Targeting Apoptosis Pathways for the Treatment of Pediatric Cancers
Evasion of apoptosis (programmed cell death) is a hallmark of human cancers. Further, most anticancer therapies that are commonly used in the clinic, e.g. chemo- or radiotherapy, primarily act by inducing cell death pathways including apoptosis in cancer cells. Thus, failure to undergo apoptosis may result in primary or acquired resistance of cancers to current treatment approaches. Understanding the molecular events that regulate apoptosis in response to anticancer therapy and how cancer cells evade apoptotic cell death provides novel opportunities for the development of molecular therapeutics that target cell death pathways. Studies over the last decade have delineated multiple defects in the apoptosis signal transduction machinery in pediatric cancers that can serve as targets for the design of novel treatment strategies. Examples for apoptosis-targeted cancer therapeutics that have already entered the clinical stage include TRAIL receptor agonists, which directly trigger programmed cell death, or small molecule inhibitors of antiapoptotic proteins such as „Inhibitor of Apoptosis“ (IAP) proteins. These agents either directly trigger apoptosis or alternatively, sensitize cancer cells for apoptosis in combination regimens, for example together with chemo- or radiotherapy. Since apoptosis pathways are also intricately linked to survival cascades, e.g. PI3K/Akt/mTOR or the NF-kB signaling, targeting key elements of these survival networks can also reactivate apoptosis. Further insights into the mechanisms of resistance of childhood cancers to apoptosis are expected to provide novel opportunities for the development of molecular-targeted cancer therapeutics for children suffering from cancer.