1. PLATINUM RESISTANCE AND SENSITIVITY IN RECURRENT OVARIAN CANCER VANDA SALUTARI UNITÀ DI GINECOLOGIA ONCOLOGICA UNIVERSITÀ CATTOLICA DEL SACRO CUORE, ROMA

5. Platinum sensitivity concept and new drugs (bevacizumab) Non high grade serous histotypes Changing the paradigm of platinum sensitivity Is there a place for a new classification? Open questions …….

6. The resistance to platin is multifactorial in cancer cells  Cisplatin can be pumped out of the cell by ATP7B  Nucleotide excision repair pathway (NER)  PARP repair of DNA damage  Aurora kinases may protect cells against chemotherapy by blocking apoptosis  Extracellular matrix produces favorable changes in tumor microenvironment that inhibit chemotherapy induced apoptosis

8. Trials exploring reversal of cisplatin resistance

9. THE EVOLUTION OF RESISTANCE

10.  Gene Ipermetilation Upregulation DNA methiltransferas e  cell adhesion  thgh junction  Leucocyte transepithelial migration Methilation inhibitors± platinum

16. Molecular changes associated with acquired resistance Reversion of BRCA germline mutations Low metilation of BRCA promoter  gene expressed at comparable levels to HR intact tumors Fusion of the promoter of ABCB1  increase in MDR1 NEWS PARP I

17. Reversal of cisplatin resistance strategies

21. Trabectedin Effects on Tumor Cells and Microenvironment A multitarget agent Adapted from D'Incalci & Galmarini. Mol Cancer Ther. 2010;9:2157-63. XPG XPF RNA pol II DNA binding and distortion DNA repair Transcription inhibition Displacement of TF and FP Pre-treatmentCycle 3 Pre-treatmentCycle 2 Tumor Microenvironment TF Tumors are organ-like structures

22. Poveda A, et al. Cancer Treat Rev. 2014;40:366-75.

23. Trab + PLD Platinum PLDPLD Later lines Increased PFSIncreased PFI Increased Overall Survival Sequence Effect – Hypothesis OBSERVATION Benefit in OS greater in PPS patients receiving Platinum right after OVA-301 -Patient selection: only the best responding patients receive Pt -But, significant extension of survival in those patients with sequence Trab+PLD – Pt, vs PLD – Pt HYPOTHESIS Sequence Effect by which Trab+PLD enhances the response to a subsequent platinum in addition to its initial direct effect Poveda A, et al. Cancer Treat Rev. 2014;40:366-75.

24. Sequence Effect – Evidence in Vitro D’Incalci M, et al. AACR-NCI-EORTC ConferenceInternational Conference on Molecular Targets and Cancer Therapeutics October 19-23, 2013. Boston, MA. C93. 24 Resistance to Trabectedin improves sensitivity to Platinum in STS and ROC cells

25. Resistance to Trabectedin Sensitizes to Platinum – in Vivo 25

26. Depletion of NER Proficient Tumor Cells Resistance to Trabectedin improves sensitivity to Platinum in STS and ROC cells D’Incalci M, et al. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 19-23, 2013. Boston, MA. Abstract C93 26

30. Integration of PARP inhibitors and anti- angiogenics

31. Selected immunotherapies under evaluation for various tumour types www.clinicaltrials.govwww.clinicaltrials.gov. Accessed September 2014. Haematologic CTLA-4 pathway targeting agents Targeting CD27 Melanoma Vaccines CTLA-4 pathway targeting agents PD-1 pathway targeting agents LAG-3 protein targeting agents GITR targeting agents CD40 agents RCC Vaccines CTLA-4 pathway targeting agents PD-1 pathway targeting agents LAG-3 protein targeting agents Pancreatic Vaccines CTLA-4 pathway targeting agents PD-1 pathway targeting agents CD40 agents Ovarian Vaccine CTLA-4 pathway targeting agents CRC CTLA-4 pathway targeting agents PC/CRPC Vaccines CTLA-4 pathway targeting agents PD-1 pathway targeting agents Breast CTLA-4 pathway targeting agents LAG-3 protein targeting agents Cervical CTLA-4 pathway targeting agents GIST CTLA-4 pathway targeting agents HCC CTLA-4 pathway targeting agents NSCLC/SCLC Vaccines PD-1 pathway targeting agents CTLA-4 pathway targeting agents NHL, AML, CLL, lymphoma Vaccines PD-1 pathway targeting agents CD40 agents Anti-4-1BB agents Anti-KIR agents

36. Thank you

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42. Nibrin may be Predictive of Trabectedin Efficacy in Ovarian Cancer Adapted from Stracker & Petrini. Nat Rev Mol Cell Biol. 2011;12:90-103 42 Nibrin (NBS1) is part of the DNA repair complex MRE11 Responsible for Nijmegen Breakage Syndrome – deficiency in B Lymphocytes Linked to different malignancies, including hepatocarcinoma, pancreatic cancer, prostate cancer, and others Tested among other related molecules as predictive factor of the efficacy of trabectedin in Ovarian Cancer patients

43. Nibrin may be Predictive of Trabectedin Efficacy in Ovarian Cancer Biomarker Analysis from Registration Study OVA-301 13 proteins related to cell proliferation, cell cycle checkpoint signaling, and DNA repair were analyzed by IHC Low protein expression of nibrin (≤5% positive tumor cells) at diagnosis correlates with a better PFS and OS Aracil M, et al. 18th ESGO International Meeting, October 19-22, 2013. Liverpool, UK 43 Platinum Sensitive patients treated with Trabectedin + PLD (N=59) PFS Nibrin  5% (N=12, C=5) Median PFS=11.5 m Nibrin >5% (N=47, C=24) Median PFS=9.6 m p=0.08 Cumulative probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Time (months) 02468101214161820222426 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Time (months) 0369121518212427303336394245 OS Nibrin  5% (N=12, C=8) Median OS=not reached Nibrin >5% (N=47, C=6) Median OS=25.7 m p=0.002

45. CONCLUSION