Current Medicinal Chemistry - Volume 18, Issue 11, 2011

During the last three decades, the advances in medical technology have elucidated many of the aspects of genetic and epigenetic pathways that commence the evolution of neoplasia. Standard therapeutic interventions include local control (surgery and/or radiotherapy) along with a combination of chemotherapeutic regimens for a systemic approach. Nevertheless, the appearance of genetically determined resistance to chemotherapeutic agents leads to treatment failures. Targeted tumor therapies consist of molecularly targeted substances that hamper the development and dissemination of malignant cells by interfering with the molecules implicated in cancer expansion and spreading. Targeted treatments, by focusing on specific molecular and cellular modifications of cancer cells, may be more successful than standard chemotherapy and, more importantly, less harmful to normal cells. There have already been some successful attempts of specialized targeting of malignant cells such as the antihormonal manipulation of testosterone and estrogen receptors in prostate and breast cancer, respectively. Our aim is to comprehensively review the current status and future directions of targeted cancer treatments focusing on colorectal cancer, the development of histone deacetylase inhibitors, the implication of endo-cannabinoid system in cancer therapies, the benefits from targeted treatment in lung adenocarcinoma patients, the incorporation of these agents in advanced gastric carcinoma, the emerging therapeutic targeted interventions in tumor-induced bone disease, the effect of targeted therapy in advanced renal cell carcinoma, and, finally, the resistance pathways to epidermal growth factor receptor tyrosine kinase inhibitors, in sufferers from non-small cell lung carcinoma. For decades before the year 2000, leucovorin (LV)-modulated 5-fluorouracil (5-FU) was the only active agent against colorectal cancer, but since then oxaliplatin and irinotecan and also three humanized monoclonal antibodies have been added in our armamentarium against this disease. These antibodies are targeting the vascular endothelial growth factor (bevacizumab) and the epidermal growth factor receptor (panitumumab and cetuximab). The purpose of adjuvant chemotherapy in colon cancer patients after a potentially therapeutic surgical resection is to eliminate micro-metastases, diminish recurrence and also augment cure rates. Adjuvant chemotherapy seems to be more beneficial in stage III (node-positive) disease, while advantage in stage II disease remains ambiguous and most authorities agree that bevacizumab and cetuximab are not recommended in this setting. On the other hand, in patients with non-operable, metastatic colorectal cancer the addition of bevacizumab to an assortment of first-line regimens have showed that improves outcomes. Nonetheless, this favourable response is accompanied by serious adverse events such as thromboembolic incidents, bleeding diathesis, bowel perforation, nephritic syndrome and hypertension. The second-line use of bevacizumab with another chemotherapeutic combination in patients who have failed to respond to the first-line bevacizumab containing regimens is still not established due to lack of sufficient evidence and more randomized clinical trials are needed. It could only be regarded as an option in a special patient group with K-ras mutations, because in those patients the administration of anti- epidermal growth factor receptor (EGFR) regimens is contraindicated. The combination of the anti-EGFR agent, cetuximab with irinotecan is valuable for patients with wild type K-ras tumors who do not respond to irinotecan and also as monotherapy for those who can not tolerate an irinotecan-based combination. Panitumumab has been used as monotherapy for patients with metastatic wild-type K-ras colorectal cancer, when all other agents have failed. The precise role of panitumumab in combination with chemotherapy, particularly for first-line therapy of metastatic colorectal cancer has to be further investigated. There is also accumulative evidence that in patients with wild type K-ras tumors, the combination of first and second line panitumumab with irinotecan or oxaliplatin regimens is more effective than chemotherapy alone but toxicity with severe diarrhoea and electrolytic disturbances was prominent. Further clinical trials comparing cetuximab versus panitumumab, but also each drug versus a bevacizumabcontaining combination are imperative. A deviant histone deacetylases activity has been recognized in several tumor types, rendering them an attractive potential therapeutic target.........

The endocannabinoid system comprises the cannabinoid receptors type 1 (CB1) and type 2 (CB2), their endogenous ligands (endocannabinoids), and the proteins responsible for their biosynthesis and degradation. This ubiquitous signalling system, that has attracted a great deal of scientist interest in the past 15 years, regulates several physiological and pathological functions. In mammals, among other functions, the endocannabinoid is involved in nervous, cardiovascular, metabolic, reproductive and immune functions. Finally, yet importantly, endocannabinoids are known to exert important antiproliferative actions in a great number of tumor cells including breast, brain, skin, thyroid, prostate and colorectal. The following review describes our current knowledge on the effects of two of the most studied endocannabinoids (AEA and 2-AG) on various types of tumor and summarizes the possible mechanism of observed antitumor effects.

