubblica), 2001
  • Landon Foundation-American Association for Cancer Research INNOVATOR Award for International Collaboration in Cancer Research, 2008
  • American Cancer Society Board of Directors, 2011
  • Mesothelioma Applied Research Foundation-Pioneer Award for work on Mesothelioma, 2014

Research Focus

h-index: 61 (https://scholar.google.pl/citations?user=3CM8k84AAAAJ&hl=en)

Studying a mesothelioma epidemic in remote villages in Cappadocia I proposed that genetics modulated asbestos and erionite carcinogenesis ("asbestos" includes different types of carcinogenic fibers, Baumann F et al., Lancet Oncol, 2013). Later I proved my hypothesis by identifying a gene, BAP1, that when mutated increased susceptibility to asbestos and caused mesothelioma and other environmentally related cancers. I named this "The BAP1 Cancer Syndrome". Studying "normal" cells from individuals affected by the BAP1 Cancer Syndrome, we discovered how BAP1 modulates gene-environment interaction and why BAP1 deficiency increases susceptibility to environmental carcinogens. We are now trying to counteract the cellular damage caused by reduced or absent levels of BAP1 for cancer prevention and therapy.

My research is a combination of field-work in the third world and in remote areas of the U.S., molecular genetics work in my laboratory, clinical-diagnostic work, and team-work. In 2008, as PI, I received the first AACR-Landon Innovator Award for International Collaboration in Cancer Research. My research team includes scientists from multiple countries who specialize in different disciplines including pathology, surgery, genetics, molecular biology, geology, mineralogy, public health and Ca2+ signaling. I am very grateful to many of them who played important roles in different periods of my research. Among them, H.I. Pass and I collaborated since 1993, and H. Yang joined our team in 2003. Since then we have always worked together.

Studying over a period of about 14 years an epidemic of mesothelioma in Cappadocia, Turkey, together with Drs. Y. I. Baris, S.A. Emri, U.A. Dogan, and others, we found that susceptibility to mesothelioma was transmitted in a Mendelian fashion. I formulated the hypothesis that the cause was gene x environment interaction and I proposed that there had to be a gene/s that when mutated increased susceptibility to carcinogenic mineral fibers and mesothelioma (Roushdy-Hammady I, et al, Lancet, 2001; Dogan UA, et al, Cancer Res, 2006; Carbone M, et al., Nat Rev Cancer, 2007). We convinced the Turkish government to build two new villages in erionite-free areas, and relocate the villagers, to eliminate exposure and thus decrease/eliminate mesothelioma in future generations in a population that our studies had shown to be unusually susceptible to mineral fiber carcinogenesis (Emri SA, Ann Transl Med, 2017, doi: 10.21037/atm.2017.04.06).

With support of a NCI-PO1 (M. Carbone, PI) I searched for a possible "mesothelioma gene" in U.S. families with high incidences of mesothelioma. As the P01 was coming to an end we finally identified the gene, BAP1, that when mutated caused an epidemic of mesothelioma, and to my surprise eye melanoma, in certain families (Testa JR, el al., Nat Genet, 2011). I named this inherited condition "The BAP1 Cancer Syndrome" characterized by the development of mesothelioma, uveal melanoma, and other cancers (Carbone M., et al., J Transl Med, 2012; Carbone M et al., Nat Rev Cancer, 2013).

We found that 100% of individuals affected by this novel cancer syndrome developed one or more tumors in their lifetime and that mesothelioma predominates upon exposure to asbestos or erionite. (Baumann F, et al., Carcinogenesis, 2015). We demonstrated that BAP1 mutations were inherited upon the course of centuries and traced the origin of a specific BAP1 mutation that we found in several U.S. families, to a family who lived in Switzerland in the 1500s and immigrated in the U.S. in the early 1700s. We implemented annual screening for skin and eye melanoma for early detection and curative resection (Carbone M, et al., PLOS, Genetics, 2015). Using a mouse BAP1 heterozygous mutant model, we demonstrated that heterozygous BAP1 mutations increase susceptibility to asbestos and mesothelioma (Napolitano A, et al., Oncogene, 2016).

