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Evasion from apoptotic cell death is reported to be a pivotal mechanism by which tumor cells acquire resistance to therapeutic treatment. Targeting the apoptotic pathways may constitute a promising strategy to counteract therapy resistance and to re-sensitize cancer cells. Expression of survivin, the smallest and structurally unique member of the inhibitor of apoptosis protein (IAP) family, has been shown to be associated with poor clinical outcome, more aggressive clinicopathologic features and resistance to both, conventional chemo and radiation therapy. Moreover, survivin detection in cancer tissue, in circulating tumor cells and in patient's serum has prognostic and predictive relevance and may display a prerequisite for marker based molecular therapies. Indeed, due to its universal over expression in malignant tissue, and its prominent role at disparate networks of cellular division, intracellular signaling, apoptosis and adaption to unfavorable surroundings, survivin has been shown to be a suitable target for a targeted therapy. The applicability of survivindriven strategies in clinical practice is currently under investigation as the first survivin antagonists (small molecule inhibitors, antisense oligonucleotides and immunotherapy) successfully entered phase I/II trials. Taken together, these data provide a rationale for the implementation of both, survivin as a molecular diagnostic tool and survivin targeted therapies, within future clinical practice.

The phosphatidylinositol 3'-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the most potent prosurvival signaling cascades that is aberrantly activated in a variety of human cancers. Recent evidence demonstrates that pathological activation of Akt also frequently occurs in neuroblastoma and correlates with poor prognosis. Thus, therapeutic targeting of PI3K/Akt/mTOR may present a promising approach for the design of molecular targeted therapies in neuroblastoma. Several strategies have in recent years been developed to interfere with distinct components of PI3K/Akt/mTOR signaling at different levels of the cascade. It will be subject to future studies to evaluate which of these compounds are most suitable for the treatment of neuroblastoma. Eventually, PI3K/Akt/mTOR targeting agents may open novel perspectives to improve the poor prognosis of patients with neuroblastoma especially in advanced stages of the disease.

Evasion of apoptosis, the cell's intrinsic death program, is a hallmark of human cancers including neuroblastoma. Also, failure to undergo apoptosis may cause treatment resistance, since the cytotoxic activity of anticancer therapies commonly used in the clinic, e.g. chemotherapy, gamma-irradiation or immunotherapy, is predominantly mediated by triggering apoptosis in tumor cells. Therefore, a better understanding of the signaling pathways and molecules that govern apoptosis in neuroblastoma cells is expected to open new avenues for the design of molecular targeted therapies for neuroblastoma.

Resistance of human cancers to current treatment approaches remains a challenge in oncology. Therefore, there has been much interest in identifying molecular pathways that are responsible for primary or acquired resistance of cancers. Since most anticancer therapies, i.e. chemotherapy or radiotherapy, primarily act by triggering programmed cell death (apoptosis) in cancer cells, defects in apoptosis programs may confer resistance. Evasion of apoptosis in rhabdomyosarcoma may be caused by the dominance of cell survival pathways, for example aberrant activation of the PI3K/Akt/mTOR cascade, or alternatively, by defective expression or function of critical mediators of apoptosis, i.e. components of the TRAIL signaling system. In addition, signaling to apoptosis can be blocked under hypoxia, a characteristic feature of most solid tumors including rhabdomyosarcoma that has been associated with poor treatment response. Thus, molecular targeted therapies that are specifically directed to the defects in apoptosis programs, open novel perspectives to restore apoptosis sensitivity in rhabdomyosarcoma.

Triggering apoptosis, the cell's intrinsic death program, is a promising approach for cancer therapy. TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of death inducing ligands, is of special interest for cancer therapy, since TRAIL has been shown to predominantly kill cancer cells, while sparing normal cells. However, since many cancers fail to undergo apoptosis in response to TRAIL treatment, TRAIL-based combination therapies have been developed for cancer-cell specific sensitization towards TRAIL. Chromatin remodelling plays an important role in gene regulation and aberrant architecture of the chromatin has been implicated in tumor formation and progression. In recent years, HDAC inhibitors (HDACI) that reverse aberrant epigenetic changes have emerged as a potential strategy to sensitize cancer cells for TRAIL-induced apoptosis. Synergistic tumor cell death has been reported in a variety of human cancers using different HDACI together with TRAIL. Here, recent advances in the understanding of the molecular events that underlie the synergistic interaction of HDACI and TRAIL are discussed as well as how this knowledge can be translated into the design of cancer-selective novel therapeutics.

Killing of tumor cells by anticancer therapies commonly used in the treatment of cancer, e.g. chemotherapy, gamma-irradiation, immunotherapy or suicide gene therapy, is predominantly mediated by triggering apoptosis, the cell's intrinsic death program. Accordingly, defects in apoptosis pathways can result in cancer resistance to current treatment approaches. Understanding the molecular mechanisms that regulate cell death programs including apoptosis, and how resistant forms of cancer evade apoptotic events, may provide novel opportunities for cancer drug development.

Apoptosis, the cell's intrinsic death program, is a key regulator of tissue homeostasis. An imbalance between cell death and proliferation may result in tumor formation. Also, killing of cancer cells by cytotoxic therapies, such as chemotherapy, gamma-irradiation or ligation of death receptors is predominantly mediated by triggering apoptosis in target cells. Death receptor signaling pathways have been implied to contribute to the efficacy of cancer therapy. Failure to undergo apoptosis in response to anticancer therapy may lead to resistance. Understanding the molecular events that regulate apoptosis induced by anticancer therapy and how cancer cells evade apoptosis may provide new opportunities for drug development. Thus, novel strategies targeting tumor cell resistance will be based on insights into the molecular mechanisms of cell death.