Mesothelioma. Mesothelioma and Asbestos 11/21/2009

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1 Mesothelioma Michele Carbone, M.D.,PH.D. Director Cancer Research Center of Hawaii Professor and Chairman, Dept. of Pathology J.A. Burns Medical School University of Hawaii Honolulu, HI Mesotheliomas were extremely rare until the second half of the 20th century Currently, there are approximately cases of mesothelioma/year in the USA Therefore, mesotheliomas are caused by a carcinogen that humans have just recently been exposed to, or exposed to in increasing amounts Mesothelioma and Asbestos The link between asbestos exposure and mesothelioma is well established Up to 5% of crocidolite miners developed mesothelioma Most mesotheliomas patients have exposures above background 1

2 TABLE 1. Asbestos exposure and human diseases based on lung content analysis Asbestos and Mesothelial cells Normal human mesothelial cells (HM) HM Exposed to Crocidolite Fibers/gX10 3, (uncoated fibers, mostly amosite 53 ); *million of fibers/dry Lung; # Fibers X10 6 /g dry lung. PTL-MM, peritoneal malignant mesothelioma Asbestos causes Human Mesothelial cells (HM) death in vitro. Research question TNF-α and its receptor TNF-R1 is induced in HM following asbestos exposure. How can asbestos cause malignant mesothelioma (MM) if human mesothelial cells (HM) exposed to asbestos die? 2

3 Finding mechanism of asbestos carcinogenesis Asbestos and TNF-α TNF-α signaling through NF-κB-dependent mechanisms increases the percent of HM that survives asbestos exposure, thus increasing the pool of asbestos-damaged HM that are susceptible to malignant transformation. crocidolite crocidolite+tnf-α (Yang et al, PNAS 2006) Asbestos + TNF-α (after 1 M) HM and macrophages co-culture 3 weeks 1.5 month 3

4 11/21/2009 TNF-a inhibits asbestos induced cytotoxicity via a NF-kB dependent pathway: a possible mechanism for asbestos induced oncogenesis. Yang H, Bocchetta M, Kroczynska B, Elmishad AG, Chen Y, Liu Z, Bubici C, Mossman BT, Pass HI, Testa JR, Franzoso G and Carbone M, Proceedings of the National Academy of Sciences USA,

5 Karain Tuzkoy Old Sarihidir 5

6 6

7 Karlik: 3 Km from Karain 7

8 Erionite and Mesothelioma We spent the following 3 years in Karain, Tuzkoy, and Karlik collecting data about: eating habits, occupation, smoking, family life style, family pedigrees, medical histories, etc. Drs. Dogan and Steele determined the chemical and crystal structure of erionite in Cappadocia My office in Sarihidir Erionite and Mesothelioma Similar amounts and types of erionite in Karlik and Karain, Tuzkoy and Sarihidir Similar amounts of erionite in the houses of Karain and Tuzkoy The chemical and crystal structure confirmed that erionite in Cappadocia is similar to the erionite found in the USA 8

9 My office in Karain 9

10 Mesothelioma Mesothelioma is a cancer in which genetics, environmental carcinogens, and viruses may act alone or interact to cause malignancy The isolation of the putative mesotheliomasusceptibility gene/s is the key to understand the precise pathogenesis of mesothelioma and to develop effective therapeutic approaches This is the main goal of our PO-1 Pathogenesis of mesothelioma, , M. Carbone PI. Louisiana Pedigree Localization of a Dominant Genetic Susceptibility Factor in Familial Malignant Mesothelioma Genotyping and Quality Control All available family members have been genotyped using the Affymetrix Genome- Wide Human SNP Array 6.0. Prior to linkage analyses, familial relationships were checked and corrected using PLINK. The results should allow us to identify the gene/s that make certain family members susceptible to MM. Problem: Insufficient number of DNA samples from affected individuals. 10