Very recently we elucidated how BAP1 modulates gene-environment interaction and cause cancer (Bononi A et al., Nature, 2017 and Bononi et al., Cell Death Differ, 2017). A commentary by I. Amelio, in Cell Death Dis, doi:10.1038/cddis.2017.293, provides a clear synopsis of these two manuscripts. For more information, to read these two papers and related commentaries and News, see my website: http://www.oakparkpathology.com/

Moreover, we found acquired, somatic BAP1 mutations in over 60% of sporadic mesotheliomas (Nasu M, et al, J Thorac Oncol, 2015). We found that about 50% of these acquired mutations encompass DNA segments of about 100-3000 kb, and thus are identified by high sensitive array-CGH, but are easily missed by conventional array-CGH and by NGS, a technique developed to detect nucleotide level mutations (Yoshikawa Y, et al., Proc Natl Aca Sci USA, 2016).

Since the publication of our discovery that individuals born with inherited BAP1 mutations are affected by the "BAP1 cancer syndrome" and that somatic BAP1 mutations are common in mesothelioma, over 400 publications from multiple laboratories around the world have confirmed and expanded our studies to include several other tumor types, including, basal and squamous cell carcinomas of the skin, squamous cell carcinoma of the esophagus, renal cell carcinoma, etc. Moreover, clinical genetic testing for BAP1 mutations is now offered worldwide.

In parallel I have studied the role of erionite in mesothelioma, and the mechanisms of asbestos carcinogenesis and of SV40 as co-factor. Briefly:

We discovered significant erionite exposure in North Dakota (ND), where we detected concentrations of erionite in cars and school buses transiting on erionite gravel-paved roads as high as in the Cappadocian villages (Carbone M, et al., Proc Natl Aca Sci USA, 2011; Maher B, Nature, 468:884-885, Dec. 2010). Following our discovery and meetings with the ND state government, the "erionite roads" were repaved with erionite-free gravel. This measure has likely saved many lives because after our discovery there has been the rapid development of the "fracking" industry to extract oil and gas in ND. The ND authorities estimate that presently over 50,000 trucks transit each day on roads that had been paved with erionite. Subsequently, we uncovered environmental exposure to asbestos in Nevada that we linked to a high incidence of mesothelioma among young adults (Baumann F, et al., J Thorac Oncol, 2015). Our work led to the "International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers" and to a consensus manuscript recommending measures to reduce exposure to environmental carcinogens to prevent cancer (Carbone M, et al., J Thorac Oncol, 2016).

Together with H. Yang we have uncovered and we are studying the role of HMGB1 in asbestos-carcinogenesis and in promoting mesothelioma growth (Yang H, et al., Proc Natl Aca Sci USA, 2006; Yang H, et al., Proc Natl Aca Sci USA, 2010; Carbone and Yang, Clin Cancer Res, 2012; Jube S, et al., Cancer Res, 2012; Qi F, et al., Am J Pathol, 2013; Yang H, et al., Cell Death Dis, 2015). We discovered that specific isoforms of HMGB1 may allow identification of individuals exposed to asbestos and among them other HMGB1 isoforms single out those who have developed mesothelioma (Napolitano A, et al., Clin Cancer Res, 2016). A clinical trial sponsored by the NCI by Drs. H.I. Pass and H.Yang, to validate these exciting findings is in progress.

My studies on SV40 revealed that human poliovaccines were contaminated until the late 70s with SV40 in many countries (Cutrone R., et al., Cancer Res, 2005). Moreover our studies revealed that SV40 preferentially cause mesothelioma in hamsters (Cicala C., et al., Am J Pathol, 1993), its presence in some human mesothelioma biopsies (Carbone M., et al., Oncogene 1994; Carbone M., et al., Nat Medicine, 1997; Gazdar AF et al., Nat Rev Cancer, 2002); that SV40 synergizes with asbestos to transform human mesothelial cells in vitro (Bocchetta M et al., Proc Natl Aca Sci USA, 2001) and to cause mesothelioma in animals (Kroczynska B. et al., Proc Natl Aca Sci USA, 2006), and we discovered novel mechanisms of SV40 carcinogenesis (Foddis R., et al, Oncogene, 2002; Bocchetta M., et al., Cancer Res, 2008) and of viral latency (Carbone M., et al., Cancer Res, 2008).

Clinical: I am board-certified in Anatomic Pathology (both in Italy and the U.S.) and specialize in pleural pathology and mesothelioma.

