Particolarità molecolari delle neoplasie sarcomatose: Quale lezione biologica possiamo trarre per tutte le altre neoplasie? Bruno Vincenzi, MD PhD Università Campus Bio-Medico di Roma
Defining sarcoma Rare tumors (less than 12.000 case in U.S.A in 2012) Clinical heterogeneity (good vs. very dismal prognosis) Histologic heterogeneity (~ 70 STSs) Molecular heterogeneity
Defining sarcoma: role of molecular heterogenety DISEASE CHROMOSOMAL CHANGE FUSION GENE FREQ Ewing s, PNET t(11;22) or t(21;22) EWS-FLI1, EWS RG 95% Synovial sarcoma t(x;18) SYT-SSX 95% Myxoid liposarcoma t(12;16) CHOP-TLS 80% Clear cell sarcoma t(12;22) EWS-ATF1 50-90% DIAGNOSIS THERAPY Desmoplastic SRCT t(11;22)(p13;q12) EWS-WT1 > 50% Alveolar rhabdomyosarcoma t(2;13) PAX-3-FKHR 70% Alveolar rhabdomyosarcoma t(1;13) PAX-7-FKHR 20% Osteosarcoma 1p-, 6q-,9p-, 13q-, 3q-, others NA Myxoid chondrosarcoma t(9;22) 50-70% PROGNOSIS Dermatofibrosarcoma t(17;22), ring chrom. COL1A1-PDGF >50%
STS STS with tumor-specific genetic alterations e.g. fusion genes involving EWSR1 ESFT FLI1 ETV1 ETV4 FEV ERG EWSR1 WT1 Desmoplastic Small Round Cell Tumor ZSG CREB1 ATF1 Clear Cell Sarcoma and Angiomatoid Fibrous Hystiocitoma
Defining sarcoma: role of molecular heterogenety FOUR GROUP OF SARCOMA
Defining sarcoma: role of molecular heterogenety GROUP 1 Nonpleomorphic histology Known pathognomonic molecular events (eg, GIST, DFSP) GROUP 2 Younger patients Nonpleomorphic histology Karyotypes of limited complexity Pathognomonic molecular events, which are likely to exist, have yet to be identified (eg, chordoma)
Defining sarcoma: role of molecular heterogenety GROUP 3 Adult Pleomorphic histology Identified molecular events (eg, DDLPS) GROUP 4 Adult Complex karyotypes pleomorphic histology No identifiable molecular events (eg, pleom. sarcoma)
Traslating molecular heterogenity into diagnostic tools TRASLOCATIONS REARRANGEMENTS RING CHROMOSOMES AMPLIFICATIONS Inflammatory myofibroblastic tumour Dermatofibrosarcoma protuberans WDLPS/DDLPD 2p23 rearrangement Ring Chromosome 17 and 22 t(17;22) (q21;q13) Supernumerary ring and gigant chromosome ALK activation COL1A1 PDGFB fusion COL1A1 PDGFB fusion MDM2 amplification
Target therapy for sarcoma DFSP COL1A1-PDGFB1 fusion gene IMATINIB Myxoid Lyposarcoma TLS-CHOP fusion gene TRABECTEDIN TGCT COL6A3-CSF1 fusion gene IMATINIB GIST KIT and PDGFRa activating mutations IMATINIB, SUNITINIB
Target therapy for GIST:imatinib 90% KIT acitivating mutations 6-8% PDGFRA acitivating mutations Imatinib at 400 mg daily 5-10% GIST WT Exon 11 KIT mutations PR was 83.5%, exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8% (P.0006) and 0.0% (P<.0001), respectively. Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 KIT mutations or had no detectable kinase mutation. Heinrich MC. et al. J Clin Oncol. 2003; 21: 4342-9.
Target therapy for GIST: role of mutational analysis CONCLUSION: The clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.
Target therapy for DFSP Imatinib at 400 mg twice daily Locally advanced or metastatic DFSP t(17;22)
Target therapy for myxoid liposarcoma t(12;16), t (12;22) TLS-CHOP fusion, EWS- CHOP fusion Binding to C/EBP α E C/EBP β promoters Arrest of lipoblast differentiation ET-743 promotes lipoblast differentiation reducing FUS-CHOP or EWS-CHOP expression
Target therapy for myxoid liposarcoma Trabectedin is Cytotoxic for Monocytes and TAMs % OF VIABLE CELLS * * IC 50 on tumour cells Taxol Cisplatin Doxorubicin % OF VIABLE CELLS % OF VIABLE CELLS * * * % OF VIABLE CELLS Drug concentrations Allavena P, et al. Cancer Res. 2005.
Target therapy for myxoid liposarcoma 30 20 10 0 CCL2 * * ** Ctrl 1.2 2.5 5 500 250 0 IL-6 * ** Ctrl 2.5 5 400 200 0 VEGF * ** Ctrl 2.5 5 400 300 200 100 0 Ang2 * ** Ctrl 2.5 5 40 20 0 TNF Ctrl 2.5 5 Trabectedin selectively reduces some inflammatory cytokines in monocytes and macrophages at infra-cytotoxic levels Allavena P, et al. Cancer Res. 2005 and 2010.
Sarcoma translational research: the near future Clinical efficacy of sunitinib in ASPS, mediated by PDGFRB, VEGFR2, and RET, which are all expressed in tumor cells.
