PD-033 Predictive testing of NSCLC chemosensitivity: A feasibility study

Poster Discussions / Basic science~Ceil and moiecu/ar biology

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Conclusions: EGF R pathway status is rather heterogeneous in NSCLC.

at Untverstty ~ Caldomta, San Franctsco, Ca/domta, USA, 2Department Innovation Therapeut]que et Oncologte Motec~atre, t N S ~ M U563, lnst]t~t, C/,audtus Regaud, 31052 Toulouse Cedex, France, 3Canoar Center at Untverstty ot Cahtom/a, San Fran¢~seo, CA 94115, USA

vlnorelblno also showed activity, but few agents achieved 100% iNTibit]on at clinically achievable concentrat]ons, with the possible e0¢capt]on of doxorubicin. which was tested at concantrat]ons similar to those obtained using liposomal preparat]ons such as Ceolyx/Doxil There was considerable heterogeneity between tumours in the inhibit]on aol'taved by docataxel, cisplatin and gamcitabine, with less vanation shown ~ r doxorubicin and etoposide Of the combinat]ons teated, cisplat]n + gamcitabine showed good ac0vity against most tumours, but docataxel + gemcitabine was not as effeot]ve However. docataxel in combination with etoposide or liposomal doxorubic~n was very active. Conclusion: These results are consistent with clinical experlenoe, and show relat]ve resistance of most NSCLC to single agents. However. several combinat]ons show greater activity, part]cularly clsplat]n + gamcitablne and suggest that combinat]on of docetaxel with liposomal dosorubicm or etopos~de may be worthwhile.

Purpose: Malignant mesothelioma oftbo pleura (MPM) is a highly aggressive

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and alternative regulat]on mechanisms may act in determining pest-recaptor transductioeal events However. at transcdpt]onal level significant correlation between up-regulation of EGF~q ligands and EGF~q and c-ERBB2 was observed, thus suggesting a relevant role of autoorine interplay in NSCLC ~2~Wnt2 as a new therapeutic target In malignant pleural rnesothelloma Z. Xu ~. J. Mazieres ~. B. He 3. L. you3. D. Jablons 3. ~cencer Center

neoplasm with a poor prugnosls and limited b'eatment options. A better understanding of its patbogenesJs is essent]al Ibr developing altemat]ve therapeutic sb'ateg~as. Experlrnental design: We previously demonstrated that the Wnt signaling pathway is act]vateq in MPM through the overexpress~on of dishevelled proteins To extend our knowledge of Writ signaling act]vat]on in MPM. we performed Wnt specific mioroarrays in normal pleura and MPM We ~und that the most common event in MPM was the upregulat]on of Wnt2 We ini'tblted Writ2 by siRNA and a monodonal anti-Writ2 ant]body and analyzed their effects on apoptosis and downstream signaling effectors We then assessed the ant]proliferative effects of the Wnt2 antibody and Alimta ®. one of the current standard tTeatments for MPM Results: We confirmed Writ2 overexpression at the mRNA and protein level in MPM call lines and t]ssuas We then demonst~'ateq that inhibit]on of Writ2 by siRNA or a monoclonal antibody induces programmed-call death in MPM calls We next analyzed the effects of the anti-Writ2 antibody and of Alimta on MPM call proliferation We found that although Wnt2 ant]body by itself had less ant]-preliferat]ve potency than Alimta ®. the two in combinat]on had substant]ally more activity than Alimta ® alone. Conclusion: We propose that intlblt]on of Wnt2 is of therapeutic interest in the development of more effective treatments ~r MPM.

Y Yoshida~ T Shibata I . A Kokubo ~. K Tsuta I . Y Matsuno 2. Y Kanai ~. H Asemura ~. R Tsuchiya ~. S Hirehashi I ~Palho/ogyDit~sion, National

Cancer Center Research tns~tute, Tokyo,Japan, 2Diagnosttc Pathology Division, Nationa/ Cancer Center Hosptta/, Japan, ~Thoracic Surgery Division, NabonaJ Cancer Center Hospita/, Japan Background: A hypothesis of mult]step carcinogenesis of lung adeno