Bone disease is a common complication of metastatic solid tumors but also of primary hematological malignancies such as multiple myeloma. Our understanding of the molecular mechanisms underlying the development of bone disease by solid tumors and multiple myeloma has been significantly improved. A complex inter-dependence exists between bone disease and malignant cell growth, creating a vicious cycle of extensive bone destruction and tumor progression. Although myeloma and solid tumors share a number of common molecular pathogenetic mechanisms, they involve distinct pathophysiological pathways, resulting in osteoclastic bone resorption and inhibition of bone formation. In this review, we analyze the molecular mechanisms, involved in tumor-induced bone disease and discuss the current therapeutic approaches and the most recent clinical developments of emerging targeted therapies.

Treatment of metastatic colorectal cancer (mCRC) has progressed significantly over the last years, particularly with the introduction of targeted therapies. Two groups of agents targeting either the epidermal growth factor receptor (EGFR) or the vascular endothelial growth factor (VEGF) have been integrated into clinical practice. Currently available agents with established role include the anti-EGFR monoclonal antibodies (mAbs) cetuximab / panitumumab and the anti-VEGF mAb bevacizumab. This review presents an update on the clinical studies evaluating the role of anti-EGFR and anti-VEGF agents in mCRC. Moreover, we provide current data regarding the mechanism of action and pathways mediating resistance to these agents. In addition, we present recent data with respect to biomarkers and we discuss future therapeutic strategies.

Non-Small-Cell Lung Cancer (NSCLC) with somatic mutations of the epidermal growth factor receptor (EGFR) is anticipated to respond to small-molecule tyrosine kinase inhibitors (TKIs) of the EGFR tyrosine kinase. There are, however, patients with EGFR mutated tumors who do not demonstrate tumor response. The most widely accepted mechanism of ‘de novo’ (inherent) resistance to these TKIs involves mutations of the KRAS gene. KRAS is a downstream mediator of EGFR-induced cell signaling, such mutations appear to be mutually exclusive from EGFR mutations in lung cancer. The first molecular modifier of resistance identified in patients who developed resistance (termed ‘acquired resistance’) to TK inhibition was a new acquired somatic EGFR mutation (T790M). Today there is an ever-growing series of molecular events that have recently come to the forefront to explain other instances of TKI resistance not attributable to T790M or KRAS. These include a number of molecules that interact with EGFR or form part of its downstream signaling pathway such as HER-2, IGFR-1, MET and B-RAF. Considering that the majority of studies carried out to date with respect to the identification of resistant clones have not used highly sensitive techniques (e.g. allelic discrimination to identify somatic mutations), coupled with the relatively low number of studies examining multiple molecular markers and the accepted molecular heterogeneity of NSCLC raise question as to the existence of ‘acquired’ versus ‘de-novo’ resistance. By examining the current knowledge base with respect to mechanisms of resistance to EGFR TKIs in NSCLC, we explore whether ‘acquired’ resistance is ‘de-novo’ resistance in disguise, and discuss the promises and limitations of molecular stratification with respect to strategies incorporating TKIs in the treatment of NSCLC.

Despite declining incidence in developed countries, gastric cancer is still the second cause of cancer death worldwide, while proximal gastric cancer is increasing in incidence. Cytotoxic combinations of platinum salts, fluoropyrimidines with or without taxanes or anthracyclines improved response rates but failed to improve the median survival of patients with advanced gastric cancer beyond the 12-month benchmark. Novel rationally designed therapies targeting molecular aberrations which are tumour-specific and pivotal for tumour survival, are urgently needed in order to improve patient outcome. Angiogenic mediators, transmembrane receptors, signal transduction molecules, transcription factors, epigenetic regulators and other biomolecules are among potential targets being modulated by monoclonal antibodies or small molecules in current phase I, II and III clinical trials. To date, only the addition of trastuzumab, an anti-HER2 monoclonal antibody combined with chemotherapy has yielded a clinically meaningful survival improvement in patients with advanced gastric cancer overexpressing HER2.

As of today, advanced non-small cell lung cancer is still an incurable disease. However, recent researches on the biology of adenocarcinoma have led to considerable progress in the treatment of this subgroup of patients. The administration of bevacizumab and pemetrexed as first-line therapy, erlotinib in the maintenance phase and erlotinib again combined with vandetanib as second-line therapy, gives patients with lung adenocarcinoma new hope. In particular, in metastatic adenocarcinoma with an EML4-ALK fusion oncogene, crizotinib (a selective, ATP-competitive, small molecule, orally bioavailable inhibitor of the ALK and MET/HGF receptor tyrosine kinases), led to a response rate of 64%, which is similar to the results achieved in chronic myeloid leukemia and GIST with imatinib. Overall, the application of all available active therapies during the natural history of adenocarcinoma may lead to a survival benefit that was unimaginable only a few years ago. This article reviews the main studies on molecular targeted therapies in various lines of treatment of advanced lung adenocarcinoma.

