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Platinum resistance and sensitivity in recurrent ovarian cancer INNOVATION IN GYNECOLOGIC CANCER: OPTIMAL THERAPY, QUALITYOF LIFE, PRECISION MEDICINE NAPOLI 26 GIUGNO 2015 Gustavo Baldassarre, MD Experimental Oncology 2 CRO-National Cancer Institute Aviano - Italy Proposed Mechanisms of Platinum resistance Mechanisms Molecular mediators Reduced Uptake Increased Efflux Increased Inactivation Down regulation of CTR1 Up-regulation of ATP7A/7B Increased levels of GSH/GST and/or Metallothionins Increased DDR Deregulated cell cycle progression CDDP binding protein Increased HR and/or NER activity Up-regulation of Cyc E Decreased levels of VDAC Regulation of Apoptosis and p53 action Increased BCL2/deacreased Bax proteins Deregulation of caspases P53 Mutation/Inactivation Increased IAPs expression (e.g. BIRC5) Regulation of Survival and authophagy Increased HER2 Increased HSPs Decreased ROS generation Modified From Galluzzi et al. Oncogene 2012 Altered miR-484 expression in EOC defines an “angiogenic” phenotype resistant to chemotherapy Modulate Angiogenesis ? Vecchione et al. PNAS 2013 Is antiangiogenic therapy a method to improve drug sensitivity? Modulate Angiogenesis ? Tumor vessels are highly inefficient and do not support the proper delivery of chemotherapy to all tumor areas Different molecular pathways should be probably altered at the same time to modulate vessels permeability and tumor perfusion It is likely that angiogenic modulators will fail as antitumor agent alone but that they will be extremely useful in combination with chemotherapy Is it realistic to use anti-angiogenic compounds targeting different pathways at the same time? Are we able to use angiogenic modulators in combination with chemotherapy using the right dose at the right time in the right patient? Platinum mechanism of resistance: New Insights Up-regulation of ABCB1 (MDR1) Up-regulation of Cyc E Inactivation of RB1 and RAD51 Reversion of BRCA1/2 Mutation Breakage of PTEN, FOXO1 and BCL2L11 genes Collectively, our findings underscore the heterogeneity and apparent adaptability of the HGSC genome under the selective pressure of chemotherapy, and indicate that overcoming resistance to conventional chemotherapy will require a diversity of approaches. Modified From Patch et al. Nature 2015 Are we ready to transfer the “genomic approach” to the clinic? Modified From Dewey et al. JAMA 2014 Genomic characterization of Human cancer is of outmost importance Based on the current knowledge and technology we are probably not ready to transfer WGS to the clinic It will be conversely important to select defined actionable mutation involved in the onset of platinum resistance It is probably true that the best therapeutic option for the future will be the association of chemotherapy with specific synergic targeted therapy Identify patients that might benefit from different drug combination will be the future challenge GEP Signature of HGSOC define a group of patients with poor prognosis Generation of platinum resistant cells as a study tool Platinum resistant cells have specific GEP mRNA/lncRNA R1 R2 C1 C2 R1 R2 C1 C2 R1 R2 C1 C2 miRNA R1 R2 C1 C2 C1 C2 R1R2 C1 C2 R1R2 Platinum resistant cells have specific GEP mRNA/lncRNA miRNA Few coding and non coding genes are commonly altered by platinum in EOC These data support the view that resistant subclones pre-exists in EOC and/or that epigenetic changes play a major role in the acquisition of resistance Combined genomic and functional studies are necessary to unveil driver alterations Human cancers evolve as Darwinian adaptive systems Pla num Sensi ve (Rec >12 m) Intermediate Pla num Sensi vity (Rec >6 <12 m) Pla num Resistant (Rec <6m) Secondary Localiza ons Primary Tumor Hys tero -ann essi Bulk tumor mass ecto my Possible evolu on of HGEOC imagined as a Darwinian adap ve system Pla num Sensi ve Pla num Resistant Passenger Altera on Driver Altera on Chemo Induced Altera on Identification of genes synthetic lethal with platinum shRNA replicates with p-value<0.05 (Zscore normalization, moderated t-test and BH method of adjustment) Gene X CDDP Outocome 010301 040069 118983 001023 052975 056462 003393 - 045248 002848 007349 4 + + 062554 058998 072522 011461 083046 062733 009874 143937 121279 083046 121279 059263 N PP N Zscore 007349 059263 057018 078037 063263 018344 045663 052985 197225 194752 055675 003961 006570 001084 033611 050779 051388 010595 033581 057595 010354 072695 010432 057595 078037 118303139674 034066 044921 008686 036965 033601 040243 003785 003961 037812 045663 049705 011461 000588 050779050872 019881 019674 039985 033574 064490 034064 040243 074234 010300 139674 000583 018344 000229 003963 033524 244436 010587 010300 010485 003859 143937 057018 006575 013814 010354 049705 046527 062733 165404 010589 010587 037812 044921 055675 001016 001084 003706 040003 063263 022255 003951 005860 049704 057189 073346 003951 014629 244436 004045 050872 062555 000508 011304 005199 040098045664 058773 010390 003837 052985 057058 022385 033524 118983 000665 058773 004908 045320 000228 004012 005936006576007264 