Current Pharmaceutical Design - Volume 18, Issue 19, 2012

Over the last decades, the issue of developing novel target-based strategies for medical treatment of human neoplasias has become more and more relevant; in this context, the wider availability of more sophisticated molecular biology techniques has fuelled great enthusiasm in the possibility to clarify in-depth the molecular features of pathways critical for cancer biology, and to design more individualizes therapies. ErbB receptor family has been representing for years the prototype for development of target-based therapies: the documentation of peculiar cutaneous toxicity, and the emergence of resistance to erbB inhibiting drugs have pioneered novel concepts and approaches, such as the use of side effects as clinical signs of response to treatment, and the need to co-target multiple molecular pathways only apparently driving different biological effects [1]: for instance, the exploitation of drugs interfering with key molecules promoting tumor neoangiogenesis has revealed that besides the VEGF inhibiting strategies [2], other antiangiogenic approaches such as vascular disrupting agents together with inhibitors of erbB receptor signalling are being actively explored, and are currently at an advanced stage of clinical development [3,4]. In this context, much attention has been focused on other receptor-driven signalling pathways including the estrogen receptor-β, the G protein coupled receptors activated by the endothelins, the FMS-like tyrosine kinase-3 and the PI3/AKT/mTOR platform [5-8]. It has also to be underlined that new molecular insights will be instrumental to also develop suitable reliable markers of drug susceptibility, and clarify the overlapping, often cross-talking pathways in order to rationally develop combinatorial approaches for target based agents. Paradigmatic examples of the “from bench to bedside” journey are represented by the development of different classes of tubulin-binding agents whose activity and mechanisms of resistance strictly rely on targeting different isoforms of β-tubulin [9-11]. In particular, the selective ability of epothilones to target the class III β-tubulin which is involved not only in microtubule dynamics but also in cell survival pathways represents the biochemical support to the high efficacy of this class of agents against very aggressive, drug resistant cancer cells [10]. Similarly, the understanding of the molecular mechanisms of action of a “classic” drug such as gemcitabine contributed to setting up the pharmacogenetic basis for individualizing drug toxicity, and the rational development of combination with other agents and even radiotherapy [12]. In this context, the advent of nanotechnology represents a sophisticated strategy to deliver higher dose of therapeutics (be they drugs or radionuclides) to the tumor compared to normal cells, thus leading to a more favourable efficacy/safety balance [13]. Finally, besides searching novel molecular targets, much attention has been recently focused on the definition of novel cellular targets such as cancer stem cells, which represent the real engine of a tumor and are characterized by completely different molecular signatures compared to their more differentiated mature progeny and also normal counterpart [14]. These observations open new perspectives in terms of overcoming the major reason for treatment failure (i.e. chemoresistance) and improving the efficacy/toxicity ratio while preserving normal cell integrity....

Members of epidermal growth factor receptor (EGFR) or ErbB receptor family play a critical role in a wide range of human cancers. In the past decade, there has been a remarkable progress in developing ErbB targeted therapeutics. However, a substantial portion of patients has non-responsive disease or subsequently shows evidence of tumour relapse following initial success with anti-ErbB agents. Improved insights into the biology of ErbB receptor family have led to more effective second- and third-generation anti-ErbB therapies. In this review, we have summarised salient features of the ErbB receptor physiology and highlighted key mechanisms involved in abnormal ErbB signalling in tumorigenesis. The rationale of anti-ErbB receptor therapies are outlined along with key mechanisms proposed for resistance to treatment as well as the current concept of combined anti-ErbB therapies. In conclusion, improved understanding of the molecular pathways that confer resistance to anti-ErbB therapeutics will be essential in minimising tumour resistance to ErbB targeted treatments.

Tumour angiogenesis (formation of new blood vessels supporting tumour growth and metastasis) is a result of complex interactions between the tumour and the surrounding microenvironment. Targeting tumours with anti-angiogenic therapy remains an exciting area of preclinical and clinical studies. Although many significant advances have been achieved and the clinical use of anti-angiogenic drugs is now well recognized in many solid malignancies, these therapies fall short of their anticipated clinical benefits and leave many unanswered questions like exact mechanism of action, patients’ selection and monitoring response to anti-angiogenic drugs. Tumour angiogenesis is controlled by complex signaling cascades and ongoing research into molecular mechanisms of tumour angiogenesis not only helps to understand its basic mechanisms but hopefully will identify new therapeutic targets. In 2012, both monoclonal antibodies and small molecule tyrosine kinase inhibitors remain the two major clinically useful therapeutic options that interfere with tumour angiogenesis in many solid malignancies.

