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Oltre la chemioterapia prof. Giuseppe Naso ONCOLOGIA MEDICA POLICLINICO UMBERTO I prof. Giuseppe Naso ONCOLOGIA MEDICA POLICLINICO UMBERTO I.

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Presentation on theme: "Oltre la chemioterapia prof. Giuseppe Naso ONCOLOGIA MEDICA POLICLINICO UMBERTO I prof. Giuseppe Naso ONCOLOGIA MEDICA POLICLINICO UMBERTO I."— Presentation transcript:

1 Oltre la chemioterapia prof. Giuseppe Naso ONCOLOGIA MEDICA POLICLINICO UMBERTO I prof. Giuseppe Naso ONCOLOGIA MEDICA POLICLINICO UMBERTO I

2 Recent gene-profiling studies have nicely confirmed that ER- positive and ER- negative breast cancer are essentially two different disease M.J.Piccart-Gebhart: JCO vol.21, 8: 2003

3 ER+ ER- HER-2+?

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5 EGF TGF Amphiregulin -cellulin HB-EGF Epiregulin Heregulins NRG2 NRG3 Heregulins -cellulin Cysteine-rich domains Tyrosine kinase domain ErbB-1 Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 ErbB-4 Her4 C-terminus 100 44 82 33 36 59 24 48 79 28 The EGFR (ErbB) family and ligands

6 R K R K Cell surface

7 R K R K

8 R K R K PI3K Shc Grb2 Ras Sos Raf MEK1/2 Akt MAPK PTEN GSK-3 mTOR FKHR Bad Intra-Cellular Signaling NF- [PI4P,PI4,5 P 2 ][PI3,4P 2 PI3,4,5 P 3 ]

9 R K R K Cell surface PI3K Shc Grb2 Ras Sos Raf MEK1/2 Akt MAPK PTEN GSK-3 mTOR FKHR Bad Intra-Cellular Signaling NF- [PI4P,PI4,5 P 2 ][PI3,4P 2 PI3,4,5 P 3 ] p27 Gene Transcription/ Cell Cycle Progression

10 R K R K Cell surface SurvivalProliferationAngiogenesisMetastasis Cellular Responses PI3K Shc Grb2 Ras Sos Raf MEK1/2 Akt MAPK PTEN GSK-3 mTOR FKHR Bad Intra-Cellular Signaling NF- [PI4P,PI4,5 P 2 ][PI3,4P 2 PI3,4,5 P 3 ] p27 Gene Transcription/ Cell Cycle Progression rho rac

11 12 KK SHC PI3K GRB2 SOS AKT RAS PTEN mTOR FKHRGSK-3BAD Cell cicle progression Survival RAF MEK 1/2 MAP Anti ErbB1-2 receptors Mabs (Trastuzumab, 2C4, C225) HER1,HER2,HER4, Tyrosine Kinase Inhibitors (ZD 1839, OSI 774, EKB 559, GW 2016, CI 1033) Ras farnesyl transferase Inhibitors (BMS 214662, R115777) RAF inhibithors mTOR inhibitors (CCI 779) Mek inhibitors (CI 1040)

12 ER AF1 AF2 ESTRADIOLO ERE ATTIVAZIONE COMPLETA DELLA TRASCRIZIONE ER TAMOXIFEN AF1 AF2 EREATTIVAZIONE PARZIALE DELLA TRASCRIZIONE (solo AF1) Meccanismo dazione di Estradiolo e Tam a confronto

13 ER AF1 AF2 ESTRADIOLO ERE ATTIVAZIONE COMPLETA DELLA TRASCRIZIONE ER AF1 AF2 BLOCCO COMPLETO DELLA TRASCRIZIONE Es A.I. FASLODEX

14 In most cases AF-1/AF-2 are present in resistant tumours, and in many of these its activity continues to regulate tumour growth

15 Tyrosine Kinase GRB2 SOS ras-GDPras-GTP raf MEK MAPK ATP forma inattivaForma attivata fos myc jun MAP La cascata delle chinasi della via ras

16 Tyrosine Kinase GRB2 SOS ras-GDPras-GTP raf MEK MAPK ATP forma inattivaForma attivata fos myc jun MAP La cascata delle chinasi della via ras AKT AF1 COREPRESSORE COATTIVATORE MAP ATP Hormone-dependent growth

