Towards Novel Paradigms for Cancer Therapy

Oncogene (2011) 30, 1–20 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc REVIEW Towards novel paradigms for cancer therapy V Pavet1, MM Portal1, JC Moulin1,2, R Herbrecht2 and H Gronemeyer1 1Department of Cancer Biology, Institut de Geńe´tique et de Biologie Molećulaire et Cellulaire (IGBMC), Illkirch, Alsace, France and 2Department of Oncology and Hematology, Hoˆpitaux Universitaires de Strasbourg, Strasbourg, France Cancer is a complex progressive multistep disorder that normal cell toward a malignant derivative. This process results from the accumulation of genetic and epigenetic shapes each tumor in such a dynamic and unique way abnormalities, which lead to the transformation of normal that it is extremely difficult to determine the alterations cells into malignant derivatives. Despite enormous progress that cause, maintain and spread the disease (Greenman in the understanding of cancer biology including the et al., 2007; Wood et al., 2007). decryption of multiple regulatory networks governing cell Historically, solid tumors have been treated by growth and death, and despite the possibility of analyzing surgery for the past 4000 years (http://www.cancer.org/ (epi)genetic deregulation at the genome-wide scale, cancer- docroot/CRI/content/CRI_2_6x_the_history_of_cancer_ targeted therapy is still the exception. In fact, to date there 72.asp?sitearea ¼ ). It was only after the discovery of are still far too few examples of therapies leading to cure; X-rays at the end of the nineteenth century that treatment-derived toxicity is a major issue, and cancer radiotherapy emerged as a novel therapeutic approach. remains to be one of the largest causes of death worldwide. Whereas localized tumors could be treated by focal The purpose of this review is to discuss the state of the art of therapy, extensive or metastatic tumors and hematolo- cancer therapy with respect to the key issue of any treatment, gical malignancies required the development of systemic namely its target selectivity. Therefore, we recapitulate and anticancer therapies. Initial efforts in anticancer drug discuss current concepts and therapies targeting tumor- discovery started in the mid-twentieth century based on specific features, including oncofusion proteins, aberrant the observation that cytotoxic agents could be used to kinase activities and epigenetic tumor makeup. We analyze kill cells displaying high proliferation rate. To date, strategies designed to induce tumor-selective death such as surgery, radiotherapy and standard systemic chemother- the use of oncolytic virus, tumoricidal proteins (NS1, Eorf4, apy still comprise the standard treatment in a majority apoptin, HAMLET (human a-lactalbumin made lethal to of proliferative diseases. Indeed, novel chemotherapeu- tumor cells)) and activation of signaling pathways involved in tic (genotoxic) compounds are continuously being tumor surveillance. We emphasize the potential of the tumor developed, despite the induction of serious side effects necrosis factor-related apoptosis-inducing ligand (TRAIL) arising from the damage caused to normal tissue. pathway, an essential component of the evolutionary Although initially the development of anticancer thera- developed defense systems that eradicate malignant cells. pies relied on empirical observations, the current Finally, we discuss the necessity of targeting tumor-initiating challenge is to develop novel therapeutic paradigms cells (TICs) to avoid relapse and increase the chances of exploiting the knowledge derived from molecular, complete remission, and describe emerging concepts that cellular and systems biology studies of tumor formation might provide novel avenues for cancer therapy. and progression (Shipley and Butera, 2009; Zhenchuk Oncogene (2011) 30, 1–20; doi:10.1038/onc.2010.460; et al., 2009). Despite the pleiotropic nature of tumors, published online 11 October 2010 several characteristics are shared by almost all malignancies namely: self-sufficiency in growth signals, Keywords: apoptosis; TRAIL/Apo2L/TNFSF10; epigenetic evasion from apoptosis/immunosurveillance, insensitiv- drug; tumor-initiating cell; dependence receptor; non- ity to growth inhibitory signals, limitless replicative coding RNA potential, sustained angiogenesis and tissue invasion/ metastasis; as well as metabolic, mitotic, oxidative and DNA damage stress (Hanahan and Weinberg, 2000; Introduction Luo et al., 2009). Consequently, a plethora of therapeutic approaches targeting the corresponding path- Cancer results from the accumulation of genetic and ways/key players that support or are essential for tumor epigenetic alterations that drive the transformation of a development are being developed and explored (Ferrara et al., 2004; Bianco et al., 2007; Berdis, 