Biomarkers of asbestos exposure and mesothelioma

Transcription

1 University of Hawai i Cancer Center Biomarkers of asbestos exposure and mesothelioma Haining Yang, PhD Professor University of Hawai i Cancer Center

2 MM is a Global l Problem: Millions of people have been exposed to asbestos and other carcinogenic fibers. MM Incidence (# patients/yr) US: 3200 Western Europe: 5000; Worldwide: unknown probably > 100,000. Genetic factor such as heterozygous BAP1 mutation predispose to MM. Long latency period between initial asbestos exposure and MM development (about years). >95% of patients present with advanced disease Prognosis of MM is ~ 12 months, except for Stage I (~ 5years).

3 MM early detection The Goal: By screening high risk of mesothelioma asbestos / erionite exposed cohorts, we will be able to catch mesothelioma at early stage increase survival.

4 SMRP Robinson, B.: Lancet, 362: , 2003.

5 Osteopontin Pass HI.: N Engl J Med, 353: , 2005.

6 Studies of Serum SMRP levels in MM Compared to asbestos exposed or normal cohorts Sensitivity Specificity Best Cut off Robinson (2003) NA Scherpereel (2006) nM Cristaudo (2007) nm Pass (2008) nm Rodriguez Portal (2009) nm Creaney (2008) nM (Robinson) nm 1.6 nm 18nM 1.8

7 Studies of Osteopontin levels Sensitivity Specificity Best Cut off Pass (2005) ng/ml Creaney (2008) ng/ml (Robinson) ng/ml 18 ng/ml 77 ng/ml

8 Fibulin-3 Pass HI, et al. N Engl J Med. 2012

9 Yang H et al, PNAS 2006, PNAS 2010, Clinical Cancer Res 2011

10 HMGB1

11 Asbestos induces programmed necrosis in HM HMGB1 is released from HM after asbestos exposure Yang H et al, PNAS 2010

12 Strong HMGB1 and TNF-α staining around areas of asbestos deposits Yang H et al, PNAS 2010

13 HMGB1 levels in the serum of mice injected with different types of fibers 40 HMGB1 ELISA - Mice injected w/ fibers 35 * HMGB1 (ng/ml) * * * * * 5 0 PBS Glass CHRY CRO ND OR TK TRE

14 Yang H et al, PNAS 2010

15 HMGB1 is highly expressed in mesothelioma tissue. Normal pleura MM 100X 400X

16 MM cells contain high levels of HMGB1 in both nucleus and cytoplasm MM cell lines secrete HMGB1 HMGB1 ELISA using cell culture medium

17 HMGB1 serum level is significantly higher in MM patients than in healthy controls.

18 BAP1 cancer syndrome: MM, CM and UVM, MBAITs, Cholangio and Renal Cell Carcinomas, and possibly others. Carbone et al., Nat. Rev Cancer 2013.

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20 Napolitano,.. Yang & Carbone. Oncogene 2016

21 Genetic factor and MM

22 Core of the 106-member nine-generation pedigree.

23 HMGB1 isoforms HMGB1 Nuclear vs. Cytoplasmic vs. Extracellular Acetylation status ACTIVE SECRETION: hyper- acetylated NLS1/2 PASSIVE RELEASE: non- acetylated NLS1/2 Redox status Fully reduced (All-thiol- HMGB1) Disulfide HMGB1 Oxidized HMGB1 Antoine DJ et al. Molecular Medicine. 2014

24 HMGB1 isoforms Asbestos-exposed HM cells HMGB1 is released (non-acetylated) t MM cell lines secrete HMGB1 HMGB1 ELISA Human MM cells secrete HMGB1

25 Asbestos-exposed HM and MM cells release different HMGB1 isoforms

26 Total and hyper-acetylated HMGB1 are biomarkers for asbestos exposure and MM

27 Working models

28 HMGB1 isoforms in sera from patients with pleural effusion

29 Other previously proposed MM biomarkers

30 Other previously proposed MM biomarkers

31 No correlation between levels of total HMGB1 and other biomarkers A 50 B 500 Hype er-acetylated HM MGB Fibulin-3 OPN Hyper-acetylated HMGB1 C Hyp per-acetylated HMGB Mesothelin

32 Combining HMGB1 with Fibulin-3 Napolitano A et al, Clinical Cancer Research 2015

33 Data from other research groups confirming our findings Tabata C et al. BMC Cancer 2013

34 Data from other research groups confirming our findings Tabata C et al. BMC Cancer 2013

35 Data from other research groups confirming our findings Ying S et al. Disease Markers 2017 g Serum HMGB1 as a Potential Biomarker for Patients with Asbestos-Related Diseases

36 Data from other research groups confirming our findings Ying S et al. Disease Markers 2017 g Serum HMGB1 as a Potential Biomarker for Patients with Asbestos-Related Diseases

37 Individuals carrying heterozygous germline BAP1 mutations can be reliably identified based on their metabolic profile Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA), revealed a clear and statistically significant separation between BAP1 WT and BAP1 +/- individuals: plasma cell extracts

38 The OPLS-DA prediction model can separate BAP1 WT and BAP1 +/- individuals and diti is NOT influenced by the year of collection, age or gender 38

39 The OPLS-DA model we established can predict BAP1 status in BAP1 unknown sample 39

40 Aloha and Mahalo!