Consortium led by Asbestos Diseases Research Institute (ADRI)

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1 Translating Research into Better Outcomes for Patients with Asbestos-Related Disease and their Families Professor Nico van Zandwijk Consortium led by Asbestos Diseases Research Institute (ADRI)

2 AUSTIN CRGH IASLC CINSW FLINDERS UWA PCH POW RNSH RPAH CCNSW CINSW NHMRC Peter Mac UTS Garvan UniMelb AMWU ACHS CRGH ADRI MONASH Guidelines Fibres Education UWA SPH Register II. Standard of Care I. Prevention ADRI III. Molecular Characterization IV. New Drug Development Early Clinical Trials NHMRC Samples ALTG BioBank Fresh Archival In vitro models RNSH RPAH RPAH CRGH Strathfield Pr. DNA Profiling Protein microrna Molecular intervention microrna RNAi Library UWA Kolling Institute CRGH Garvan Garvan UWA/LIWA UWA/LIWA ADRI ADRI ADRI IASLC UTS APAF Strathfield Pr. UNSW In vivo models RPAH Flinders MC CRGH CRGH CRGH BWCRL UTS NKI ANZAC NKI

3 ADRI: Basic Research MalignantMesothelioma Molecular Characterisation Novel therapeutic targets Circulating mirnas mirna/protein in Tumour samples Chemosensitising targets New druggable targets

4 NEW BIOMARKERS FOR MALIGNANT MESOTHELIOMA (MM): For rapid Diagnosis, estimation of Prognosis and prediction of Response to Therapy Cell-free micrornas Plasma/serum protein markers Tumour proteins&micrornas Biobank:Archival MM series (paraffin) &High-quality frozen blood and tissue samples from MM patients and controls Archive 160 cases Frozen 50 cases

5 INVESTIGATING NEW THERAPEUTIC OPTIONS FOR MALIGNANT MESOTHLIOMA New targets RNAi screening for new targets, validation New models Epigenetics & tumour suppressor genes biology & targets In vitro model of chronic asbestos exposure to test preventive measures Spheroids for in vitro analysis of candidate targets Rat syngraft model for in vivo characterisation and drug testing Accessing pharma pipelines

6 Markers for early detection of malignant mesothelioma At present there is no reliable marker for the early stages of the disease Mesothelin, osteopontin and megakaryocyte-potentiating factor levels in serum have been evaluated, but have not yet achieved the specificity and sensitivity required for routine screening Circulating nucleic acids, including micrornas (mirnas), show promise Circulating nucleic acids, including micrornas (mirnas), show promise as biomarkers of many pathophysiological conditions, including a number of cancers.

7 Extracellular mirnas Stable mirnas are readily detectable in various bodily fluids: Blood (plasma/serum) Saliva Urine Breast milk Detected in (& indicative of): Cancer Heart disease Liver failure Pregnancy

8 Evaluation of candidate micrornas as specific & sensitive early markers of mesothelioma

9 Biomarker A biomarkeris defined as a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes or pharmacological responses to a specified therapeutic intervention. Biomarker Definitions Working Group: Clin Pharmacol Ther 2001; 69: 89-95

10 Predictive and Prognostic Biomarkers Prognostic factor: provides information about the patient s overall cancer outcome regardless of treatment Predictive factor: is a patient or tumor characteristic that identifies a better outcome from treatment

11 Inflammation & Mesothelioma Symptoms related to systemic inflammation are common in Mesothelioma Fever/sweats Anorexia Weight loss Known prognostic factors in Mesothelioma Elevated number of white cells in the blood Elevated number of platelets in blood

12 Research Question Is blood NLR a useful prognostic test for Mesothelioma patients? Hypothesis : Patients withlow NLRhave abetter survival?

13 Patients & Methods Retrospective chart review

14 Retrospective Chart Review 173 MM patients identified

15 Overall Survival Median survival: 10.6 months

16 Gender Median Survival: Female: 15.2 months Male: 9.8 months P=0.044

17 Histological Subtype Median Survival Epithelioid: 15.2 months Non-epithelioid: 5.8 months P<0.001

18 NLR Median Survival <5: 16.7 months 5: 6.6 months P<0.001 Kao et al, Clin Cancer Res 2010

19 NLR in chemotherapy-naïve group Median Survival <5: 19.2 months 5: 6.6 months P<0.001 HR % CI, p<0.001

20 NLR in patients who received therapy Median Survival <5: 10.4 months 5: 3.8 months P=0.025 HR % CI, p=0.028

21 RNAi screen for potential targets Rational target selection Function Nucleic acid metabolism DNA repair & replication Short MM survival genes Poor prognosis in solid tumours Gene groups (and examples) Purine synthesis (IMPDH2, AK1), Pyrimidine synthesis (TYMS, DHFR, TK1, TK2, UMPS, CTPS, DGUOK, DCK, DTYMK), Other/both (RRM1, RRM2, DPYD, PRPS1, NME1, NME2) Cyclins (CCNB1, CCNB2), cyclin-dependent kinases (CDK1, CDC6, CDC25), regulators (CDK7), kinases (PRKCI), others (CHEK1, BIRC5, EME1, FANCA, GTFH2, RAD21, PLK1) HSP90B1, ANX4, MTDH, GRAOV2, TSG101 GBX2, MKI67, HCFC1, HEC, RNF2, USP22, BUB1, CCNB1 Transcription factors Future therapeutic application? Hypoxic/glycolytic genes (HIF1A, ARNT), drug metabolism (NFE2L2), resistance (YBX1) & replication (E2F2, E2F7)

22 Latency Period (between first asbestos exposure and diagnosis) Malignant mesothelioma years Lung Cancer 20 years Long period of carcinogenesis allowing intervention = chemoprevention

23 Research at the Asbestos Diseases Research Institute(Sydney) Prevention through Education ( increasing Awareness about the dangers of Asbestos in Australia/Asia) National Guidelines for Treatment of Mesothelioma New Markers for Early detection/diagnosis New Markers for Prognosis/Prediction of Response to therapy New drug development/ new treatment targets (Testing new molecules in cell cultures/ experimental animals/ clinical trials) New methods to dissolve asbestos fibres trapped in the lungs of high-risk individuals (experimental/animal phase)

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