Current Drug Targets - Volume 11, Issue 1, 2010

Despite significant advances in the treatment of non-small cell lung cancer (NSCLC) over the past several years, the prognosis for patients with advanced disease is still very poor. NSCLC patients treated with standard regimens containing cisplatin or carboplatin have a median survival of 8-11 months for patients with Stage IV disease and 5-7 months for patients with relapsed disease. Evaluation of new treatment strategies is ongoing to identify more effective treatment for patients with NSCLC. Pemetrexed, a pyrriol (2,3-d) pyrimidine antifolate is unique among the folate antagonists in that it is a powerful inhibitor of not only thymidylate synthase (TS) but also dihydrofolate reductase (DHFR) and the purine synthetic enzyme, glycinamide ribonucleotide formyltransferase (GARFT). It was approved for the treatment of mesothelioma and non-small cell lung cancer, currently being evaluated for the treatment of a variety of other solid tumors. Pemetrexed shows clear activity in non-small cell lung cancer. The first phase III study of pemetrexed in NSCLC established similar efficacy and a favorable safety profile for pemetrexed compared with docetaxel in the second-line setting. A second phase III study of pemetrexed in NSCLC reported noninferior efficacy and better tolerability for cisplatin plus pemetrexed than for cisplatin plus gemcitabine in the frontline setting. The knowledge of mechanisms of action of pemetrexed, and the understanding of the determinants of response, may allow the clinician to select patients who are more likely to respond to this drug, either used alone or in combination. This issue of Current Drug Targets tries to describe the pharmacology and mechanisms of action, clinical activity, predictive markers for hematological toxicity, and current status and future directions of the pemetrexed and the combination with platinums, gemcitabine, anti-angiogenic agents (bevacizumab and small molecule tyrosine kinase inhibitors), inhibitors of epidermal growth factor receptor (cetuximab and erlotinib), inhibitor of the protein kinase β (enzastaurin), and radiation therapy in patients with non-small cell lung cancer as well as lung adenocarcinoma, mixed subtype with bronchioloalveolar carcinoma features.

Pemetrexed is a novel third-generation multitargeted antifolate agent used in the first- and second-line treatment of unresectable pleural mesothelioma and advanced non-small cell lung cancer (NSCLC). Owing to its mild toxicity, this compound is a preferred partner in the multidrug regimens. In the last few decades, better understanding of molecular oncology and genetics has allowed for the development of an array of molecular targeted agents, many of which have been found active in NSCLC. It has been hoped that these compounds will disrupt tumor signaling pathways complementary to those targeted by chemotherapy. This review outlines the current preclinical and clinical studies using pemetrexed in combination with targeted agents in advanced NSCLC. Clinical experience with the use of these combinations is still limited and mostly includes phase I and II trials. These investigations have mainly focused on compounds previously shown to be active in NSCLC: anti-angiogenic agents (bevacizumab and small molecule tyrosine kinase inhibitors) and inhibitors of epidermal growth factor receptor (cetuximab and erlotinib). Preliminary results have shown the feasibility of these combinations and their promising activity but large phase III studies are warranted to verify the real value of this strategy. Combinations of pemetrexed with other targeted agents, such as mTOR inhibitors and compounds targeting proteasome are still at early stages of development.

Conventional regimens have limited impact against NSCLC. Current research is focusing on multiple pathways as potential targets, and this review describes pharmacological aspects underlying the combination of the PKCβ-inhibitor enzastaurin with the multitargeted antifolate pemetrexed. Pemetrexed is commonly used, alone or combined with platinum compounds, in NSCLC treatment, and ongoing studies are evaluating its target, thymidylate synthase (TS), as predictor of drug activity. Enzastaurin is a biological targeted agent actively being investigated against different tumors as single agent or in combination. All the downstream events following PKCβ inhibition by enzastaurin are not completely known, and assays to evaluate possible biomarkers, such as expression of PKC, VEGF and GSK3β, in tissues and/or in blood samples, are being developed. Enzastaurin-pemetrexed combination was synergistic in preclinical models, including NSCLC cells, where enzastaurin reduced phosphoCdc25C, resulting in G2/M-checkpoint abrogation, and Akt and GSK3β phosphorylation, favoring apoptosis induction in pemetrexed-damaged cells. Enzastaurin also significantly reduced VEGF secretion and pemetrexed-induced upregulation of TS expression, possibly via E2F-1 reduction, while the combination decreased TS activity. Similarly, the accumulation of deoxyuridine (a marker of TS inhibition) and the reduction of GSK3β phosphorylation were detectable in clinical samples from a phase-Ib trial of pemetrexed-enzastaurin combination. In conclusion, the favorable toxicity profile and the multiple effects of enzastaurin on signaling pathways involved in cell cycle control, apoptosis and angiogenesis, as well as on proteins involved in pemetrexed activity, provide experimental basis for future studies on enzastaurin-pemetrexed combination and their possible pharmacodynamic markers in NSCLC patients.