11 What should we do in the meantime Goal of my research: identify some point in the evolution of the (mesothelioma) process that is vulnerable to intervention : Diminish exposure Old Sarihidir 11

12 New Sarihidir The new village of Tuzkoy Did we really diminish erionite exposure in New Tuzkoy? Were the air concentration of erionite in new Tuzkoy significantly lower than in other mesothelioma villages? I started a collaboration with the EPA to measure air concentration of erionite and test this hypothesis Team-April 08 12

13 New Tuzkoy Village Field sampling consider significant increases in airborne particulate after Industrialization: tractors vs horses, or more primitive farming tools that would not stir up as much dust. 13

14 What about them? What should we do in the meantime Goal of my research: identify some point in the evolution of the (mesothelioma) process that is vulnerable to intervention : Diminish exposure. Done identify high risk patients for early treatment Asbestos exposure, mesothelioma, and serum osteopontin levels. Pass HI, Lott D, Leonardo F., Harbut M, Liu Z, Tang M., M. Carbone, et al., New Engl J Med,

15 Early detection: Can we save lives? The Cappadocian villages are the ideal cohort that may benefit from the availability of early markers for MM. We applied to the EDRN to conduct a 4 year prospective study to validate Osteopontin and Mesothelin as early markers for the detection of mesothelioma. We asked the Turkish Ministry of Health to build a mesothelioma referral clinic in Cappadocia to provide logistical support for our study and to help the villagers. The outcome was positive. We got both, the grant and the hospital. Aug 15, 07 meeting in Honolulu. April 2008 meeting in Tuzkoy: Health Center is ready. Sample size Based on an estimated incidence of mesothelioma of 1.5/100 per year, we would expect 6 individuals in a cohort of 400 would develop mesothelioma each year. To conduct a similar study in the US with an incidence of MM of about 10/1,000,000 we would need to study approximately 600,000 people for 4 years! The results will possibly benefit the Turkish villagers AND many million people exposed to asbestos and to other carcinogenic mineral fibers in the US and worldwide. 1. Baseline Activity Study Design 400 villagers: blood collection (for both serum and plasma); CT scan -- to determine whether they have non-diagnosed MM. 400 Control: age-matched, sex-matched, and tobacco-matched controls from the University of Hacettepe in Ankara establish baseline geographical differences in markers between exposed villagers and non-exposed Turks. SMRP will be tested in serum, osteopontin will be tested in both serum and plasma. 50 of the study participants will be randomly selected to be members of the sub cohort for additional activities during the follow-up visits. 15

16 Conclusions Erionite Occurrences in the Western U.S. 1. The Turkish cohort is ideal to study gene environment interaction and cancer and to try to isolate the gene tht predisposes to mineral fiber carcinogenesis. 2. The MM villages in Cappadocia have an ideal cohort to test the clinical relevance of early detection markers for MM and Cancer. 3. In addition this research shows how research in a third world country can benefit patients in both the third world and the US 4. Finally we show that research can be a positive political ambassador for the US in Muslim countries. 5. The results of the studies are relevant to the villagers and to millions of people worldwide exposed to asbestos and erionite. 6. IN FACT. Sheppard, 1996, Occurrences of erionite in sedimentary rocks of the western United States Erionite in the US Active Funding, M.Carbone PI Pathogenesis of Mesothelioma: NCI-PO-1 (JR Testa, B Mossman, and HI Pass co-pis) Mechanisms of SV40 asbestos-co-carcinogenesis in mesothelioma: NCI RO SV40 in human tumors: NCI RO AACR Landon Innovator Award for International Cancer Research: Mesothelioma epidemic in Cappadocia: (M. Tuncer, IY Baris, N. Cox, UA Dogan, HI.Pass, I. Steele, JR Testa, H. Yang, co PIs). USA-Australia Mesothelioma Consortium: NIH UO-1, H.I. Pass PI, M. Carbone, co-pi. 16

17 THANKS! 17

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