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Current Drug Targets, 2010, 11, 12-28
Pharmacological Aspects of the Enzastaurin-Pemetrexed Combination in Non-Small Cell Lung Cancer (NSCLC) Elisa Giovannetti1, Richard Honeywell1, Axel R. Hanauske2, Christina Tekle1,3, Bart Kuenen1,5, Jennifer Sigmond1, Giuseppe Giaccone4 and Godefridus J. Peters*,1 1
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; 2Eli Lilly and Company, Indianapolis, IN, USA; 3Department of Tumour Biology, Institute for Cancer Research, University of Oslo, The Norwegian Radium Hospital, Oslo, Norway; 4Medical Oncology Branch, National Cancer Institute, Bethesda, MD, USA; 5Martini Hospital, Groningen, The Netherlands Abstract: 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 PKC-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 PKC inhibition by enzastaurin are not completely known, and assays to evaluate possible biomarkers, such as expression of PKC, VEGF and GSK3, 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 GSK3 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 GSK3 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.
Keywords: New anticancer targeted agents, drug combination, protein kinase C, thymidylate synthase, angiogenesis, apoptosis. INTRODUCTION Lung cancer is one of the most commonly occurring malignancies worldwide and is the leading cause of cancerrelated deaths in the Western World in both men and women. Non-small-cell lung cancer (NSCLC) accounts for more than 85% of primary lung cancers and approximately two-thirds of NSCLC patients are diagnosed at an advanced stage [1], for which platinum-based regimens are standard first line treatment [2]. Pooled data from older randomized trials of cisplatin-based chemotherapy versus best supportive care showed that cisplatin-based chemotherapy was associated with a modest improvement in overall survival (OS) [3]. In more recent randomized trials, new cytotoxic drugs such as paclitaxel, docetaxel, vinorelbine, or gemcitabine in combination with a platinum compound have shown an absolute 15-20% improvement of survival in favor of chemotherapy vs. best supportive care. In particular, the one-year survival rate for best supportive care was 11-17% vs. 30-35% for chemotherapy, which prolonged median *Address correspondence to this author at the Dept of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; Tel: (31) - 20 - 4442633; Fax: (31) - 20 – 4443844; E-mail:
[email protected] 1389-4501/10 $55.00+.00
survival by 3-4 months [4]. However, none of the last generation doublets was shown to be superior to the others and they all seemed to have reached the therapeutic plateau, with objective response rates of 30% to 40%, median survival time of 8 to 10 months, and 1-year survival rate of 30% to 40% [5]. Indeed, a four-arm randomized phase III trial demonstrated no substantial differences in response rate, time to progression (TTP) and OS among paclitaxel (24-hour infusion)-cisplatin, docetaxel-cisplatin, paclitaxel-carboplatin and gemcitabine-cisplatin combination [5]. The dose limiting toxicity profile of these regimens, as well as response rates not exceeding 40%, warrant novel strategies and new combination regimens against NSCLC. Recent advances in our understanding of the molecular basis of NSCLC have enabled the development of new, rationally designed, targeted antitumor agents. Most new therapies can be broadly classified as targeted “cytotoxic agents” or targeted “biological agents.” Cytotoxic drugs inflict cell death by affecting processes that are commonly overactive or enhanced in tumor compared with normal cells, such as DNA synthesis. Biologic agents interact with receptors, ligands, signaling molecules, or genes that are pivotal in tumor growth and development, and they can inhibit tumor cell proliferation, induce programmed cell © 2010 Bentham Science Publishers Ltd.
Pemetrexed and Enzastaurin in Lung Cancer
Current Drug Targets, 2010, Vol. 11, No. 1
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Fig. (1). Molecular mechanisms underlying the synergistic interaction of enzastaurin and pemetrexed.
death, inhibit angiogenesis, or enhance antitumor immune response [6]. The present review deals with the pharmacology of pemetrexed and enzastaurin for the treatment of NSCLC. Pemetrexed is a cytotoxic drug already commonly used, alone or in combination with platinum compounds, in the treatment of mesothelioma and NSCLC [7-9]. In contrast, enzastaurin is a novel biological targeted agent which inhibits PKC and is currently actively being investigated in multiple clinical trials as a single agent or in combination with other agents for treatment of various hematologic malignancies and solid tumors, including NSCLC [10, http://www.clinicaltrials. gov/]. Several studies focussed on the clinical trials and pharmacogenetic determinants of these drugs, and in this article, we have tried to highlight aspects that are more important for their synergistic combination (Fig. 1). Other issues are the identification of new pharmacogenetic biomarkers which would help in the selection of the optimal combination schedule and the development of new technologies to decipher pharmacogenetic markers of chemosensitivity and/or resistance which might be applied to the patient before and during treatment, using samples from surrogate tissues. PEMETREXED: CLINICAL USE AND MOLECULAR DETERMINANTS The multitargeted antifolate pemetrexed was firstly registered by the Food and Drug Administration (FDA) for
the treatment of malignant pleural mesothelioma, based on a randomized, phase III, single-blind, multicenter trial which compared cisplatin alone versus cisplatin plus pemetrexed. In that trial the addition of pemetrexed to cisplatin significantly improved both the survival, by 3 months, and the overall response rate [7]. Pemetrexed appeared also active as single agent in phase II and III trials for second-line therapy of patients with locally advanced or metastatic NSCLC after earlier chemotherapy. In August 2004, the FDA approved pemetrexed for second-line NSCLC based on data from a randomized, noninferiority phase III trial [8]. In that trial, median survival with pemetrexed (500 mg/m2 every 3 weeks, with vitamin B12 and folic acid supplementation) was 8.3 months versus 7.9 months with docetaxel (75 mg/m2 every 3 weeks; not significantly different). Response rates and TTP for both agents were comparable. However, the incidence of side effects (grade 3 or 4 neutropenia, febrile neutropenia, and neutropenia with infections) with pemetrexed was significantly lower than with docetaxel (p 0.004), and hospitalizations for neutropenic fever (p
