Current Drug Targets - Volume 12, Issue 14, 2011

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.

Heat shock proteins (Hsp) are highly conserved proteins and their expression is dependent on the level of various cellular stresses. Hsp work as a molecular chaperon for several cellular proteins and have cytoprotective roles. Their function is essential for normal cell viability and growth. Hsp90 interacts with proteins mediating cell signaling involved in essential processes such as proliferation, cell cycle control, angiogenesis and apoptosis. The naturally occurring Hsp90 inhibitor geldanamycin (GA) was the first to demonstrate anticancer activity but its significant toxicity profile in pre-clinical models precluded its clinical development. Subsequent, several Hsp90 inhibitors have been developed and underwent clinical development with favorable safety profiles. Several initial clinical studies have shown promising anticancer activity of Hsp90 inhibitors mainly in breast cancer, non small cell lung carcinoma (NSCLC), gastrointestinal stromal tumors (GIST) and various hematological malignancies. The universal involvement of Hsp90 in multiple oncogenic processes makes Hsp90 inhibitors ideal compounds to be explored as a single agent or in combination with other anticancer therapies.

Vascular Disrupting Agents (VDA) are a potential new class of oncology drugs that have garnered attention recently as a number of these agents have entered into Phase 2-3 studies. Currently available data suggest how the subsequent evolution of these agents into clinical practice may proceed, with new therapeutic paradigms based on similarities, differences and interactions with current standard of care agents. In particular, the broadly successful group of agents targeting angiogenesis through the Vascular Endothelial Growth Factor (VEGF) pathway, can be contrasted to the VDAs that principally disrupt established tumor vasculature through a different set of molecular targets. Although the angiogenesis inhibitors may benchmark where other vascularly targeted agents such as VDAs may be successful, the differences in terms of efficacy and safety profiles lead to important differentiation in how VDAs are likely to be used. Although the majority of VDAs bind tubulin, significant differences also exist between VDAs and cytotoxic agents, including tubulin targeted agents such as taxanes and vinca alkyloids. Clinical trial data is now available for several VDAs allowing such assessment. Data of yet has been the strongest in NSCLC, with indications of how these drugs may be developed beneficially in subsets of patients such as those with squamous cell histology or at risk of bleeding events. Other indications being aggressively pursued include prostate carcinoma, ovarian carcinoma, sarcomas and astrocytomas. The field also continues to advance with investigation into how to optimally schedule administration of VDAs and what effects might be class effects and/or markers of efficacy.

Insulin-like growth factor type-1 receptor (IGF-1R) plays a central role in cell proliferation and survival and is overexpressed in many tumor types. Notably, IGF-1R-mediated signaling confers resistance to diverse cytotoxic, hormonal, and biologic agents, suggesting that therapies targeting IGF-1R may be effective against a broad range of human malignancies. Cixutumumab (IMC-A12; ImClone Systems) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically inhibits IGF-1R signaling. Binding of cixutumumab to IGF-1R results in receptor internalization and degradation. Because cixutumumab is an IgG1 monoclonal antibody, it may induce additional cytotoxicity via immune effector mechanisms such as antibody-dependent cellular cytotoxicity. In preclinical studies, cixutumumab monotherapy resulted in growth inhibition of multiple experimental cancers. Moreover, cixutumumab safely enhanced the tumor growth inhibitory and cytotoxic effects of a broad range of chemotherapeutics, and modulated the action of agents that target hormone receptors and signal transduction, which may have implications for cancer therapy. Herein, we review published preclinical and clinical data for cixutumumab and provide a comprehensive overview of selected clinical studies.