Selected Publications for years 2016/2017:

(for a complete CV and to read the publications see: http://www.oakparkpathology.com/About)

  • Bononi A, Yang H, Giorgi C, Patergnani S, Pellegrini L, Su M, Xie G, Signorato V, Pastorino S, Morris P, Sakamoto G, Kuchay S, Gaudino G, Pass HI, Napolitano A, Pinton P, Jia W, Carbone M. (2017). Germline BAP1mutations induce a Warburg effect. Cell Death Differ, June 30. doi: 10.1038/cdd,2017.95. Epub ahead of print.
  • Bononi A, Giorgi C, Patergnani S, Larson D, Verbruggen K, Tanji M, Pellegrini L, Signorato V, Olivetto F, Pastorino S, Nasu M, MNapolitano A, Gaudino G, Morris ,Sakamoto G, Ferris LK, Danese A, Raimondi A, Tacchetti C, Kuchay S, Pass HI, Affar EB, Yang H, Pinto0n P, Carbone M. (2017). BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation. Nature, 546:549-553. doi: 10.1038/nature22798.
  • Mao W, Zhang X, Guo Z, Gao Z, Pass HI, Yang H, Carbone M. (2017). Mesothelioma in Eastern China is Mostly Prevalent Among Young Women. JAMA Oncol, 3:562-564.
  • Yoshikawa Y, Emi M, Hashimoto-Tamahoki T, Ohmuraya M, Sato A, Tsujimura T, Hasegawa S, Nakano T, Nasu M, Pastorino S, Szymiczek A, Bononi A, Tanji M, Pagano I, Gaudino G, Napolitano A, Goparajiu C, Pass HI, Yang H, Carbone M. (2016). High-density array-CGH with targeted NGS unmask multiple non-contiguous minute deletions on chromosome 3p21 in mesothelioma. Proc Natl Aca Sci USA, 113:13432-13437.
  • Napolitano, A, Pellegrini L, Dey A, Larson D, Tanji M, Flores EG, Kendrick B, Lapid D, Powers A, Kanodia S, Pastorino S, Pass HI, Dixit V, Yang H, Carbone M. (2016). Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene, 35:1996-2002.

Publication list via PubMed

Active Grants

  • M. Carbone, Co-I, H.I. Pass & H. Yang, Co-PIs
    NIH/NCI
    U01CA214195-01
    "The EDRN Mesothelioma Biomarker Discovery Laboratory"
    Determine the ability of serum mesothelin, serum HMGB1, and the combination of these two biomarkers as a diagnostic, pre-diagnostic as well as prognostic tool for MPM.
    09/20/16-08/31/21
  • M. Carbone, PI
    1R01CA198138-01 NIH/NCI
    "Germline BAP1 Mutations and Malignant Mesothelioma: Mechanisms and Early Detection"
    The proposed studies will determine how BAP1 mutations increase susceptibility to MM and evaluate whether HMGB1 can be used as a biomarker for early detection of malignant mesothelioma in this high risk cohort.
    07/01/15-06/30/20
  • M. Carbone, S. Kanodia, T. Mak, H.I. Pass, H. Yang, Co-PIs DoD CA150671
    DoD Peer Reviewed Cancer Research Program Translational Team Science Award
    "HMGB1 and Its Isoforms As Biomarkers For Mineral Fiber Exposure and MM Detection"
    Our proposed studies will significantly enhance our knowledge of how mesothelioma develops, elucidate which isoform of HMGB1 is required at what stages of disease, and prospectively evaluate HMGB1 and its isoforms as a novel biomarker to distinguish between asbestos exposure and malignant mesothelioma.
    07/01/16 – 06/30/19
  • M. Carbone & H. Yang, Co-PIs DoD CA150220
    DoD Peer Reviewed Cancer Research Program Idea Award with Special Focus
    "Identification and validation of novel germline DNA variants associated to increased risk of malignant mesothelioma"
    The objective of our research is to identify which are these genetic modifications that confer higher risk of developing mesothelioma. Identifying, among the millions of individuals exposed to asbestos (many belonging to the military), those at higher risk of mesothelioma, will allow us to implement personalized programs of screening and early detection and treatment of mesothelioma for these individuals.
    10/01/16-10/31/18

Philanthropy: Support from the University of Hawaii Foundation that received unrestricted donations to support my mesothelioma research from Riviera United-4-a Cure Foundation, and from Honeywell International Inc.