Farnesyl transferase inhibitors in the treatment of breast cancer

Until recently, the therapeutic treatment of breast cancer has been dominated by endocrine-based drugs (oestrogen receptor antagonists, aromatase inhibitors etc.) and conventional cytotoxics (doxorubicin, cyclophosphamide, 5-fluorouracil etc.). However, the advent of new generation signal transduction inhibitor drugs targeted against the molecular abnormalities of breast cancer (e.g., the antibody trastuzumab, directed against the cERBB2 receptor) has the promise of providing a new era of more tumour selective therapy. Inhibitors of the enzyme farnesyl transferase (FTIs) are now undergoing early-stage clinical trials, including in patients with advanced breast cancer. Although originally developed as inhibitors of RAS signal transduction pathways, it is now apparent that these drugs are better described as prenylation inhibitors; the addition of a 15-carbon prenyl or farnesyl moiety by farnesyl transferase being critical to the function of a number of proteins, including RAS. At least three FTIs are currently undergoing clinical evaluation; R115777 (tipifarnib, Zarnestra), SCH66336 (lonafarnib, Sarasar) and BMS-214662. In terms of their potential use in the chemotherapeutic treatment of advanced breast cancer, a Phase II trial of R115777 (using either continuous or intermittent twice-daily oral dosing) has demonstrated promising activity (approximately 10% partial response rate). Overall, however, the single agent activity of FTIs in various Phase II trials has been rather modest (as well as the above mentioned breast cancer trial, some responses have been seen in patients with acute and chronic myeloid leukaemias). The main dose-limiting toxicities that have been reported are myelosuppression and fatigue and neurotoxicity (with R115777). Two Phase III trials of R115777 in colorectal (versus placebo) and pancreatic (with gemcitabine versus placebo) cancer have failed to show a survival benefit. It is likely that the future clinical direction of FTIs will be as combination therapy, especially with the taxanes, where synergy has been seen in a variety of preclinical studies.     

Farnesyl transferase inhibitors in the treatment of breast cancer

Until recently, the therapeutic treatment of breast cancer has been dominated by endocrine-based drugs (oestrogen receptor antagonists, aromatase inhibitors etc.) and conventional cytotoxics (doxorubicin, cyclophosphamide, 5fluorouracil etc.). However, the advent of new generation signal transduction inhibitor drugs targeted against the molecular abnormalities of breast cancer (e.g., the antibody trastuzumab, directed against the cERBB2 receptor) has the promise of providing a new era of more tumour selective therapy. Inhibitors of the enzyme farnesyl transferase (FTIs) are now undergoing early-stage clinical trials, including in patients with advanced breast cancer. Although originally developed as inhibitors of RAS signal transduction pathways, it is now apparent that these drugs are better described as prenylation inhibitors; the addition of a 15-carbon prenyl or farnesyl moiety by farnesyl transferase being critical to the function of a number of proteins, including RAS. At least three FTIs are currently undergoing clinical evaluation; R115777 (tipifarnib, Zarnestra^®), SCH66336 (lonafarnib, Sarasar^®) and BMS-214662. In terms of their potential use in the chemotherapeutic treatment of advanced breast cancer, a Phase II trial of R115777 (using either continuous or intermittent twice-daily oral dosing) has demonstrated promising activity (~ 10% partial response rate). Overall, however, the single agent activity of FTIs in various Phase II trials has been rather modest (as well as the above mentioned breast cancer trial, some responses have been seen in patients with acute and chronic myeloid leukaemias). The main dose-limiting toxicities that have been reported are myelosuppression and fatigue and neurotoxicity (with R115777). Two Phase III trials of R115777 in colorectal (versus placebo) and pancreatic (with gemcitabine versus placebo) cancer have failed to show a survival benefit. It is likely that the future clinical direction of FTIs will be as combination therapy, especially with the taxanes, where synergy has been seen in a variety of preclinical studies.     