Poly(ADP-ribose) polymerase (PARP) is a critical DNA repair enzyme involved in DNA single-strand break repair via the base excision repair pathway. PARP inhibitors have been shown to sensitize tumors to DNA-damaging agents and to also selectively kill homologous recombination repair-defective cancers, such as those arising in BRCA1 and BRCA2 mutation carriers. Recent proof-of-concept clinical studies have demonstrated the safety and substantial antitumor activity of the PARP inhibitor, olaparib in BRCA1/2 mutation carriers, highlighting the wide therapeutic window that can be achieved with this synthetic lethal strategy. Likewise, the PARP inhibitor, BSI-201, in combination with carboplatin and gemcitabine have produced promising results in “triple-negative” breast cancers. There are also currently numerous other PARP inhibitors in clinical development. The potential broader therapeutic application of these approaches to a wide range of sporadic tumors harboring specific defects in the homologous recombination repair pathway has generated a great deal of excitement within the oncology community. This review discusses the rationale for targeting PARP and details the strategies and challenges involved in the clinical development of such inhibitors and their future potential applications in cancer medicine.

The hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/c-MET) receptor tyrosine kinase (RTK) pathway plays a pleotropic role in cell proliferation, migration, invasion, angiogenesis and survival. Although it has critical physiological functions in embryonic development and tissue repair, this signaling cascade is frequently deregulated in a wide range of tumors. Aberrant HGF/c-MET signaling, driven by various mechanisms, including constitutive activation and over-expression, has multifunctional effects in oncogenesis and is implicated in the acquisition of an aggressive phenotype with metastatic potential. The central role of c-MET activity in cancer progression, as well as disparities between quiescent HGF/c-MET signaling in normal tissue and overexpression in tumor may provide a degree of tumor selectivity for therapeutic intervention, making HGF or c-MET inhibition an attractive proposition in oncology. This review focuses on the underlying oncogenic role of aberrant HGF/c-MET signaling in malignant progression, as well as recent preclinical and clinical data on the different strategies employed in inhibiting HGF/c-MET function.

The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to cancer development and progression. They were first recognized as pro-viral integration sites for the Moloney Murine Leukemia virus. Unlike other kinases, they possess a hinge region which creates a unique binding pocket for ATP. Absence of a regulatory domain means that these proteins are constitutively active once transcribed. Pim kinases are critical downstream effectors of the ABL (ableson), JAK2 (janus kinase 2), and Flt-3 (FMS related tyrosine kinase 1) oncogenes and are required by them to drive tumorigenesis. Recent investigations have established that the Pim kinases function as effective inhibitors of apoptosis and when overexpressed, produce resistance to the mTOR (mammalian target of rapamycin) inhibitor, rapamycin . Overexpression of the PIM kinases has been reported in several hematological and solid tumors (PIM 1), myeloma, lymphoma, leukemia (PIM 2) and adenocarcinomas (PIM 3). As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Novel small molecule inhibitors of the human Pim kinases have been designed and are currently undergoing preclinical evaluation.

The Aurora family of serine/threonine kinases is essential for chromosome alignment, segregation, centrosomal maturation, mitotic spindle formation, and cytokinesis during mitosis. Their fundamental role in cell cycle regulation and aberrant expression in a broad range of malignancies prompted the development of small molecules that selectively inhibit their activity. Recent studies have revealed new insights into the cellular effects of Aurora kinase inhibition. Moreover, early phase clinical studies have shown that these agents have therapeutic efficacy. In this review, we will outline the functions of Aurora kinases in normal cell division and in malignancy. We will focus on recent preclinical and clinical studies that have explored the mechanism of action and clinical effect of Aurora inhibitors in cancer treatment.

Tumor necrosis factor-related apoptosis-inducing ligand or Apo2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) superfamily that induces apoptosis upon binding to its death domain-containing transmembrane receptors. The preferential toxicity of TRAIL to cancer cells and the sparing of normal cells make it an ideal cancer therapeutic agent. TRAIL induces apoptosis via the extrinsic death receptor apoptotic pathway and activates the JNK, ERK, Akt and NF-κB signaling cascades. However, not all cancer cells are sensitive to TRAIL therapy. This may limit its efficacy in the clinic, although ways have already been identified to overcome resistance by combining TRAIL with chemotherapeutic and other biological agents. This review focuses on TRAIL receptor-targeting as anticancer therapy, the apoptotic signaling pathways induced by TRAIL receptors, the prognostic implications of TRAIL receptor expression and modulation by combination therapies. The mechanisms of TRAIL resistance and strategies to overcome drug resistance will also be addressed. Finally, the progress of TRAIL and DR4/DR5-specific agonistic antibodies in clinical trials and the development of new receptor-selective TRAIL variants are discussed including future directions for apoptosis inducing therapy.