17 Che succede se si utilizzano contemporaneamente un antiestrogeno e un inibitore della TK attivata dagli EGFRs ?

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22 Effects of ER and EGFR blockade are: Reproducible: Total cell kill has been achieved in 5/6 experiments by 4 months using Tamoxifen and Iressa Seen with other anti-hormonal drugs: Faslodex plus Iressa achieved a total cell kill by 3 months Observed in other cell lines: T47D cells show equivalent early responses

23 Role of HER2 in breast cancer HER2 gene amplification or receptor overexpression occurs in approximately 25 % of breast cancers HER2-positive tumours are associated with poor prognosis

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25 HER2 status as a prognostic indicator n=86 node-positive patients/Southern blot assay/median follow-up 46 months ER = oestrogen receptor PR = progesterone receptor Slamon DJ et al. Science 1987; 235: 177–182

26 HER2 status as a prognostic indicator: Disease-free survival of node-positive breast cancer patients related to HER2 status 100 80 60 40 20 0 0122436486072 Disease-free survival probability Time (months) HER2 gene <3 copies HER2 gene 3 copies Log rank p=0.001 Seshadri R et al. J Clin Oncol 1993; 11: 1936–1942

27 HER2 status as a prognostic indicator: Survival of node-negative breast cancer patients related to HER2 status 1.00 0.75 0.50 0.25 0 Cumulative probability 024487296120144 Not amplified Amplified Amplified: >10 copies/nucleus Not amplified: <3 copies/nucleus Borderline: excluded Time to death (months) Log rank p<0.001 Ross JS, Fletcher JA. Stem Cells 1998; 16: 413–428

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29 HER hierarchy

30 Bivalence of EGF-like ligands

31 Relative potency of HER dimers

32 HER2-promoted recycling of HER1 cbl

33 Eligible patients (n=469) No prior anthracyclines Prior anthracyclines Paclitaxel (n=96) Trastuzumab + Paclitaxel (n=92) AC (n=138) Trastuzumab + AC (n=143) Metastatic breast cancer erbB2 overexpression No prior chemotherapy for MBC Measurable disease KPS 60% Slamon et Al N Engl J Med, March 2001 Herceptin ® in breast cancer: what evidence do we have?

34 Slamon DJ at al. 2001 os = p 0.05

35 Herceptin + Taxani (+/- Platino) TTP (3 studi randomizzati) Slamon NEJM 2001 Robert SABCS 2002 Marty ECCO 2003 p=0.001

36 Herceptin + Taxani (+/- Platino) OS (3 studi randomizzati) Slamon NEJM 2001 Robert SABCS 2002 Marty ECCO 2003 p=0.5 p=0.001 p=NR

37 Goal of the second-generation HER2 programme For example Better response rate Longer duration of response More clinical benefit in tumours that express intermediate (2+ or 1+) or even low levels (0) of HER2 Develop an agent with clinical activity superior to Herceptin ®

38 Pertuximab (2C4)

39 Anti-HER2 epitope map Extracellular domain CRD-2 Intracellular domain TK CT CRD-1 Bald L, Fendly B 7C2 (aa 23–53) Herceptin ® (aa 529–625) 2C4 Pertuximab (aa 22–584)

40 Inhibition of heregulin binding by 2C4, a monoclonal antibody to HER2 Bound/total 2C4 (nM) 0.10 0.08 0.06 0.04 0.02 0.00 0.1110100 HER2:HER3 HER3

41 Inhibition of ligand binding by 2C4 to HER2-containing receptor complexes EGFR/HER2 HER3/HER2 HER4/HER2 Receptor combination EGF HRG Relative ligand binding (%) 100 80 60 40 20 0 Control 2C4

42 Effect of Herceptin ® or 2C4 on ligand-mediated MAP kinase activation EGF–+++–––––– TGF ––––+++––– HRG–––––––+++ 2C4––+––+––+– Herceptin ® –––+––+––+

43 Summary In contrast to Herceptin ®, 2C4 is very effective in Blocking HER2 association with other HER family members Inhibiting HER2 activation and subsequent downstream signalling suppressing the growth of tumours with ligand-activated HER2