The incidence of lung cancer in 2007 is estimated to be 213,380 with 160,390 deaths in the United States. It contributed to 31% of male and 26% of female cancer-related deaths and is the largest cause of cancer-related mortality in both men and women. Despite some advances in the treatment of advanced non-small cell lung cancer (NSCLC), the introduction of third-generation cytotoxic agents (vinorelbine, gemcitabine, docetaxel, irinotecan, and paclitaxel) has not achieved a breakthrough in the dismal prognosis of this disease. Several meta-analyses have proved the superiority of 2- drug chemotherapy and cisplatin-based chemotherapy, but no gold standard exists. This paper summarizes the clinical data of a new cytotoxic agent, pemetrexed, and its combination with platinums in the treatment of NSCLC. The addition of vascular endothelial growth factor (VEGF) inhibitor (bevacizumab) or an EGFR-targeted drug (cetuximab) to pemetrexed/platinum in NSCLC, and the role of pemetrexed/platinum in adjuvant chemotherapy for early-stage NSCLC were also discussed in this paper.

Pemetrexed is a newer antifolate drug that has been approved as first-line treatment for patients with advanced non-squamous, non-small cell lung cancer (NSCLC) in combination with cisplatin, and as single agent for relapsed or chemotherapy refractory NSCLC after platinum-containing chemotherapy, at a dose of 500 mg/m2. Pemetrexed undergoes intracellular activation by poly-γ-glutamylation, that is essential for its antiproliferative activity. Polyglutamate derivatives mainly inhibit three key enzymes of intracellular folate metabolism, i.e. thymidylates synthase (TYMS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), with TYMS being the most relevant target. Pemetrexed undergoes rapid renal elimination as unchanged parent compound, with a terminal half-life of between two to five hours. In later clinical development, the usefulness of supplementation with folic acid and vitamin B12 became evident, to control pemetrexed-related toxicity. The results from the phase III upfront registration study, a retrospective observational data, and a recent maintenance study of pemetrexed in NSCLC suggest histological subtype to be the most important predictive marker for clinical outcome in patients receiving pemetrexed. Pemetrexed is active in patients with non-squamous cell NSCLC while no benefit is seen in patients with squamous-cell histology, possibly as a result of different expression of intratumoral TYMS. These are important steps towards individualisation of anticancer treatment in patients with advanced NSCLC.

Pemetrexed is a multi-targeted anti metabolite that inhibits several key folate-dependent enzymes in the thymidine and purine biosynthetic pathways, including thymidylate synthase. It is currently approved for use in patients with non-small cell lung cancer and malignant mesothelioma. The sporadic and unpredictable occurrence of haematological toxicities of pemetrexed leading to potentially life threatening complications during the early developmental phase, prompted urgent need to identify potential predictive factors for haematological toxicities from pemetrexed. There is a well established association between elevated plasma homocysteine concentration, which is indicative of impaired functional folate status, and increased risk of haematological toxicity from pemetrexed. The decrease in incidence of toxicity after vitamin supplementation confirms the importance of functional folate status as a predictor for haematological toxicity. We review other factors that have a documented impact on haematological toxicity, including pemetrexed schedule, and pharmacokinetic parameters that are indicative of the extent of drug exposure. Further potential factors are explored in this review, such as the genotype of the pemetrexed metabolising enzymes and varying incidences of polymorphism of these genotypes in different ethnic groups that may account for the ethnic differences in neutropenic response to pemetrexed.

Despite improvements in first-line therapy for advanced NSCLC all patients with metastatic disease will progress at some point. Patients with favorable prognostic factors such as good performance status, non-squamous histology, stable weight, and perhaps female gender are more likely to receive second-line chemotherapy. Currently the United States FDA recognizes three single agents (docetaxel, erlotinib, and pemetrexed) as established for providing a benefit in patients who have experienced progression after first-line therapy. This review focuses on the role of PEM in the treatment of advanced NSCLC in patients who have experienced disease progression during or after first-line therapy. The multi-targeted antifolate pemetrexed is equivalent to docetaxel for second-line therapy and with less toxicity.

