Marc Ladanyi

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Anna M. Czarnecka

Polska Akademia NaukI

Bora Gurel

Kocaeli University

Nor Hayati Othman

Universiti Sains Malaysia

Ahmed Hegazi

National Research Center of Egypt

Prof Henry Ademola Adeola

University of Cape Town

Giuseppe Argenziano

Università della Campania Luigi Vanvitelli

Aimilios Lallas

Aristotle University of Thessaloniki

Gouda M El-labban

Suez Canal University

Kai Skaftnesmo

University of Bergen

Michael Geusz

Bowling Green State University

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A multicenter effort to identify driver mutations and employ targeted therapy in patients with lung adenocarcinomas: The Lung Cancer Mutation Consortium (LCMC)

8019 Background: The detection of driver mutations in the EGFR and ALK genes and targeted therapy... more 8019 Background: The detection of driver mutations in the EGFR and ALK genes and targeted therapy has transformed treatment of lung cancer. The LCMC was established in 2009 to assay lung adenocarcinomas for driver genomic alterations in 10 genes and to study and treat patients by their molecular subtypes. Methods: The 14-member LCMC enrolled patients with metastatic adenocarcinoma of the lung and tested their tumors in CLIA laboratories for KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, and NRAS mutations using multiplexed assays, and for ALK rearrangements and MET amplifications using fluorescence in situ hybridization (FISH). Results: 1,102 eligible patients were enrolled; 1,007 underwent testing for at least one genomic alteration with 733 undergoing testing for all 10 genes. 600 patients were women (60%) with a median age of 63; 341 were never smokers (34%) and 589 former smokers (58%). A driver alteration was detected in 622 (62%) of the 1,007 with any genotyping, and in 465 (63%) of the 733 fully genotyped cases. Among the tumors with full genotyping, drivers were found as follows: KRAS 182 (25%), sensitizing EGFR 107 (15%), ALK rearrangements 56 (8%), other EGFR 43 (6%), two genes 29 (4%), BRAF 16 (2%), HER2 15 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;1%), and AKT1 0 (0%). Results were used to select targeted therapy or targeted trials in 279 patients with a driver alteration (28% of 1,007 total). Among 938 patients with clinical follow-up and treatment information, 264 with a driver alteration treated with a targeted agent had a median survival of 3.5 years; 313 with a driver who did not receive targeted therapy had a median survival of 2.4 years; while 361 without an identified driver had a median survival of 2.1 years (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001). Conclusions: An actionable driver alteration was detected in 62% of tumors from patients with lung adenocarcinomas, leading to use of a targeted therapy in 28%. The patients with an identified driver treated with a targeted agent lived longer than those patients who did not receive targeted therapy. Multiplexed genomic testing can aid physicians in matching patients with targeted treatments and appropriate clinical trials.

The NPM/ALK gene fusion in the pathogenesis of anaplastic large cell lymphoma

Cancer Surveys, 1997

The cloning of the t(2;5) translocation breakpoints and the identification of the NPM/ALK fusion ... more The cloning of the t(2;5) translocation breakpoints and the identification of the NPM/ALK fusion in Ki-1 ALCL have brought forth from this heterogeneous morphological grouping a subset of cases defined by an aetiological genetic alteration. The analysis of NPM/ALK positive lymphomas as a single clinicopathological entity has already begun to clarify and explain some previous clinical observations in Ki-1 ALCL. It has also confirmed that HD is pathogenetically unrelated to NPM/ALK positive Ki-1 ALCL. This is yet another example of the overall nosological evolution from morphological entities to pathogenetic entities among lymphomas, leukaemias and, more recently, sarcomas. Although much work remains to be done on the mechanism of NPM/ALK lymphomagenesis, rational treatment approaches are now within reach. Such novel approaches could target NPM/ALK at the level of the genomic sequence, transcript, protein or its downstream targets, when the latter are further elucidated. Systems developed to inhibit other fusion transcripts and oncogenic tyrosine kinases can now be applied to NPM/ALK positive lymphomas. Furthermore, the strong and highly selective surface expression of CD30 in Ki-1 ALCL may provide a basis for the targeted delivery of these novel therapeutic agents.

Proteasome addiction defined in Ewing's sarcoma is effectively targeted by a novel class of 19S proteasome inhibitors

Cancer research, Aug 2, 2016

Ewing's sarcoma (EWS) is a primitive round cell sarcoma with a peak incidence in adolescence ... more Ewing's sarcoma (EWS) is a primitive round cell sarcoma with a peak incidence in adolescence that is driven by a chimeric oncogene created from the fusion of the EWSR1 gene with a member of the ETS family of genes. Patients with metastatic and recurrent disease have dismal outcomes and need better therapeutic options. We screened a library of 309,989 chemical compounds for growth inhibition of EWS cells to provide the basis for the development of novel therapies, and to discover vulnerable pathways that might broaden our understanding of the pathobiology of this aggressive sarcoma. This screening campaign identified a class of benzyl-4-piperidone compounds which selectively inhibit growth of EWS cell lines by inducing apoptosis. These agents disrupt 19S proteasome function through inhibition of the deubiquitinating enzymes USP14 and UCHL5. Functional genomic data from a genome-wide shRNA screen in EWS cells also identified the proteasome as a node of vulnerability in EWS cells, ...

Marc Ladanyi

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