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carcinoma from atypical adenornatous hyperplasia (AAJ~ to invaslve adeno carcinoma through bronchioloalveolar carcinoma (BAC) has been proposed However. the ganet]c alterations that play a role during these processes are not yet dear Recently. somatic mutations of the epidermal growth factor receptor (EGFR) gene were found in lung adenocarcinoma We e~amined the status of EGFR mutat]ons in AAH and BAC to elucidate the role they play dunng mult]stage of lung adenocarcinoma Methods: We e~amined the status of EGFR mutat]ons in exons 18. 19 and 21 and K~'as mutations at codon 12 and 13 using direct sequencing of polymerase chain reaction products. Tumor calls were microdissected from Ibrmalir-. fixed archives. Pathological cJagnosls was made in acoordanca with the WHO classJficat]on as revised In 1999. All cases of BAC In tils study were nonmuanous subtype. Results: We Ibund somatic EGFR mutat]ons in 3% (1/35) of AAH. 10.9% (4/37) of BAC and 41.9% (13/31) of invaslve adenocarcinoma. Sixteen of 18 EGFR mutations ware ~und in ~ o n 19 and 2 were in e~on 21 Among the 16 EGFR mutat]ons in e~on 19. 13 were delet]ons of 15bp and one was an insert]on/duplicat]on of 18bp Mutat]ons of the K-ras gene were detected in 26 7% (8/30) of AAH. 16 7% (5/30) of BAC and 10% (3/30) of invasive adenocarcinoma None of the tumors with EGFR mutat]ons had Kras mutation simultaneously Pat]ents who had invasive adenocarcinoma with EGFR mutat]ons ware younger than those without mutat]ons (60 6 vs 67 4 years, p=0.03). We analyzed 24 pat]ents with multiple lung lesions and 13 pat]ents had at least one lesion that had edther an EGFR or K~as mutation. Among them. 4 pat]ents had invasive adenocarclnoma with EGFR mutat]on and AAH with K ras mutation. Five pat]ents had invasive adenocarclnoma with EGFR mutat]on, while n e ~ e r EGFR nor Kras mutations were found in AAH. In all cases each les~on had a clfferent mutation status. Conclusions: We found that EGFR mutations in AAH and BAC were less frequent compared to those detected in invasive adenocarcinoma These results suggest that tumors with EGFR mutat]ons may progress more rapidly and develop into invasive cancar faster than those without mutations Alternat]vely it is also possible that some invasive adenocarcinomas with EGFR mutat]ons may not ~ll¢~v the AAH-adenocarcinoma sequence Onoogenic activation of EGFR may also cantdbute to the early step of lung adenocarcinoma development as K-ras does so The genetic alterations responsible for the development of lung adenocarcinoma oocur randomly even under exposure to the same carcinogen.

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L. You. B. He. Z. Xu. K. Uematsu. J. Mazlerea. I. Mikami. N. Reguart. E McComick. D. Jablons. UCSf,, San Francisco, USA

Prs(:lctlve tesUng of NSCLC chemossnsltlvlty: A faaslblllty

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study D Y~annalds~ ~ Mndi 3. J Rahamim 3. S I~Jllard~. S Glaysher~. A. Femande ~. L. Knight ~. T. Gulliford ~. I. Cree ~. ~Portsmou~ Hospitals

NHS Trust, Portsmouth, UK, ~Oncotogy Centre, Derriford Hospital, Plymouth, UK, 3Thorac/c Surgery, Derntord Hospttal, Plymouth, UK Background: Treatment of norPsmall call lung cancer (NSCLC) currently uses a relatively small repertoire of drugs, of which docatasel, clsplat]n and gemcitabine are the most commoHy used The aim of this study was to e0¢amine the chemosensitJvity profile of NSCLC with respect to drugs commonly used in this disease Methods: A total of 23 specimens were obtained from surgical resect]ons of NSCLC tumoure, and tested in the ATP~)ased tumour chemosensit]vity assay (ATP-TCA) as previously published [1. 2] There were sufficient cells for testing in 21 specimens Up to 12 drugs or combinat]ons ware tested per pat]ent at six concanb'ations within the dinically achievable range calculated from pharmacokinet]c data. The ir~ibit]on at each cancanb-ation was calculated to obtan an act]v~ty<-,oncantTationcurve and the results compared using a sensitivity index [2]. A'TP -TCA ~ r L u ~ B Tumour= [n • ,11}

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MutaUons of the epidermal growth factor receptor gene In atypical adsnomatous hyperplasla and bronchloloalveolar carcinoma of the lung

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Figure I Results of ATP-TCA testing in NSCLC A sensitivity ind~ of 0 is complete inhibit]on. <,300 indicates probable olinical activity, and >3,50 indicates resistance The range (vert]cal bars) gives an indicat]on of the degree of heterogeneity of chemosensit]vity present between individual tumours

Results: The results (Figure 1) show limited single agent c~splat]n, docataxel and gemc~tabine activity. Doxorubic~n. etoposide, innoteoan, gem~abine, and

Inhibition of Wnt-2-medlatsd signaling Induces programmed cell death In non-small-call lung cancer calls

In this report, we have demonstTated that Wnt-2 protein is over-e=pressed in freshly resected human non-small call lung cancer (NSCLC) t]ssues We have also developed a monoelonal ant]body against the N-terminus of human Wnt2 protein T~s monooloeal anfibody induces apoptosis in human NSCLC cell lines that over-e=press Wnt-2 protein Incubafion of this antibody with normal human airway calls leoldng Wnt-2 e0¢pression does not induce apoptosis Writ-2 signaling blockade by the anb Wnt 2 ant]body is confirmed by down~'egulat]on of cytosolic 13cater=n and reduction in TCF dependent tTanscnpt]onal activity (TOPFLASH assay). In addition. Writ 2 speclfic small interfering RNA (s~RNA) treatment in the NSCLC cell line A549 also down~'egulated cytosolic 13catenin and inducad apoptosls. Moreever. down regulat]on of an inhibitor of apoptosis