In the last decades, the active research in the field of tumor angiogenesis has led to the development of a class of agents providing an effective inhibition of neo-vessel formation through the blockade of VEGF related pathways. More recently, the identification of other factors involved in tumor angiogenesis, such as platelet-derived growth factor, fibroblast growth factor and Angiopoietins has emphasized the need to develop agents targeting multiple pro-angiogenic pathways. Although contrasting data are currently available regarding the clinical efficacy of multikinase inhibitors, Sunitinib, Sorafenib and Pazopanib have displayed encouraging results, and have fuelled further evaluations. Moreover, definitive data are also eagerly awaited regarding the clinical role of angiopoietins inhibitors. On the other hand, the existence of morphological, functional and architectural differences between normal and tumor vasculature has provided solid basis for the development of a novel class of compounds, known as Vascular Disrupting Agents (VDAs) able to selectively disrupt existing tumor vessels. After initial concerns related to the potential development of severe cardiovascular toxicities, further clinical investigations have shown a safe toxicity profile for these agents. Moreover, despite the discouraging data on dolostatin-10 and ASA404, several VDAs, including CAP4, Ombrabulin and Pinabulin have already shown promising activity in phase I-II clinical trials warranting more advanced evaluations. In this review we aimed at summarizing the most relevant VEGF-independent strategies targeting tumor vasculature, focusing on the clinical development of novel antiangiogenic agents including multikinase and angiopoietins inhibitors as well as VDAs.

Gynecologic cancer is a major burden in both developed and developing countries. Almost a half million deaths from gynecologic cancer are reported each year. Understanding the molecular biology of cancer is a principle resource leading to the identification of new potential therapeutic targets, which may be parlayed into novel therapeutic options in gynecologic cancer. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase, which plays a pivotal role in many aspects of malignant growth including cancer cell survival, migration, invasion, angiogenesis and metastasis. Various human cancer tissues have demonstrated high expression of FAK or activated FAK, which has been correlated with survival of cancer patients. Among gynecologic cancers, reports have emerged demonstrating that FAK is involved in the pathogenesis of ovarian, endometrial, and cervical cancers. In addition, the polycomb group protein enhancer of Zeste homologue 2 (EZH2), Dll4/notch and EphA2 has also emerged as important regulators of endothelial cell biology and angiogenesis. Herein, we review the role of these new targets in tumor angiogenesis and the rationale for further clinical development.

To assure their growth advantage cancer cells require the appropriation of key pathways, such as those controlled by G-protein coupled receptor (GPCR), that influence cell growth, migration, and death, as well as the expansion of vascular networks. Accumulating molecular and in vivo evidences demonstrate that the activation of the endothelin-1 (ET-1) axis elicites pleiotropic effects on tumour cells and on the tumour microenvironment as well, modulating epithelial to mesenchymal transition, chemoresistance, and other tumourassociated processes. As ET-1 axis blockade has been shown to reduce tumor growth in preclinical models, several small molecule antagonists of ET-1 receptors are currently undergoing clinical trial as novel agents in cancer therapy. To fully appreciate the potential hegemony of the ET-1 axis in cancer, here we review emerging preclinical and clinical data outlining the spectrum of cellular activities triggered by ET-1 signaling and the challenges facing molecular targeted therapy. Because scaffold proteins, such as β-arrestin, create signalling platforms that drive cellular transformation upon GPCR activation, mechanisms mediated by β-arrestin in ET-1 signalling are discussed. Deeper understanding of molecular mechanisms activated by ET-1 receptor, as well as of how pathway crosstalk can influence ET-1 signalling outcome in cancer, is of paramount translational relevance in the study of ET-1 receptor-targeted therapy. The improved knowledge of the interconnected molecular mechanism promoted by ET-1 axis in cancer will certainly result in more effective and durable mechanism-guided combinations of ET-1 receptor antagonists with cytotoxic drugs or other targeted agents in the clinical management of ET-1 axis-dependent malignancies.

While it is well documented that the mitogenic actions of estrogens are critical in the development and progression of human breast and some gynecologic cancers, only latest data demonstrate a crucial involvement of estrogen-signaling in the carcinogenesis of non-classical estrogen target tissues, as colon, prostate, lung, skin, and brain. Only recently it has also been found out that the biological effects of estrogens are mediated by two distinct estrogen receptors (ERs), ERα and ERβ, and that their relative levels in a given cell are important determinants of response to estradiol and selective estrogen receptor modulators. Indeed, although ERα and ERβ have similar structure, they produce different effects, and there is currently increasing evidence that, for some tumors, an imbalanced ERβ expression might play a pivotal role in tumor development and progression. However, the prognostic value, the potential significance in predicting response to endocrine therapy, and, eventually, the utility of ERβ as a therapeutic target need to be assessed in large-scale and prospective clinical studies. This review examines the experimental and clinical evidences for a role of ERβ in carcinogenesis of classical and nonclassical estrogen target tissues. If anomalies of ERβ expression could be demonstrated to represent a critical step in the development and progression of some types of cancers, its re-expression by genetic engineering, as well as the use of targeted ERβ therapies would constitute new important therapeutic approaches.