44 TC neo-ANGIOGENESIS NC CELL GROWTH HYPOSSIA (HIF-1 HIF-2) CELL GROWTH (Apoptotic blockade) neo-LYNPHOGENESIS VEGF-A VEGF-B VEGF-C VEGF-D ONCOGENES ACTIVATION ONCO-SUPPRESSOR GENES INACTIVATION MSR – NER – BER - OSR

45 The switch to an angiogenic phenotype represent a pivotal step in the multistage process toward malignancy (Folkman 1996) For solid tumors to grow beyond 1-2 mm 3 they require increased access to oxygen and nutrients from the blood supply (Folkman 1971) 1-2 mm 3INTRODUCTION Angiogenesis is required for solid tumor growth

46 Tumor angiogenesis begins when growing tumors, in response to hypoxia or other stimuli, secrete angiogenic factors Vascular endotelial growth factor is one of the most potent promoters of angiogenesis and has been identified as a fundamental regulator of tumor neovascolarizzazion INTRODUCTION Solid tumors stimulate angiogenesis by secreting angiogenic factors

47 INTRODUCTION Tumor angiogenesis promotes tumor growth and metastasis The creation of new blood vessels and lymphatic tissue by solid tumors allows them to enlarge and to metastasize to distal sites Inhibition of tumor angiogenesis, therefore, has the potential to inhibit tumor growth and spread VEGF levels apper to have prognostic significance in human tumors ( LAM, breast cancer, colon cancer,hepatocellular cancer, NSCLC and ovarian cancer)

48 The vascular endothelial growth factor (VEGF) family are critical tumor secreted signaling molecules that stimulate angiogenesis and lymphangiogenesis There are five members of the VEGF family (VEGF-A, placental growth factor, VEGF-B, VEGF-C, VEGF-D, VEGF-E) VEGF is a diffusabile endothelian cell-specific mitogen pro-angiogenic factor that increases vascular permeability VEGF-B VEGF-A VEGF-E VEGF-C VEGF-D INTRODUCTION The VEGF family are critical tumor-secreted angiogenic factors

49 VEGFR-1 is activated by VEGF-A and VEGF-B VEGFR-2 is activated by VEGF-A, VEGF-C, VEGF-D, and VEGF-E VEGFR-3 is activated by VEGF-C and VEGF-D Different VEGF family members bind and activate different VEGF receptors on endothelial cells

50 Monoclonal antibody, specific for VEGF A Derived from the murine antibody A4.6.1, comprises 93% human antibody and 7% murine derived antigen-binding-protein, the humanization proving a longer half-life and less immunogenicity Able to neutralize the biological properties of human VEGF, including endothelian cell mitogenic activity, vascular permeability-enhancing activity and angiogenic properties( Kim K.1992) The antibody did not recognize the other growth factor tested including FGF, EGF, PDGF BEVACIZUMAB (avastin; Genentech)

51 BEVACIZUMAB: Preclinical Studies Extensive preclinical studies have demonstrated the efficacy in different cell lines subcutaneously injcect into nude mice ( Kim KJ 1993) while did not reveal a direct effect on the growth of tumor cells (Warren RS 1995) TUMOR SUPPRESSION IS MEDIATED THROUGH INHIBITION OF NEOVASCULARIZZATION Warren and coworkers demonstrated that treatment with anti- VEGF ab was effective in suppressing primary tumor growth as well liver metastatis growth in a murine model of Colorectal cancer

52 BEVACIZUMAB: Clinical Studies More than 30 clinical trials with Bevacizumab in solid tumors and hematologic malignancies are planned, ongoing or recenttly completed In general, the therapeutic strategies being evaluated can be diveded into the following categories: Bevacizumab monotherapyBevacizumab monotherapy Bevacizumab in combination with chemotherapy or radiotherapyBevacizumab in combination with chemotherapy or radiotherapy Bevacizumab in combination with other putative anti-angiogenic strategies ( low-dose INF, thalidomide..)Bevacizumab in combination with other putative anti-angiogenic strategies ( low-dose INF, thalidomide..) Bevacizumab in combination with tumor-target therapies ( erlotinib, trastuzumab, imatinib)Bevacizumab in combination with tumor-target therapies ( erlotinib, trastuzumab, imatinib) Bevacizumab in combination with immunotherapyBevacizumab in combination with immunotherapy