057189 115997 053079 045248 003963 052984 033611 004044 036970 058165 074233 020521 033501 048974 147821 235597 010432 040098 045665 046527 123325 003393 013720 000519 058885 007264 008037 017062 033505 073346 083757 018981 034066 107185 013168 004526 005946006498 022388 083368 001028 055425 000651 046424 010390 000228 006575 020307 049405 009825009947 004045 004012 048731 029426 001028 004266 034235 058885 064490 121207 074234 038740 017062 021467 019674 107185 006348 006497 244439 194752 045190 048731 001481 002749 004908004245 016776 010595 007921 033505 045665 045189 010262 036965 034064 003785 003837 006255 197225 009825 001065 002749 017279 049853 062555 008754 020307 001085 001268 033581 001009 045189 006039 029371 051311 026542 040123 046424 153659 007842 013563 051311 016291 045312 055425 001912 001268 022385 039926 049764 010589 003529 006593 006570 019009 018981 020352 058203 058998 072522 038740 005199 005801 029371 062554 118303 011210 000509 001427 006592 019080 050436 048974 083757 011210 034235 000519 000588 013720 018559 045190 058165 147821 014629 008760017392 019080 244438 008686 022037 033500 039749 005867 006576 007921 018917 009874 005936 165404 002484003580 004044 016291 036970 052984 021467 057374 123325 115997 040123 048493 051388 006498 029426 033596 083754 006174 040003 039749 057374 001024 003551 020069 022388 001051 013814 062800078299 000583 003859 005801 021939 039985 050778 010982 235597 010282 001024 003580 005946 008754 045312 046559 050778 001427 005860 001912 021508 017392 020352 033501 029082 033500 033574 219934 003703 006594 062550 019881 021508 056437 219934 010262 009947 000508 003551003596 004266 016776 049853 049764 056437 074233 078299 153659196963 000509 019009 007940 007176 003660 056543 057058 001009 011304 033561 017279 000651 001065 007626 007842 049855 049405 244439 001481 003596 022255 008037 029082029054 056543 026542 001051 003660 004526 006497 018559 021939 033596 048493 006593 013563 057373 007940 020069 046559 013168 006150 049855 057373 244438 001085 007176 029054 010982 006594 022037 033561 083368 196963 006255 004245 039926 050436 121207 006348005867 010282 003703 018917 003529 062550 062800 083754 002484 N N N P P N N N P N P P N 0 N P P N N N N N N NN N P N N N N N N N 000249 000514 000249 000514 000516 000516 001485 001485 N 004858 004000 005837 002892003575 003775 003595 003704 003842 003781 006177 003736 004587 006177 003704 003842 005302 003736 002325 003595 004587 004000 003575 004858 005837 002892 003775 N N N N 008747 N 018858 013460 008747 020192 019945 019802 019920 020193 020308 020308 019802 019920 020192 049278 049689 033534 036049 033580 039675 039914 033575 033580033534 036049 039837 039675039815 033575 039834 039914 039834 019945 N N N N 020193 018858 013460 N P N -2 + 052923 053388 052975 053079 052923 056462 049704 045664 006039 003706 000229 001016 P - 006592 006174 001023 2 + 040069 033601 008760 000665 - 053388 045320 002848 - 010485 010301 072695 049689 049278 039837 N N 052645 051880 051882 052938 051880 051882 052645 052938 N 002325 0 1000 sequence 058660 072315 074360 074360 062709 062709 057075 058660 057075 072315 194974196691 226466 010305 174055 010781 010305 010781 005302 500 N N N NN N NN N N N N N NN N N N N N NN NN N N N N N N N N NN N N N NN NN N N NN N NN N 196691 236560 255915 174055 236560 NN 255915 195146 194974 195146 1500 2000 Platinum mechanism of resistance: on target effects Deregulated cell cycle progression CDDP CDDP Palbociclib LE001 LY 2835219 CDKs Inhibitors LY2606368 MK-1775 AG-024322 CDK6 Knock-down sensitizes EOC cells to Platinum-induced cell death Ctr Sh IC50 = 201 μg/ml Cells Survival (% of Untreated) Absorbance CDK6 Sh IC50 = 105 μg/ml MDAH CDBCA μg/ml Ctr Sh IC50 = 5.7 μg/ml CDK 4 Vinculin CDK6 Sh IC50 = 0.2 μg/ml Cells Survival (% of Untreated) CDK 6 OVCAR-8 CDDP μg/ml Dall’Acqua et al. in preparation Conclusion Platinum resistance could be due to different molecular mechanisms It could be worth to explore antiangiogenic therapies as chemo-sensitizers CCNE2 gains are associated with de novo resistance Chemotherapy does not induces specific changes in cheomresistant HGSOC patients, suggesting that original heteroclonality of the tumors is responsible of acquired resistance Functional genomic approaches are valuable tools to find gene(s) involved in synthetic lethality with platinum treatment The work within multidisciplinary translational research group will likely represents the future of EOC care. ACKNOWLEDGEMENTS CRO National Cancer Institute -Aviano- Italy Experimental Oncology 2 Barbara Belletti, PhD Sara Benevol, BS Alessandra Dall’Acqua, PhD St. Sara D’Andrea, BS Ilenia Pellizzari, PhD Valentina Ranzuglia, PhD St. Maura Sonego, PhD Monica Schiappacassi, PhD Andrea Vecchione, MD PhD Gennaro Chiappetta & Daniela Califano MITO Translational Research Group The CRO OCTRG Clinical Oncology Roberto Sorio, MD Gynaecological Oncology Giorgio Giorda, MD Pathology Unit Vincenzo Canzonieri, MD Epidemiology Unit Jerry Polesel, PhD Università La Sapienza, Roma INT G. Pascale, Napoli Different Institutions
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