FMS-like tyrosine kinase-3 (FLT3) is a tyrosine kinase receptor involved in the survival and expansion of hematopoietic stem progenitors. A constitutively activated, mutated form of FLT3, is expressed in approximately 30% of de novo acute myeloid leukemia (AML) and about 6% of acute lymphoblastic leukemia (ALL) cases. Since mutant FLT3 has emerged as an attractive therapeutic target, there are several FLT3 inhibitors currently undergoing evaluation in different phases of clinical trials. However, although many aspects of the intracellular signaling mediated by oncogenic FLT3 have been revealed, what is the best strategy to inhibit FLT3 and how FLT3 inhibitors should be developed for AML treatment is poorly defined. Despite promising in vitro studies, where most FLT3 inhibitors show potent efficacy at nanomolar concentrations, clinical responses in AML patients are moderate and temporary. Furthermore, under prolonged therapy, FLT3 mutation-positive leukemic cells rapidly develop resistance to FLT3 inhibitors when used as monotherapy. Considering that there is no uniform mechanism of resistance triggered by FLT3 inhibitors, it will be necessary to develop new agents that target FLT3, and that can be used consecutively or in combination with conventional cytotoxic therapeutics. On the other hand, given that overexpression of FLT3 ligand (FL), occurring after myelosuppressive therapy, reduces the efficacy of FLT3 inhibitors, targeting both FL and FLT3 kinase, might be more effective approach in AML treatment. Here, we summarize up-to-date studies on FLT3 structure, its mutation status and role in malignant signal trafficking. We also review why FLT3 targeted therapies have not revolutionized AML treatment.

Background: The mammalian target of rapamycin (mTOR) is a protein kinase involved in the phosphatidylinositol 3-Kinase (PI3K)/AKT signalling pathway with a central role in the control of cell growth, survival and angiogenesis. Multiple and frequent dysregulations of this pathway in human tumors make it a central target in the development of new anticancer treatments. Objective: To review the most significant data on mTOR pathway, role of mTOR inhibitors in cancer treatment, preclinical and clinical data of the three first generation mTOR inhibitors (temsirolimus, everolimus and deferolimus), rationales, preclinical and clinical data of second generation mTOR inhibitors. Methods: Review of published literature on mTOR and related pathways, rapalogs and novel mTOR inhibitors. Results/conclusions: Temsirolimus and everolimus have been approved for the treatment of metastatic Renal Cell Carcinoma (RCC), temsirolimus also for Mantle Cell Lymphoma (MCL) and everolimus will be approved for pancreatic neuroendocrine tumors; all three rapalogs are currently evaluated in phase III studies in several tumors. Only limited published data are available on new mTOR inhibitors; however, in vitro and in vivo in preclinical studies they have shown a significant antiproliferative activity against a broad panel of tumors and a favourable safety profile, with disease stabilization or even tumor regression, either as single agent or in combination.

Tubulin is the target of some of the most widely used and time-honored anticancer tubulin-binding agents (TBAs). The clinical usefulness of many TBAs has been held back as a result of tumor cell drug-resistance. The elucidation of the three-dimensional structure of αβ-tubulin dimer has provided an opportunity for rational drug design aimed at generating compounds that will target tubulin in therapeutically more efficacious ways compared to presently available drugs. An issue to be addressed is which one(s) of the tubulin species, their isotypes, or their posttranslationally modified forms, should be specifically targeted in cancer chemotherapy. This review offers a critical appraisal of current knowledge on tubulins in cancer and an update on new anti-neoplastic microtubule-targeted treatment strategies. Specifically, it examines, across disciplines, cellular/molecular, biochemical, clinical/pathological, and pharmacological aspects of β-tubulin isotypes, posttranslational modifications of tubulin dimers, γ-tubulin and microtubule nucleation, and microtubule regulatory proteins. Emphasis is placed on the overexpression of (i) the βIII isotype, which functions as a survival factor associated with dynamic instability of microtubules; (ii) γ-tubulin, a key microtubule nucleating protein; and (iii) the microtubule severing enzyme spastin, involved in cell motility and proliferation of glioblastoma cells. The role of βIII-tubulin in resistance of cancer cells to taxanes is examined. Attention is called to the novel concept that βIII-tubulin functions as a "gateway" for prosurvival signals in partnership with GTPases, such as GBP1. Appraisal is also offered on epothilones and the concept of hypersensitization to TBAs as promising therapeutic strategies in taxane resistant epithelial cancers and in high-grade gliomas.