53 Bevacizumab phase I-II clinical trial efficacy results in breast cancer 3mg/kg 10mg/Kg 20mg/Kg Total N° of Pts 18 41 16 75 Objective Response Rate (n/%) 1 (5.6%) 3 (7.3%) 1 (6.3%) 5 (6.7) Median Response Duration (months) 3.1 5.6 8.0 5.6 Stable disease at 154 days 2 (11%) 7 (17%) 3 (19%) 12 (16%) Median Survaival (months) 14.0 12.8 7.6 10.2 Sledge GW et al. JCO 2003

54 BEVACIZUMAB:Summary of trials in solid tumor

55 Inhibition of Ubiquitin-Proteasome pathway Bortezomib

56 Lemivita di una proteina è determinata in gran parte dal suo residuo terminale Residui altamente stabilizzanti (t1/2 >20 ore) Ala Cys Gly Met Pro Ser Thr Val Residui intrinsecamente destabilizzanti (t1/2= da 2 a 390 min.) Arg His He Leu Lys Phe Trp Tyr Residui destabilizzanti solo dopo modificazione chimica Asn Asp Gln Glu

57 The Proteasome: Enzyme with Important Impact on Multiple Regulatory Pathways Is found in all eukariotic cells, from yeast to man Is present in the cytoplasm and nucleus Degrades more than 80% proteins

58 Tumor microenvironment Extracellular matrix

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70 Inibitori di traduzione del segnale: Ras e FT-I

71 Neoplastic Transformation Inactivation of Rb and p53 Immortalization telomerase activation Activation of ras-pathway Weinberg, A. 2003

72 Farnesyl-transferase inhibitors The ras gene is mutated in one fifth of all human cancers.

73 RAS

74 ras (p21) G-Protein (intrinseca attività GTP-asica) ras agisce come un interruttore molecolare che si alterna da una forma inattiva (ras-GDP) ad una forma attiva (ras-GTP)

75 The switch function of RAS

76 Tyrosine Kinase GRB2 SOS ras-GDPras-GTP raf MEK MAPK ATP forma inattivaForma attivata fos myc jun MAP La cascata delle chinasi della via ras

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78 Prenilazione Carbossi-terminale (C-terminale) CAAX CC – CXC - CCXX Farnesilazione es.: ras,rho Geranil-geranilazione es.:rab C=cisteina A=residui alifatici X=qualunque aminoacido Gruppo Farnesile (C15) Gruppo Geranilgeranile (C20)

79 C15

80 Classes of FTase inhibitors Peptide CAAX peptidomimetics : L-778,123 Nonpeptide CAAX peptidomimetics : Tipifarnib, Sarosat Bisubstrate Inhibitors : BMS-214662 Inhibitors classes I Inhibitors classes II

81 Peptide CAAX peptidomimetics : L-778,123 Nonpeptide CAAX peptidomimetics : Tipifarnib, Sarosat Bisubstrate Inhibitors : BMS-214662

82 Phase I-II studies with farnesyl-trasferase inhibitors in clinical development DrugCompany Route RD DLT Activity R115777 Janssen/ oral 300 mg bid, 7-14 Myelosuppression, 1 PR NSCLC Zarnestra Ortho-Biotechfatigue, Tipifarnib neurotoxicity,skin SCH66336Schering – Ploughoral 350 mg bid, 7-14Nausea, vomiting, 1 PR NSCLC Sarosar diarrhea, fatigue BMS-214662Bristol Meyer iv 300 mg/m2 24 h liver, neuropathy - Squibb c.i weekly L-778,123Merckiv560 mg/m2 c.i. 7-14 Myelosuppression, sonnolence, fatigue -

83 Tipifarnib (R115777): Phase II clinical trials Johnston SR.: SABCS 2000

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85 Combination of 2 selective inhibitors approach

86 EGFR VEGF Endothelial cells Cancer cells Angiogenesis Cell Proliferation Tortora 2004 Erlotinib Cetuximab, etc Bevacizumab etc. Combined blockade of EGFR and VEGF

87 Jung YD et al, Eur J Cancer 2002; 38: 1133-40. Ciardiello F et al. Clin Cancer Res 2000; 6: 3739-3747

88 EGFR VEGF Endothelial cells Cancer cells TGF KDR Angiogenesis Cell Proliferation ZD6474 Tortora & Ciardiello, 2002 ZD6474 Inhibits KDR and EGFR

