Current Cancer Drug Targets - Volume 13, Issue 3, 2013

AKT/PKB (Protein Kinase B) are central proteins mediating signals from receptor tyrosine kinases and phosphatidylinositol 3-kinase. AKT kinases are involved in a number of important cellular processes including cell proliferation and survival, cell size in response to nutrient availability, tumor invasion/metastasis, and angiogenesis. Various components of the AKT signaling pathway are encoded by tumor suppressor genes and oncogenes whose loss or activation, respectively, plays an important role in tumorigenesis. The growing body of evidence connecting deregulated AKT signaling with sporadic human cancers and inherited cancer predisposition syndromes is discussed. We also highlight new findings regarding the involvement of activating mutations of AKT1, AKT2, and AKT3 in somatic overgrowth disorders: Proteus syndrome, hypoglycemia with hypertrophy, and hemimegalencephaly, respectively. In addition, we review recent literature documenting the various ways the AKT signaling pathway is activated in human cancers and consequences for molecularly targeted therapies.

Studies on erythropoietin regulation led to discovery of hypoxia-inducible factor 1 (HIF-1), a transcription factor which is central component of oxygen sensing mechanism in mammalian cells. The number of HIF-1 and hypoxiaregulated target genes has grown exponentially and includes genes that encode proteins with roles in erythropoiesis, angiogenesis, glycolytic pathway, glucose transport, metastasis, and cell survival. Thus, HIF-1 claimed the role of the master that orchestrates cellular responses to oxygen deprivation. In addition, HIF-1 is also activated or influenced through oxygen-independent mechanisms via growth factors, deregulated oncogenes, and/or tumor suppressors. Whereas HIF prolyl hydroxylases (PHDs) regulate HIF-1 (and subsequently identified HIF-2) during hypoxia, the PI3K, AKT and MAPK pathways mediate primarily non-hypoxic HIF regulation. Here we will focus primarily on pathways that lead to HIF activation via PI3K/AKT, and mTOR/p70S6K1. In addition, recent studies have revealed novel factors and mechanisms that regulate oxygen-independent HIF-1α and HIF-2α degradation. HIFs play important roles in many processes in health and disease. Consequently, HIFs and pathways (PI3K/AKT and mTOR/p70S6K1) that lead to normoxic HIF activation are considered potential therapeutic targets in these pathologies.

Humans are exposed to heavy metals through a variety of occupational and non-occupational means. Growing evidence has accumulated that prolonged exposure to these heavy metals is associated with cancer occurrence at various body sites including lung, liver, bladder, colon, and skin. Much research effort has been placed on discovering the mechanisms by which heavy metals induce different kinds of cancers. Results from these mechanistic studies have varied for different metals, but increased activation of signaling pathways is often observed. This review will focus on the signaling molecules including epidermal growth factor receptor (EGFR), phosphatidyl inositol 3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR) in carcinogenesis and cancer progression; and how these molecules are affected by the exposure to heavy metals: arsenic, chromium, nickel, and cadmium. Furthermore, drug targets for the prevention and therapy of cancers induced by heavy metals will be discussed with a focus on drugs that are currently in clinical trials for these targets.

The mammalian target of rapamycin (mTOR) plays a critical role in the regulation of cell growth, proliferation, and metabolism by integrating growth factor stimulation and energy/nutrient input through a complex signaling network. The mTOR kinase is a part of two structurally and functionally distinct multiple protein complexes, mTORC1 and mTORC2. The mammalian target of rapamycin complex 1 (mTORC1) is rapamycin-sensitive and mediates temporal control of cell growth by regulating several cellular processes, such as translation, transcription, and nutrient transport while the mammalian target of rapamycin complex 2 (mTORC2) is insensitive to rapamycin and is involved in spatial control of cell growth via cytoskeleton regulation. Here we discuss the mechanism of mTOR regulation in tumor malignancy through a variety of signaling pathways and the potential of mTOR inhibitors for the treatment of cancer.

Dendritic cells (DCs) have traditionally been viewed as constituting an ‘information management’ system that functions solely to integrate a diverse array of incoming signals, in order to induce immune reactivity. In recent years, however, there has been a shift towards viewing these cells as key regulators in the orchestration of immunological tolerance, with increasing recognition that they are capable of suppressing T-cell responses depending on signalling processes and localised biochemical conditions. Indoleamine 2,3-dioxygenase (IDO) competent (IDO+) DCs are a subset of human DCs which are programmed to a tolerogenic state and play a vital role in establishing and maintaining a tumoursuppressing milieu. The expression of IDO in these DCs represents a key mechanism responsible for inducing the tolerogenic state. However, the mechanisms by which IDO becomes dysregulated in this subset of DCs have not yet been described. In this review, the function of IDO+ DCs within the cancer-tolerogenic milieu, as well as the signals responsible for expression of IDO in this subset, will be discussed.