Among the drugs targeting microtubule functions by interfering with tubulin subunits, epothilones represent a class of anticancer agents which recently entered clinical development. Although epothilones share mechanisms of action similar to taxanes, they have non-overlapping mechanisms of resistance; in particular, while overexpression of class III β-tubulin plays a major role in taxane resistance, epothilones display their highest efficacy in class III β-tubulin overexpressing malignancies. Three compounds belonging to this family (patupilone, ixabepilone and sagopilone), have been actively investigated in clinical trials, and some of them are at an advanced stage of development. This review provides a comprehensive analysis of the available literature on epothilones, focusing on their clinical development and potential as an additional weapon in the arsenal against tumors.

The microtubule (MT) represents a highly validated target for therapy. Insights into the complex nature of the dynamic microtubule physiology will provide the basis for developing novel microtubule targeting agents with enhanced efficacy and minimised toxicity. In this article, with an emphasis on translational applications, we have summarised relevant aspects of tubulin physiology in the context of developing MT binding agents as therapeutic agents. Case studies were included to illustrate therapeutic developments in prostate cancer and current strategies to discover novel agents or targets for therapy.

Gemcitabine is one of the most widely used pyrimidine analogues, with a well-established role as a first- and second-line treatment of several types of tumors. Several preclinical and clinical studies have been done to obtain information on molecular determinants of gemcitabine activity and metabolism, in order to predict whether this drug will be effective and safe for the individual patient. Among these molecular determinants, the mRNA and protein expression of equilibrative transporter-1 (ENT1) and ribonucleotide reductase (RR) emerged as possible predictors of drug activity in studies on pancreatic and non-small cell lung cancer. However, cytidine deaminase polymorphisms and activity were correlated with clinical outcome and severe toxicities, whereas further studies should evaluate both P53 dependent and independent pathways involved in gemcitabine induced apoptosis. Improved knowledge on these determinants is critical for the optimal development of combination of gemcitabine with other conventional or biological therapies, as well as to exploit the radiosensitizing potential of gemcitabine. Emerging technologies such as massive parallel sequencing, gene expression arrays and proteomics may identify novel biomarkers in tumor material, while polymorphisms and phenotyping analysis should unravel factors involved in drug toxicity. Validation of these markers in preclinical models should be used for the appropriate patient enrolment into subsequent prospective studies. Hopefully, novel pharmacogenetic biomarkers will be validated in these prospective studies and used to select cancer patients to be treated with gemcitabine-based regimens in the near future or to enroll them in studies with prodrugs in order to bypass resistance mechanisms.

Chemoradiotherapy is an important treatment paradigm in oncology and is part of the curative treatment for many solid cancers, such as lung, pancreatic and cervical cancers. One of the main goals in oncology research is to develop approaches that can improve the efficacy of chemoradiotherapy while minimizing treatment toxicity. A new and exciting approach is to incorporate advances in nanomedicine into chemoradiotherapy. Nanoparticles possess unique properties, such as preferential accumulation in tumors and minimal uptake in normal tissues, that make them ideally suited for delivering chemotherapy in chemoradiotherapy. In this review, we plan to discuss the rationale and evidence for applying nanomedicine to chemoradiotherapy.

Cancer stem cells (CSCs) were identified in human leukemias in landmark studies of John Dick and his colleagues. Subsequently, similar cancer stem-like cells were identified in solid tumors of the breast, colon, brain and other sites. CSCs have distinct markers and are highly tumorigenic compared to other subsets. They can differentiate into all the cell phenotypes of the parental tumor. Other key features include activation of pluripotency genes (Oct4, Sox2, Nanog), self-renewal, formation of tumor spheres in low-adherence cultures, and multi-drug resistance. Clinically, drug resistance is probably the most important feature, because CSCs resist conventional cancer therapies and are likely to play a major role in cancer relapse. Based on their properties, several molecules have been targeted for therapy with drugs as follows. 1) The self-renewal pathways Wnt/β-catenin, Hedgehog and Notch. 2) The aryl hydrocarbon receptor (AHR), with tranilast and other AHR agonists. 3) Cytokines and inflammatory pathways (e.g., IL-6, IL-8, NF-κB). 4) TGF-β and epithelial- to-mesenchymal transition (EMT) pathways. 5) Homing molecules involved in metastasis; most notably CXCR4 or its ligand CXCL12. 6) Growth factors, their receptors and coreceptors (such as neuropilin-1), and signaling components (e.g., tyrosine kinases). 7) Cell-surface markers (CD44 and integrins). Several drugs have been identified by screening or other observations (salinomycin, metformin, tesmilifene, sulforaphane, curcumin, piperine and others). Some of these drugs are at preclinical or early clinical phases of development, and it remains to be seen how many will progress to clinical application. This review focuses on some promising new developments in anti-CSC drug therapy.