gms | German Medical Science

27. Deutscher Krebskongress

Deutsche Krebsgesellschaft e. V.

22. - 26.03.2006, Berlin

Particularities in the Development of Targeted Therapies

Meeting Abstract

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  • corresponding author presenting/speaker Christian Dittrich - CEADDP – ACR-ITR VIEenna, LBI-ACR VIEnna and CESAR - Center for Oncology & Hematology, Kaiser Franz Josef-Spital, Vienna, Austria, Wien, Österreich

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocIS024

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Veröffentlicht: 20. März 2006

© 2006 Dittrich.
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Both, theoretical background and clinical experience support that the clinical development of targeted therapies differs from that of cytotoxic drugs. The following features are of preponderant importance: 1) Identification of a relevant target, e.g. a structure which represents the cause of the disease or a disease-maintaining factor; 2) Targets are relevant if they are present in all patients afflicted from disease. This expectation is fulfilled e.g. in form of the PML/RARa fusion protein which is represented by the t(15,17) translocation, a condition which is induced in APL. A further example is represented by HER2/neu over-expression in breast cancer playing a direct role in the pathogenesis of the disease; 3) Targets have to be drugable; 4) Targets have to be proven relevant in conjunction with/restricted to specific therapeutic approaches; e.g. over-expression of EGFR is frequently associated with malignant transformation. Whereas initially the response to the low molecular weight tyrosine kinase inhibitor gefitinib (Iressaâ) did not show an association between its antitumoral activity in xenografts with differing levels of EGFR expression, a such is present if global EGFR expression is substituted with specific mutations of EGFR; 5) Methods of target identification and/or quantification have to be validated. Response to the monoclonal antibody cetuximab (Erbituxâ) in EGFR-negative tumors reflects a lack of sensitivity of the available immunohistochemical test method for the target. In contrast thereto, BCR-ABL represents an almost ideal molecularly quantifiable target to be treated with imatinib (Glivecâ); 6) Knowledge on the stability of the target expression has to be generated; 7) Identification of reliable surrogate parameters for antitumoral efficacy is critical; 8) Difficulty in using surrogate parameters in multi-targeted monotherapies and in combined targeted therapies exists; 9) Determination of MTD represents no primary developmental goal but should merely be substituted with a maximum target inhibiting dose; 10) Identification oh the (maximum) dose which allows continuous (peroral) application of a drug without stopping due to toxicity represents a relevant goal; 11) RECIST is not representative any more for reliable response evaluation since the mechanism of response of new targeted substances may lead to perseveration in (external) size even if tumors respond (shrink internally). Supported by FFG.