Background and Aim: Heat shock protein 90 (HSP90) and mammalian target of rapamycin (mTOR) are involved in the molecular pathogenesis of advanced oral squamous cell carcinoma. HSP90 inhibitors are capable of effectively interfering with multiple signaling pathways, including the mTOR signaling pathway. However, the combined effects of HSP90 and mTOR inhibitors on oral squamous cell carcinoma are still unknown. In this study, we investigated the dual treatment of the novel HSP90 inhibitor NVP-AUY922 and temsirolimus against oral squamous cell carcinoma. Materials and Methods: The effect of the combination of NVP-AUY922 and temsirolimus on oral squamous cell carcinoma in vitro and in vivo was determined by MTS assay and mouse xenograft models. The effect of the combination on angiogenesis was determined by tube formation assay and angioreactor. Results: The combination treatment of NVP-AUY922 and temsirolimus significantly inhibited the proliferation of SAS oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. We have clearly shown that the combination treatment of NVP-AUY922 and temsirolimus inhibited vascular formation both in vitro and in vivo. Moreover, the combination treatment of NVP-AUY922 and temsirolimus prolonged the survival rate in mice xenografted with oral squamous cell carcinoma. Conclusions: Here, we showed the activity of a combination of mTOR and HSP90 inhibitors for the treatment of advanced oral squamous carcinoma.

The recent discoveries of genomic and molecular markers in hepatocellular carcinoma (HCC) have improved the understanding about the complexity of the signal transduction pathways as well as their relevance in normal and liver cancer cells. The identification of the functional repercussions of punctual mutations and crosstalk among cell signaling will promote the identification of specific combinatorial targeted molecular therapies to specific subsets of patients which will allow the development of personalized-based therapy and increase the survival of patients. Numerous molecular targets are in the cross-road between oncogenic and anti-apoptotic programs, genetic or epigenetic alterations, which overall may have a similar cellular phenotype. The standard antineoplastic chemotherapeutic regimes based on cytotoxic agents leads to significant side effect and modest response rates, marginal changes in natural history, and toxicities that may impact the quality of life of patients. Different strategies involving gene therapy, targeted antibodies or small molecules have been used to regulate cell death/proliferation signals, as well as angiogenesis in liver tumors. In this sense, Sorafenib recently approved for renal cell carcinoma, represents the first tyrosine kinase inhibitor (TKI) licensed for the treatment of patients with advanced HCC. This review summarizes the current status of molecular receptor TKI-based targeted therapy in HCC driving different pathways involved in cell survival, proliferation, migration, angiogenesis and metastasis, which include the regulation of Raf/MEK/ERK, PI3K/Akt/mTOR, and Jak/STAT cell signaling. The study also provides information about cell signaling crosstalk relevant in tyrosine kinase receptors (TKR)-based systemic therapy in HCC.

Biological agents, such as multikinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors, have replaced immunotherapy as the standard of care for metastatic renal cell carcinoma (mRCC). Several clinical trials have been performed, aimed to identify new feasible therapeutic targets. AKT, PI3K, STAT3, NOTCH-1, α5β1-integrin, CD70 and G250 are just examples of these opening frontiers. Novel agents, combination and sequences are emerging from the 887 clinical studies presently in course in mRCC to optimize patient outcomes. This report not includes studies on chemotherapy, local approaches, immunotherapy, surgical trials and other categories, but provides an update on ongoing phase I, II and III trials and preliminary results on targeted agents, used alone, in sequences or in combination for mRCC.

One of the major causes of failure in cancer chemotherapy is multidrug resistance (MDR), where cancer cells simultaneously become resistant to different anticancer drugs. Over-expression of membrane efflux pumps like Pglycoprotein (P-gp) that recognizes different chemotherapeutic agents and transports them out of the cell, plays a major role in MDR. The shortcoming of P-gp inhibitors in clinic has been attributed to their non-specific action on P-gp and/or non-selective distribution to non-target organs that leads to intolerable side effects by the P-gp inhibitor at doses required for P-gp inhibition upon systemic administration. Another major issue is the reduced elimination of P-gp substrates (e.g. anticancer drugs) and intolerable toxicities by anticancer drugs when co-administered with P-gp inhibitors. To overcome these shortcomings, new generation of P-gp inhibitors with improved specificity for P-gp have been developed. More recently, attention has been paid to the use of drug delivery systems primarily to restrict P-gp inhibition to tumor and reduce the non-selective inhibition of P-gp in non-target organs. This review will provide an overview and update on the status of P-gp inhibition approaches and the role of drug delivery systems in overcoming P-gp mediated MDR.