Surgery has been the mainstay of renal cell carcinoma (RCC) treatment for resectable tumours. In stages I-III disease, nephrectomy is the standard of care and may be curative. Historically, patients presenting with stage IV disease may achieve improved survival with debulking nephrectomy, which is commonly performed prior to systemic therapy. The response rate of immunotherapy is low, with a smaller percentage exhibiting complete remission upon treatment. Therefore, new therapeutic approaches against metastatic RCC are necessary. Recently, molecular mechanisms responsible for the proliferation of RCC have been identified, and molecular targeted therapy has developed. Clear cell RCC commonly features mutation or inactivation of the von Hippel- Lindau (VHL) gene and resultant over-expression of vascular endothelial growth factor (VEGF). The first drug to validate VEGF as a target in the treatment of clear cell RCC was the monoclonal antibody bevacizumab. Sunitinib is now a standard first-line therapy for advanced disease and sorafenib is among the second-line treatment options. Mammalian target of rapamycin (mTOR) is a second validated therapeutic target as the mTOR inhibitor temsirolimus has been shown to prolong survival in first-line treatment of poor prognosis RCC of all histologies. Everolimus is an oral mTOR inhibitor and has been shown to prolong progression-free survival (PFS) when used in second-line treatment. This review describes recent advances in molecular targeted therapy for metastatic RCC, focusing on chemical structure and mechanism of action of VEGFR and mTOR inhibitors.

Post translational modification of histones and non-histone proteins by acetylation play a key role in tumourigenesis. Histone deacetylases (HDACs) are enzymes involved in remodelling of chromatin by deacetylating the lysine residues and play a pivotal role in epigenetic regulation of gene expression. An aberrant activity of HDACs has been documented in several types of cancers and HDACs have emerged as an attractive therapeutic target. HDAC inhibitors (HDACi) are a structurally diverse group of anti-cancer agents which have a potential role in regulation of gene expression and induction of cell death, cell cycle arrest, and differentiation by altering the acetylation status of histone and non-histone proteins. HDACi have pleiotropic effects on malignant cells and have demonstrated potent anti-cancer activity in pre-clinical studies. A number of clinical trials of HDACi as a monotherapy and/or in combination with conventional and novel chemotherapeutic drugs in solid and haematologic tumours have been published with variable efficacy.

Cinnamic acid and its phenolic analogues are natural substances. Chemically, in cinnamic acids the 3-phenyl acrylic acid functionality offers three main reactive sites; substitution at the phenyl ring, addition at the α,β-unsaturation and the reactions of the carboxylic acid functionality. Owing to these chemical aspects cinnamic acid derivatives received much attention in medicinal research as traditional as well as recent synthetic antitumor agents. We observed that in spite of their rich medicinal tradition, cinnamic acid derivatives and their anticancer potentials remained underutilized for several decades since the first published clinical use in 1905. In last two decades, there has been huge attention towards various cinnamoyl derivatives and their antitumor efficacy. This review provides a comprehensive and unprecedented literature compilation concerning the synthesis and biological evaluation of various cinnamoyl acids, esters, amides, hydrazides and related derivatives in anticancer research. We envisage that our effort in this review contributes a much needed and timely addition to the literature of medicinal research.

Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc- containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. The inappropriate expression of these MMPs constitutes part of the pathogenic mechanism in several diseases, therefore they are subject to inhibition. They can be inhibited by endogenous proteinase inhibitors such as α2-macroglobulin or by the family of tissue inhibitors of metalloproteinases (TIMPs), which are glycoproteins of molecular weight 21-30 kDa, consisting of 184- 194 amino acid residues. Recently, many different classes of synthetic inhibitors have been developed in which the hydroxamic acidbased class of compounds (hydroxamates) have been most widely studied, as their hydroxamic acid group (CONHOH) enables them to act as a bidentate ligand with the zinc ion present in MMPs, leading to much stronger interaction with the receptor as compared to any other class of inhibitors. The present review describes in detail the recent development on this class of MMP inihibitors. Compounds like 12,17e, f, g and h, 45j, 45k, 50f, 62a, 63a, and 63b have been reported to be highly promising for further development.

Tuberculosis is a major global health challenge and is far from being controlled. Development of resistance to currently available drugs due to the successful adaptation of the pathogen has been a major contributing factor for its control failure. Presently, there is an immense interest in identification of pathways, unique to the intracellular environment that could be utilized for the development of new and better drugs. In this sequence, targeting essential functions of Mycobacterium tuberculosis has emerged as a reliable strategy for containing the spread of the disease by this organism. The fact that iron has been known to be the key player required for its survival and ability to spread infection, the organism must carefully balance iron acquisition with iron uptake for its infectivity. Conversely, this iron homeostatic process could be disrupted to interfere with the survival and replication of this bacterium in host. Urgency to develop such an approach has been further strengthened with the worldwide recrudescence of tuberculosis especially in the developing nations of the world. In the current review, we have focused on the recent developments in targeting the essential functions of mycobacterium especially interfering in its iron homeostatic process. The relevance of iron for mycobacterial virulence, the intracellular survival and the immense potential of targeting iron-sulfur (Fe-S) cluster containing proteins in tuberculosis drug discovery has been discussed.