Personalized Treatment for Malignant Mesothelioma

Transcription

1 Personalized Treatment for Malignant Mesothelioma RN Taub (Onc) J Chabot (Surg) A Borczuk (Path) J Sonnet (Surg) M Kluger (Surg) R Fawwaz (Nuc. Med) E Hare (Onc) Columbia University Mesothelioma Center

2 Not all mesothelioma patients are helped by drugs Different DNA RNA Proteins

3 CELL DNA, RNA, PROTEIN NUCLEUS CHROMOSOMES DNA PACKED TIGHT DNA proteins DNA, RNA, PROTEIN

4 Gene chip technology can ---Help determine mechanisms of tumor intiation, progression, metastasis, and prognosis. ---Help diagnose new disease, detect minimal residual disease or recurrent disease. ----Help identify new DNA, RNA, or protein targets for new therapies.

5 Adeno/squam /Meso /ca /norm/ca /meso EARLY STUDIES OF GENE MICROARRAYS IN MESOTHELIOMA, A BORCZUK, R TAUB, C POWELL, ASCO 2002

6 16 Specimens b = biphasic e = epithelioid Microarray Clustering of Peritoneal Mesothelioma Specimens R index=1 D index=0

7 p16 P16 and Fascin Fascin

8 Deletion of p16, Increased Fascin in Biphasic Mesothelioma H&E P16 Fascin Epithelial P16 (+) Fascin (-) B Biphasic P16 (-) Fascin (+) Biphasic CFP FFF A Borczuk, MD

9 Sarcomatoid tumors grow faster and are more invasive. Normal Epithelioid Biphasic

10 Clustering of LCM dissected epithelioid mesothelioma Survival 60 days Survival 1960 days Unsupervised clustering using gene expression data U133Plus 2.0 Affymetrix arrays on LCM tumor cells. A Borczuk, MD

11 Clustering of LCM dissected epithelioid mesothelioma Survival 60 days Survival 1960 days Unsupervised clustering using gene expression data U133Plus 2.0 Affymetrix arrays on LCM tumor cells. A Borczuk, MD

12 Supervised class comparison -BRB tools software Good vs poor prognosis epithelial mesothelioma tumors Number of genes significant at level of the univariate test: 39 Global test: probability of getting at least 39 genes significant by chance (at the level) if there are no real differences between the classes: Gene expression decreased in poor prognosis epithelial mesothelioma (20 sets) p15, p16 cell cycle {Consider treating with FLAVOPRIDOL, MTAP strategies, ohters} DSCAML1, DTCN6 cell adhesion DTX4 - SLC7A2 aa transporter PTGS1 (COX1) LIMA,CMYA5 cytoskeleton PKDIL2, CDK5RAP2 differentiation SLAIN 1 Stem cell marker? FAM107B, MPPE1,LOC22170, MGC39372,MRIP - unknown Gene expression increased in poor prognosis epithelial mesothelioma (19 sets) Col3A1 ECM ANLN, NDE,CENPK,CENPF, SPBC24, KIF11 mitosis/spindle related EZH2 histone methylation; { treatable with VORINOSTAT} poor prognosis in prostate CA.; involved? Recruits DNA methyltransferase activity. MDM1 - unknown UHRF1 regulates TOPO2a expression. {treatable with DOXORUBICIN, OTHERS} LDLR LDL receptor Zinc finger TF motif (227921_at) - unknown TRIM59 - unknown PAK3 - unknown

13 OTHER CURRENT PROGRAMS IN GENOMIC NURTURED TREATMENT OF MESOTHELIOMA Antibodies to mesothelin, a protein produced abundantly by many mesothelioma cells, is being used for both detection and treatment. Some mesotheliomas produce a specific antigen, ESO-1, that is being used to produce a vaccine. Specific MicroRNA s, small RNA fragments that do NOT make protein but do regulate gene expression, have recently been identified and may be important in mesothelioma pathogenesis. Direct gene therapy is still on the horizon.

14 SUMMARY: Mesothelioma Management has always been personalized. Each patient s mesothelioma tumor possesses unique DNA, RNA, and protein sequences, which determine tumor growth rate, invasiveness, metastatic capability, and response to therapy. Each patient has a unique medical past history, family history, unique asbestos exposure history, unique set of comorbidities. Each patient responds in a unique way to chemotherapy, radiation, immunotherapy, symptom management, and his/her doctor. Each patient has unique: hopes, aspirations and coping skills.

15 Conclusion We don t know enough about mesothelioma to genomically personalize treatment one patient at a time. Genomic personalization may be mostly relevant for defining different subsets of mesothelioma patients. Genomic technology will aid in detection of minimal disease by blood tests, and will define many future targets for drug treatment, and possibly for directed gene therapy.