Pemetrexed is a multitargeted antifolate that inhibits at least three folate dependent enzymes involved in DNA synthesis. Gemcitabine is a broadly active pyrimidine nucleoside antimetabolite that is incorporated into DNA and causes chain termination. Both pemetrexed and gemcitabine, as single agents, have shown antitumor activity in a wide range of solid tumors, including non-small-cell lung cancer (NSCLC). Based on preclinical in vitro and in vivo synergism of the combination of pemetrexed and gemcitabine, the 2 drugs were studied in several phase I and II trials in patients with advanced NSCLC. The published studies found response rates between 13 to 31%, with overall survival times similar to established standard chemotherapy regimens. The grade 3 or 4 toxicities with this combination are mainly haematologic, dermatologic and transaminitis. In this paper, we review the pemetrexed-gemcitabine combination in the treatment of NSCLC patients with regards to the rationale, clinical activity as well as the future directions for this new 2-drug combination.

Approximately one out of every three patients with non-small cell lung cancer (NSCLC) has locally advanced disease that is surgically unresectable. If their performance status allow, it is current practice to treat these patients with a combination of chemotherapy and external beam irradiation. There have been several studies supporting the addition of chemotherapy to radiation, particularly when delivered concurrently. There is a debate over which treatment agents and schedules are the most optimal, even with the most proven treatments delivering only modest results, with high rates of local and distant disease failure. Advances in imaging, radiation planning and delivery technology have allowed the potential for improvement of the therapeutic ratio by reducing normal tissue exposure and ensuring for more precise delivery, while new systemic agents show promising activity in NSCLC. Pemetrexed is a pyrrolopyrimidine-based folate anti-metabolite that works by inhibiting a variety of enzymes of thymidylate and purine synthesis, thus leading to cell stasis and death. Similar to other cytotoxic antifolates, pemetrexed has been shown in pre-clinical study to act as an effective radiosensitizer. At present, it is being studied in phase I and II studies when combined with other systemic agents and radiation therapy in the treatment of locally advanced NSCLC, and the results have been promising. It has the advantage of allowing relatively safe delivery of full systemic doses when combined with other agents and radiation therapy, a distinction over combined modality treatments. Its efficacy, particularly in non-squamous NSCLC, in phase I and II studies has lead to investigations in the phase III setting where a more defined role for pemetrexed in locally advanced non-squamous NSCLC will potentially be defined. This review summarizes the use of combined modality treatment in locally advanced NSCLC, outlines recent advances in radiation planning and treatment, and reviews the current data on the use of concurrent chemoradiation regimens featuring pemetrexed.

Bronchioloalveolar carcinoma (BAC) and adenocarcinoma with bronchioloalveolar features (ADC-WBF) belong to the same anatomo-clinical entity and show very similar epidemiologic, clinical and biological characteristics. However there is a lack of consensus for the treatment of unresectable forms. Although epidermal growth factor receptor tyrosine kinase inhibitors and paclitaxel do have some efficacy, the aim of this review is to assess the role that pemetrexed, a new generation antifolate, could play in this context. Pemetrexed has proved to be particularly effective in advanced lung adenocarcinomas and unresectable mesotheliomas, and cases of major and sustained responses of ADCWBF to pemetrexed have been reported. The preclinical rationale explaining this efficacy is that it inhibits the growth of BAC cell lines in vitro. BAC tumors overexpress FR-α, a protein involved in pemetrexed intracellular transport, at rates higher than those observed in lung adenocarcinomas and mesotheliomas and it would seem that pemetrexed efficacy is correlated to FR-α expression. The role played by thymidylate synthase expression level in sensitivity to pemetrexed also needs to be specifically explored in ADC-WBF. The results of two phase II trials, SWOG 0526 and IFCT 05-04, will hopefully provide decisive information on the relevance of pemetrexed in ADC-WBF management and the molecular predictors of response.

Platinum-based doublet chemotherapy is now established as a standard of care in the adjuvant treatment of resected stage II and stage IIIA nonsmall cell lung cancer, and seems reasonable also in resected stage IB when the primary tumor measures ≥4 cm. Several issues remain unresolved, however, including individualized selection of both the optimal platinum (cisplatin vs carboplatin), and the optimal nonplatinum drug; and identification of patients who will not need chemotherapy (“surgically cured”), as well as patients who cannot benefit because of inherently drug resistant disease. Furthermore, while efficacy remains a priority, it is also necessary to improve the management of toxicity, both because it may compromise dose intensity and because it carries a risk of morbidity and even mortality. Other issues, such as the role of postoperative radiotherapy, the choice between neoadjuvant and adjuvant approaches, the role of targeted agents, and the possibility of harm and how it can be mediated, also merit serious attention. Finally the durability of benefit, the question of late toxicity, and the importance of smoking cessation are also open questions. I will discuss a potential role for pemetrexed in the adjuvant treatment of early stage nonsmall cell lung cancer with some of these issues in mind.

