oa Editorial [Hot Topic: Targeted Therapies in Oncology (Guest Editor: Monica M. Mita)]

Welcome to this special issue of Current Drug Targets in which we review some of the very promising new targets and therapeutic approaches which epitomize the drive towards personalized, molecular-based anti-cancer care. The spectrum of targets we discuss include kinases, chaperone proteins, receptors and enzymes. The aurora family of serine/threonine kinases, essential for chromosome alignment, segregation and cytokinesis during the extremely complex process of mitosis, are receiving increasing attention as discussed by Kelly et al. Cell survival depends on the accuracy of mitosis and thus any defect in its many fidelity-monitoring checkpoints, designed to ensure accurate mitotic spatial and temporal coordination, may well contribute to genomic instability. Both in terms of initial tumor development and in the development of therapy resistance, modulators of genomic instability are of major interest. Aurora kinases are frequently over-expressed in human tumors, which has lent support to the development of small molecules that inhibit their activity with varying degrees of selectivity. Therapeutic efficacy has been demonstrated with these agents - a key question being how much of this efficacy is directly related to direct aurora kinase inhibition. In CML, while most of these agents activity may be explained by direct abl inhibition, there is evidence that other factors are involved [1]. The generally modest response rate seen in patients with solid tumors receiving aurora kinase inhibitors has been discouraging and lends urgency to developing an understanding of the modes of resistance to these agents. Recent data which exploit structural knowledge of the binding modes of aurora kinase inhibitors and polo-like kinase inhibitors [2], give us clear guidance on authentication of mitotic targets and on their interrelated control mechanisms [3]. A second family of serine/threonine kinases that regulate several signaling pathways critical in cancer development and progression, the PIM kinases, are discussed by Swords et al. PIM kinases, which possess a hinge region that constitutes a unique ATP-binding pocket, are key downstream effectors of the ABL, JAK2, c-Myc and Flt-3 oncogenes. PIM kinases are also key, particularly in hematologic malignancies, in resistance to mTOR (mammalian target of rapamycin) inhibitors. The therapeutic benefit of combined PIM and mTOR inhibition is an urgent research issue. Recent data on the role of Pim-3 as an accelerant in the development of hepatocellular carcinoma provide a strong rationale for giving this generally refractory tumor a high priority in the further development of Pim kinase inhibitors, which may well have a very broad spectrum of anti-cancer activity [4]. The hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/c-MET) receptor tyrosine kinase pathway offers a similarly exciting broad-spectrum target as discussed by Yap et al. Aside from a pleotropic role, and frequent dysregulation in a wide range of cancer histologies, this pathway, because of a marked differential expression in cancers, may represent a particularly significant opportunity for therapeutic intervention. Ethnic variations in met mutation-associated lung cancers are a good example of how we now need to factor molecular biology into our eligibility criteria for early phase studies [5]. As with the other kinase targets reviewed in this issue, an increasing understanding of the interdigitating pathways involved in mediating c-MET's role in cancer will guide the development of rational combination regimens [6]. Spear et al. update us on the vascular disrupting agents (VDA) which selectively target tumor vasculature in a manner distinct from that seen with VEGF-targeted angiogenesis inhibitors. VDA mainly affect existent cancer blood vessels rather than inhibiting new vessel growth by disturbance of the relatively immature, structurally disorganized neoplasm-associated vasculature. The range of chemically distinct VDA pose an interesting developmental therapeutics challenge - the integration of adapted radiological methods to both pre-clinical and human studies is an important tool in addressing this challenge [7, 8]. Mahalingam et al. review the current status of our research into the tumor necrosis factor-related apoptosis-inducing ligand or Apo2 ligand (TRAIL/Apo2L) as a therapeutic approach. While the preferential toxicity of TRAIL to cancer cells offers promise of selectivity, combination approaches will clearly be necessary in those cancer histologies where innate sensitivity is lacking. Recombinant human TRAIL (rhTRAIL), agonistic anti-DR4 and anti-DR5 antibodies are leaders among many approaches under investigation. As other approaches towards apoptosis manipulation in cancer evolve, so does the potential for synergy with TRAIL-based approaches [9-11]. Insulin-like growth factor type-1 receptor (IGF-1R) is over-expressed in many tumor types and its signaling is associated with resistance to a broad range of our current anti-cancer approaches. By focusing on the development of Cixutumumab, a fully human immunoglobulin G1 monoclonal antibody that specifically inhibits IGF-1R signaling, Rowinsky et al. update us on the exciting potential of this approach. Potential synergies with other novel targets (e.g. Notch-1 [12], caspases [13]) will rapidly expand our focus on the IGF family as therapeutic targets. The current efforts to define, isolate, study, modulate the behavior of, and to deplete reservoirs of cancer stem cells rank high among the most exciting current developmental therapeutics endeavors. We know of at least 3 critical stem cell modifying pathways which involve Notch, Wnt/catenin, and the Hedgehog cascade. Weiss et al. give us a thorough review on the status of the latter pathway as a therapeutic pathway in cancer. Even as the first agents directed at this pathway are about to enter our clinical practice, we still have much to learn about how exactly hedgehog perturbation may optimally be addressed. As one would expect with a complex process that is essential to our existence, there are clearly multiple interlocked pathways that regulate stem cell behavior [14, 15]. As one watches this puzzle unfold, it seems we have much to be grateful for that we already see marked responses to smo inhibitors even while most of the biology of cancer stem cells has yet to be defined. That many of these responses are seen in tumors that are relatively insensitive to current standard approaches is particularly gratifying. Sandhu et al. update us on another very exciting broad-spectrum target, the DNA repair enzyme, poly(ADP-ribose) polymerase (PARP), which is a key component of the base excision repair pathway of DNA single-strand break repair. PARP inhibitors are exciting both because of their ability to increase the sensitivity of tumors to DNA-damaging agents and their ability as single agents to be lethal to homologous recombination repair-defective (e.g. BRCA1 and BRCA2 mutation-associated) cancer. Key future studies will determine whether PARP inhibitors can induce synthetic lethality in cancers without BRCA-dependent DNA repair pathway defects. The recent finding that PARP inhibition can inhibit homology dependant repair by suppressing expression of BRCA1 and RAD51 is very exciting and provides a strong rationale for novel combination therapies [16]. As stated so simply and elegantly by Benson et al. “A cancer drug target is only truly validated by demonstrating that a given therapeutic agent is clinically effective and acts through the target against which it was designed” [17]. We look forward to the targets discussed in this issue proving their value to our patients with cancer.