Future Cancer Therapy with Molecularly Targeted Therapeutics: Challenges and Strategies

Abstract

In a pharmaceutical industry in which nine out of ten attempts to bring a product to market fail, oncology is among the most challenging therapeutic area (Kola and Landis, 2004;Kamb et al., 2007). In the recent article published in the Nature Rev. Drug Discov. (Arrowsmith, 2011), 83 Phase III and submission failures during 2007 to 2010 were divided according to therapeutic area and reason for failure. Largest numbers of failures was in the area of cancer (28%) followed by neurodegeneration (18%). The 66% of the failures across all therapeutic areas were attributed to lack of effi cacy and 21% of the failures were due to safety issues. Therefore, there is a desperate need for new drugs, especially in the cancer treatment.As a rational approach to cancer therapy in the middle of the last century, a new class of drug discoveries emerged to exploit the differential dependence of proliferating cancer cells on vital functions such as DNA metabolism, replication, chromosome segregation and cytokinesis. These efforts ultimately produced range of nucleoside analogues, DNA-modifying chemicals and natural products -the traditional chemotherapeutic (cytotoxic) agents. The mechanism of action of these Invited ReviewBiomol Ther 19(4), 371-389 (2011) www.biomolther.org drugs-inhibition of essential cellular functions-dictates a narrow therapeutic window (Kamb et al., 2007). A new strategy for cancer therapy has emerged during the past decade based on molecular targets that are less likely to be essential in all cells in the body, therefore more apt to confer a wider therapeutic window than traditional cytotoxic drugs (Kamb et al., 2007;Reichert and Wenger, 2008).In this review, some of the strategies and the opportunities in the molecular targeted oncology drug discovery are discussed. EXCEPTIONAL HETEROGENEITY AND ADAPTABIL-ITY OF CANCER: MAJOR CHALLENGES IN ONCOL-OGY DRUG DISCOVERYCancer is an extraordinarily heterogeneous disease with somatic alterations arise as individual cancer develops (Greenman et al., 2007;Kamb et al., 2007;Harris and McCormick, 2010). This exceptional heterogeneity of cancer is refl ected in observed differences in drug responses, and is the probable cause of acquired resistance. It is also presumably related to drug sensitivity and tumor aggressiveness which display a wide range of variation among malignancies.Due to the heterogeneity both among the cells of an individual tumor and among different cancers, the effi cacy predictions made from xenograft animal models often fail (Kamb, 2005), which presents signifi cant challenges in the oncology drug discovery where advancement of compounds largely based on a pharmacological effect in the xenograft models. Even though xenograft represents signifi cant aspects of the tumor from which it was derived, it probably captures only a fraction of the total genetic and epigenetic heterogeneity of a given tumor subtype. Low response rate in phase I oncology trials is refl ective of poor predictability of clinical effi cacy based on these xenograft mo...

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