Sarcoma translational research: the near future Clinical benefits 70 % of SD 20% OF PR 1 PD
Sarcoma translational research: the near future CASE REPORT PATIENT 1 (Rearrangements involving the ALK locus on chromosome 2p23) 13 weeks of treatment with crizotinib PR PATIENT 2( No AKL rearrangement) PD after 8 weeks
Sarcoma translational research: the near future 2011: Insulin-like growth factor signalling for sarcoma subtypes, including Ewing s sarcoma ANTI- IGF-1R: FIGITUMUMAB
Sarcoma translational research: the near future Phase l trial in patients with soft-tissue sarcoma (STS) including Ewing s sarcoma enrolled 24 patients, 16 with Ewing s sarcoma PRIMARY END POINT Safety and tolerability of figitumumab. SECONDARY END POINT Pharmacokinetic profiling and preliminary antitumour activity (according to RECIST criteria)
Sarcoma translational research: the near future Figitumumab is well tolerated and has antitumour activity in Ewing s sarcoma Objective response in 2 cases SD in 8 patients
Sarcoma translational research: the near future VEGFR overespressed Primary End point PFS at 9 months according to RECIST criteria Sorafenib did not reach the predefined level of activity and provided stable disease of limited duration for patients with advanced and pretreated angiosarcoma.
Sarcoma translational research: the near future pivotal phase III trial in patients with metastatic soft-tissue sarcoma (STS) NO GIST or adypocytic sarcomas whose disease has progressed during or following prior chemotherapy randomized, double-blind, placebo-controlled enrolled 369 patients
Sarcoma translational research: the near future PRIMARY END POINT progression-free survival (PFS) These PFS benefits were consistently seen across a lot of patient subgroups based on STS histology, including leiomyosarcoma, synovial sarcoma, and other types of sarcoma
Sarcoma translational research: the near future IGF R1 Figitumumab IGF R1 P13K/AKT/mTOR ANGIOGENESIS Deferolimus, Everolimus Bevacizumab Sunitinib Sorafenib Pazopanib mtor VEGF a VEGFR 1/ 2/ 3; PGFR; KIT; FLT3; RET; CSF 1 RAF1, VEGFR 1/ 2/ 3 PDGFR, VEGFR, c kit
Sarcoma translational research: the near future RIDAFOROLIMUS PI3K TSC PTEN PI3K AKT mtor mtor signaling dysregulated in multiple sarcomas ridaforolimus is a rapamycin analog and potent mtor inhibitor FKBP Ridaforolimus 4E-BP1 clinical activity in sarcomas in phase I and II studies
Sarcoma translational research: the near future pivotal phase III trial in patients with metastatic disease who have had a favorable outcome to chemotherapy 1. patients with ongoing CR, PR, or SD following prior therapy 2. disease status confirmed through independent radiographic review prior to randomization randomized, double-blinded, placebo-controlled trial 1:1 randomization, oral ridaforolimus vs placebo enrolling approximately 650 patients 13 years of age multicenter trial: approximately 150 centers worldwide
Sarcoma translational research: the near future PRIMARY ENDPOINT progression-free survival (PFS) SECONDARY ENDPOINTS overall survival (OS) best target lesion response improvement in cancer-related symptoms safety and tolerability CAMBRIDGE, Mass., Jan 18, 2011 ARIAD Announces Oral Ridaforolimus Achieved Primary Endpoint of Improved Progression- Free Survival in Patients with Metastatic Soft-Tissue or Bone Sarcomas in the Phase 3 SUCCEED Trial
Sarcoma biomarkers for prognosis and therapy: future perspective mirna Cytokines Vascular spread biomarkers CTC
Sarcoma biomarkers for prognosis and therapy: future perspective D-dimer levels as possible marker of tumor progression and prognosis in musculoskeletal sarcoma ( Sleeman et al., 2011) VEGF-CmRNA and VEGF-C protein relative as biomarkers of lympahtic metastasis (Pollock et al., 2010) NOTCH pathway probabily acts in metastatic spread in osteosacroma (Bray SJ et al.,2006)
Sarcoma biomarkers for prognosis and therapy: future perspective Upregulation of mir-21 in osteosarcomas increcreased cell invasion and migration (Lulla RR et al., 2011) Downregulation of mir155 causes growth arrest in DDLPS (Zhang, P. et al.2012) Mir125 a is upregulated in SS causing cell proliferation (Hisaoka, M. et al., 2011)
Sarcoma biomarkers for prognosis and therapy: future perspective Circulating tumor cells Ewing s sarcoma CTCs/DTCs are strong predictor of recurrent disease in patients with Ewing family tumors (Avigad et al,. 2004) excellent prognosis in a subset of patients with ES + CD56 positive DTCs (Ash et al,., 2011)
Sarcoma biomarkers for prognosis and therapy: future perspective Circulating tumor cells Osteosarcoma CTCs specific mrnas correlate with dismal prognosis and metastases risk (Wong IH,2000) DTCs are very common in osteosarcoma patients and correlate with dismal prognosis (Bruland et al., 2005)
Conclusion Rare tumors Molecular hetorogenty is a useful tool togheter histology for: - Diagnosis -Therapy - Prognosis Thus, the biology of sarcomas suggests that they can represent a paradigm among solid tumors for the translation of gene expression into clinical care.