Both the multi-targeted antifolate pemetrexed and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib have established roles in the treatment of advanced non-small cell lung cancer (NSCLC). Given different mechanisms of action and minimal overlapping toxicities, combinations of these agents have been considered. However, four previous phase III trials investigating concurrent chemotherapy with or without EGFR TKIs showed no clinical benefit. Based on preclinical data, we developed a model of pharmacodynamic separation to avoid potential negative interactions between chemotherapy and EGFR TKIs in NSCLC tumors containing wild-type EGFR gene. This review summarizes the background, scientific rationale and early clinical data in support of intercalation of intermittent erlotinib dosing with pemetrexed as a means of achieving pharmacodynamic separation. Ongoing research efforts investigating this concept are reviewed.

Despite recent advances, treatment of leukemia is often not curative. New insights indicate that this may be attributable to a small population of therapy-resistant malignant cells with self-renewal capacity and the ability to generate large numbers of more differentiated leukemia cells. These leukemia-initiating cells are commonly referred to as Leukemia Stem Cells (LSCs). LSCs are regarded as the root of leukemia origin and leukemia recurrence after seemingly successful therapy. Not surprisingly therefore, contemporary leukemia research has focused on ways to specifically eliminate LSCs, leading to the identification of several promising anti-LSC strategies. Firstly, LSCs may be eliminated by antibody- or ligand-based cell surface delivery of therapeutics such as naked antibodies, immunotoxins, and immunocytokines. This approach exploits LSC-associated surface antigens, such as CD33, CD44, CD96, CD123 and CLL-1 for LSC-selective therapy and aims to spare normal hematopoietic stem cells. A second strategy aims to disrupt the interactions between LSCs and their highly specialized niche. These interactions appear to be pivotal for maintenance of the stem cell-like characteristics of LSCs. A third strategy centers on the selective modulation of aberrantly activated signaling pathways central to LSC biology. A fourth strategy, dubbed ‘epigenetic reprogramming’, aims to selectively reverse epigenetic alterations that are implicated in ontogeny and maintenance of LSCs. In this review, we will discuss the rationale for these LSCs-targeted strategies and highlight recent advances that may ultimately help pave the way towards selective LSCs-elimination.

Coenzyme Q10 (CoQ10, or ubiquinone) is an electron carrier of the mitochondrial respiratory chain (electron transport chain) with antioxidant properties. In view of the involvement of CoQ10 in oxidative phosphorylation and cellular antioxidant protection a deficiency in this quinone would be expected to contribute to disease pathophysiology by causing a failure in energy metabolism and antioxidant status. Indeed, a deficit in CoQ10 status has been determined in a number of neuromuscular and neurodegenerative disorders. Primary disorders of CoQ10 biosynthesis are potentially treatable conditions and therefore a high degree of clinical awareness about this condition is essential. A secondary loss of CoQ10 status following HMG-Coa reductase inhibitor (statins) treatment has been implicated in the pathophysiology of the myotoxicity associated with this pharmacotherapy. CoQ10 and its analogue, idebenone, have been widely used in the treatment of neurodegenerative and neuromuscular disorders. These compounds could potentially play a role in the treatment of mitochondrial disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, and other conditions which have been linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10, as well as the rationale and the role in clinical practice of CoQ10 supplementation in different neurological and muscular diseases, from primary CoQ10 deficiency to neurodegenerative disorders. We also briefly report a case of the myopathic form of CoQ10 deficiency.

White adipose tissue (WAT) is an important endocrine organ that secretes approximately 30 biologically active peptides and proteins, collectively termed “adipokines”. These are either produced exclusively by WAT (mainly adiponectin, leptin and resistin) or also by other tissues [e.g. tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, plasminogen activator inhibitor (PAI)-1, angiotensinogen]. Adipokines play a central role in body homeostasis including the regulation of food intake and energy balance, insulin action, lipid and glucose metabolism, angiogenesis and vascular remodelling, regulation of blood pressure and coagulation. Excess WAT, especially visceral obesity, is linked to obesityrelated health problems through insulin resistance (IR) [leading to type 2 diabetes mellitus (T2DM)] and systemic lowgrade inflammation [leading to cardiovascular disease (CVD)]. The adipokines are important mediators of these adverse effects. This review describes the role of proinflammatory adipokines in the pathogenesis of IR and of the chronic inflammatory state associated with visceral obesity. Moreover, it summarises treatment options for the normalisation of adipokine levels, which might confer an additional clinical benefit in the effort to prevent or treat obesity-related T2DM and CVD.