89 ZD6474 is a potent orally-active inhibitor of VEGF-signalling Inhibits VEGF-induced hypotension, vascular permeability and angiogenesis in vivo Broad-spectrum anti-tumour activity in mouse models consistent with an anti-angiogenic mechanism Dosing for > 100 days has been feasible in man Phase I adverse events generally mild Anti-VEGF activity suggested by hypertension and delay in dermal wound angiogenesis ZD6474: Phase I Studies

90 controllo Gefitinib Gefitinib >ZD6474 controllo Cetuximab Cetuximab > ZD6474 ZD6474 inibisce la crescita di tumori divenuti resistenti a Gefitinib o Cetuximab Ciardiello et al., 2004

91 AZD2171 Enzastaurin Agents affecting all VEGFRs

92 AZD2171 AZD2171 is an oral therapy with potential application in multiple tumor types AZD2171 has activity against VEGF receptors 1, 2 & 3- No activity on EGFR Phase I clinical studies in refractory solid tumors underway Manageable toxicity in early phase I AZD2171 VEGFR3 (Flt-4) VEGFR1 (Flt-1) VEGFR2 (KDR)

93 Lilly Research Laboratories Not for Promotional USE Company Confidential Copyright © 2004 Eli Lilly and Company MW = 552.08 Potent oral selective inhibitor of PKC (IC 50 = 0.006 M) Is an acyclic indolylmaleimide that competes with the ATP binding site preventing substrate phosphorylation Inactive against other kinases Antiangiogenic activity in preclinical models. Well tolerated in preclinical toxicology studies. Administered once daily PO. Normal volunteer and Phase I studies completed. Phase II studies ongoing. Enzastaurin

94 Lilly Research Laboratories Not for Promotional USE Company Confidential Copyright © 2004 Eli Lilly and Company Receptor VEGF DAGIP3/Ca 2+ PKC- COX2 mRNA Tumor invasion Angiogenesis ENZASTAURIN Activation GSK3 AKT Caspase 9 Apoptosis Protein translation IL-6 IL-8 PKC- and the Proposed Action of Enzastaurin on Angiogenesis and Apoptosis

95 Pericytes protects endothelial cells from apoptosis and overexpress PDGF-R PDGF-R is overexpressed by many tumors PDGF-R and VEGF cooperate Blood vessels are not only endothelial cells ( L.M. Ellis ) Improving Anti-VEGF therapy by expanding the targets

96 PTK787 SU11248 Multiple target agents affecting VEGFRs (and PDGF-R)

97 Complete inhibitor of the VEGF receptor tyrosine kinases VEGFR1(FLT-1), VEGFR2 (KDR) and VEGFR3 (FLT-4). It also inhibits PDGF-R. Well tolerated up to 1250 mg/day (phase III dose, used up to 15 mo) Rapidly absorbed (1 to 2.5 hours), T1/2: 3-6 hrs Renal metabolism PTK787/ZK 222584 Formula: C 24 H 21 N 4 Cl MW = 346.82 PTK787/ZK 222584 Formula: C 24 H 21 N 4 Cl MW = 346.82 PTK/ZK: A multi-VEGF receptor tyrosine kinase inhibitor

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99 Conclusioni (I)

100 Genes changing in association with response Good responders Poor responders 14 genes shared biologically responsive biologically refractory 256 genes 49 genes

101 Response in patients treated with FAC/paclitaxel preoperative chemotherapy Hortobagyi GN ASCO 2002 150 Genes pCRNoPCR

102 Conclusioni (II)

103 …A targeted therapy only works when the target is present and plays an important role in the cancer…

104 IRESSA and NSCLC: a very important lesson No target 10-12% of Response Target 100% of Response

105 Prof. Enrico Cortesi dott.ssa A. De Benedetto dott. A. Lugini dott. A. Padovani dott.ssa R. Ferraldeschi dott.ssa G. Dauria dott. P. Ceratti dott.ssa N. Pizzardi dott.ssa L. Mentuccia dott.ssa M. Mazzoli dr. V. Picone Oncologia Medica B Univ. Di Roma La Sapienza


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