2008; Lane Correspondence: Dr V Pavet or Dr H Gronemeyer, Department of and Chabner, 2009; Desgrosellier and Cheresh, 2010; Cancer Biology, Institut de Geńe´tique et de Biologie Molećulaire et Tennant et al., 2010) (Figure 1). However, irrespective Cellulaire, 1 Rue Laurent Fries, BP10142, Illkirch-Strasbourg, of the accumulating knowledge on tumor-specific Alsace 67404, France. E-mails: [email protected] or [email protected] features, at present the corresponding targeted therapies Received 6 May 2010; revised 10 August 2010; accepted 1 September have only in rare cases led to cure. Indeed, the first 2010; published online 11 October 2010 curative cancer therapy that could be understood from Novel paradigms for cancer therapy V Pavet et al 2 Figure 1 Tumor-specific features targeted for cancer therapy. General features of tumor development are depicted as red spheroids. Blue spheroids exemplify factors/processes that are integral components of the corresponding feature and which are currently being targeted for cancer therapy; numbers refer to the following publications: (1) Tennant et al., 2010; (2) Desgrosellier and Cheresh, 2010; (3) Lessene et al., 2008 (4) Lane and Chabner, 2009; (5) Bianco et al., 2007; (6) Granchi et al., 2010; (7) Ferrara et al., 2004 and (8) Berdis, 2008. the underlying biology concerns cancers with very multifactorial events. However, tumors display certain specific somatic gene aberrations, such as defined common characteristics, some of which have been and chromosomal translocations in a subtype of acute are at the basis of anticancer drug development leukemia (Melnick and Licht, 1999). The therapeutic (Figure 1). Although it is not on the focus of this review success was due to the removal of the cause of the to enter in detail along these lines of therapy, this section malignancy, as was shown for acute promyelocytic briefly summarizes current approaches that target three leukemia (APL), which is caused by the formation of features of tumor growth, namely self-sufficiency in leukemogenic fusion proteins in hematopoietic progeni- growth signals, sustained angiogenesis (neovasculariza- tors (Melnick and Licht, 1999). Treatment of APL tion) and resistance to apoptotic stimuli. patients with compounds that eradicate the leukemo- Self-sufficiency in growth signals: A key feature of genic fusion protein (all trans-retinoic acid (ATRA), normal cell proliferation is the fact that normal cells arsenic trioxide; see below) cures most of the patients require mitogenic signals in order to switch from a (Kogan, 2009; Nasr et al., 2009). However, as a vast quiescent to a proliferative state. Under normal condi- majority of cancers arise as a result of the accumulation tions, soluble mitogenic factors are not cell auto- of multiple (epi)genetic mutations, only in very parti- nomously produced but are rather secreted by a cular cases the identification and subsequent targeting of different cell type. In contrast, a majority of tumor cells a specific aberration may be feasible. Nevertheless, the are capable of producing their own growth signals, thus example of APL demonstrates that a targetable ‘achilles promoting uncontrolled proliferation. Moreover, it has heel’ of a given tumor can, in principle, be found. been shown that cancer cells can overexpress cell surface The conceptual basis of this review is the argument receptors involved in the transduction of growth signals that the major challenges in cancer therapy are: (1) the as well as display ligand-independent signaling. These selective eradication of cancer cells, (2) the discovery of two characteristics have been reported for the epidermal robust biomarkers for predicting therapeutic response to growth factor receptors, which are transmembrane a given therapy and (3) the identification and targeting tyrosine kinase receptors involved in cell proliferation of tumor-initiating cells (TICs), which might constitute a and survival (Yarden and Ullrich, 1988). Epidermal highly dangerous compartment of a tumor that needs to growth factor receptor was the first molecular target for be eliminated for complete remission. In the following which monoclonal antibody (cetuximab) was developed sections we analyze the conceptual basis of current for cancer therapy. The interaction with cetuximab cancer therapies with respect to cancer selectivity and promotes receptor internalization and degradation, thus discuss known compounds, targets and pathways that blocking downstream signaling pathways involved in can be exploited to achieve tumor-selective killing. cell proliferation/differentiation, invasion, angiogenesis and apoptosis (Masui et al., 1986; Martinelli et al., 2009). Cetuximab has been already approved for Current therapeutic paradigms

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