Contrary to the Classical Greek poet Archilochus' phrase “The fox knows many things but the hedgehog knows one big thing”, the Hedgehog (HH) signaling pathway knows at least 3 ways to promote or support carcinogenesis. In this review, we provide a summary of the HH signaling pathway, and detail the clinical relevance and treatment of patients. Finally, future directions in exploiting this promising pathway will be addressed.

Recent meta-analyses have revealed that the risk of bone fracture is increased in both type 1 and type 2 diabetic patients. Low bone mineral density (BMD) can not necessarily explain the link, because BMD is increased rather than decreased in type 2 diabetes, while it is consistently low in type 1 diabetes subjects. Although multiple factors could influence the quality of bone and increase the bone fragility in diabetes, there is accumulating evidence for the association between osteoporosis and vascular calcification, which is an independent predictor of cardiovascular disease morbidity and mortality. Advanced glycation end products (AGEs) are formed by a non-enzymatic reaction between aldehydes of reducing sugars and the amino groups of proteins, lipids and nucleic acids that could contribute to the aging of macromolecules. The formation and accumulation of AGEs have been known to progress at an accelerated rate under diabetes. There is a growing body of evidence that AGEs and their receptor (RAGE) system elicit oxidative stress generation and subsequently evoke inflammatory responses in vascular wall cells, osteoblasts and osteoclasts, thereby being involved in both vascular calcification and osteoporosis in diabetes. Further, cross-linking in the organic bone matrix by AGEs could adversely affect the fracture resistance of bone. Therefore, in this paper, I review the pathophysiological role of the AGEs-RAGE-oxidative stress system in decreased BMD and increased bone fragility in diabetes. I also discuss here the potential therapeutic interventions of the AGEs-RAGE axis for preventing osteoporosis in diabetes.

Obesity and degenerative joint disease (osteoarthritis, OA) are two multifactorial pathologies that are becoming major medical issues with the aging of the world population. The relationship of OA with obesity is complex, involving both biomechanical and metabolic links. Dysregulated production of adipose tissue-derived inflammatory mediators, hyperlipidemia, and increased systemic oxidative stress are conditions frequently associated with obesity that may favor joint degeneration. In addition, it is remarkable that many regulatory factors have been implicated in the development, maintenance and function of both adipose tissues and cartilage and other articular joint tissues. Disturbances in these factors may underlie additional links between obesity and OA. In this review, molecular players at the intersection of adipose tissue and joint cell biology - including differentiation signals and transcription factors, extracellular matrix components and remodelers, joint cell- and adipose tissue cell-derived mediators (cytokines, adipokines), hypoxia inducible transcription factors, lipids, advanced glycation end products and miRNAs - are reviewed, with emphasis on their dysregulation in obesity and OA. Knowledge of these factors may illuminate a novel, adipocentric avenue for the pathogenesis and therapy of OA and other joint diseases.

Malaria has emerged as one of the most debilitating parasitic infection with about 500 million cases reported annually and one million deaths worldwide. Currently, Plasmodium falciparum has developed resistance to almost all classes of antimalarials, thus precluding the use of those agents which once formed the cornerstone of malaria therapy. In lieu of this phenomenon, and taking into consideration the absence of an effective vaccine for malaria, the only way to combat the deadly parasite is to enrich the antimalarial cache with new molecules acting on fresh targets in the parasite. After potential targets have been validated, these targets can be used as basis for screening compounds to identify new leads followed by lead optimization. This review discusses novel targets of the malaria parasite that can be utilized to treat the disease.