Docetaxel/trastuzumab combination therapy for the treatment of breast cancer

Trastuzumab is a humanised monoclonal antibody that targets the extra cellular domain of human epidermal growth factor receptor-2 (HER-2), which is overexpressed in approximately 20% of human breast cancers. Clinical benefit has been shown in breast cancer patients with HER-2 amplification or overexpression when trastuzumab is used alone or in combination with chemotherapy. Docetaxel is one of the most potent chemotherapy agents in the treatment of patients with metastatic and early-stage breast cancer. The rationale for combining these two drugs is based not only on preclinical synergic data, but also on expanding clinical results. This article reviews the results of trials investigating this two-drug combination, as well as the triple combinations including docetaxel and trastuzumab with platinum salts. These combinations appear to be amongst the most active therapies for the treatment of patients with HER-2-positive breast cancer in metastatic and potentially adjuvant settings.     

Docetaxel/trastuzumab combination therapy for the treatment of breast cancer

Trastuzumab is a humanised monoclonal antibody that targets the extra cellular domain of human epidermal growth factor receptor-2 (HER-2), which is overexpressed in ~ 20% of human breast cancers. Clinical benefit has been shown in breast cancer patients with HER-2 amplification or overexpression when trastuzumab is used alone or in combination with chemotherapy. Docetaxel is one of the most potent chemotherapy agents in the treatment of patients with metastatic and early-stage breast cancer. The rationale for combining these two drugs is based not only on preclinical synergic data, but also on expanding clinical results. This article reviews the results of trials investigating this two-drug combination, as well as the triple combinations including docetaxel and trastuzumab with platinum salts. These combinations appear to be amongst the most active therapies for the treatment of patients with HER-2-positive breast cancer in metastatic and potentially adjuvant settings.     

Chemotherapy of breast cancer: are the taxanes going to change the natural history of breast cancer?

Among the novel chemotherapeutic drugs introduced in the last decade, taxanes have emerged as the most powerful compounds and results available to date suggest that they will be remembered in the future as the breast cancer chemotherapy of the 1990s. The two taxanes (paclitaxel, Taxol?, Bristol-Myers Squibb and docetaxel, Taxotere?, Rhône-Poulenc Rorer) share some characteristics, but are also significantly different both in preclinical profile and, most importantly, in clinical characteristics. The main clinical differences are related to their different efficacy-toxicity ratio in relation to dose and schedule; the differing integrability of paclitaxel and docetaxel in anthracycline-taxane containing regimens, secondary to major differences in pharmacokinetic interactions between each taxane and the anthracyclines, and; the potential differences in level of synergism between each taxane and herceptin (HeR2Neu antibody/trastuzumab, Genentech/Roche). In clinical practice, the taxanes are now standard therapy in metastatic breast cancer after prior chemotherapy, in particular anthracyclines, has failed. Their role in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging and sheds new light on the potential role of taxanes in the adjuvant setting. However, the impact of taxanes on the natural history of breast cancer is yet to be defined, despite the trend of results suggesting that these agents have the potential for significant improvements in advanced and, most importantly, adjuvant therapy of breast cancer. The results of all completed or ongoing Phase III trials in first-line metastatic and the adjuvant setting will help determine if taxanes will further improve the outcome of breast cancer or not.     

Trastuzumab-based combination therapy for breast cancer

Trastuzumab, a humanised monoclonal antibody directed against the extracellular domain of HER-2, has been shown to be active against HER-2-overexpressing metastatic breast cancer, either as single agent or when used in combination with chemotherapy. In preclinical models, trastuzumab has shown additive and even synergistic anti-tumour activity with the most active chemotherapeutic agents used in the treatment of breast cancer. In a large, randomised, Phase III trial, the combination of trastuzumab plus chemotherapy was shown to improve response rate and survival. The high incidence of cardiotoxicity seen with the combination of trastuzumab plus anthracycline drugs prompted carrying out of several clinical studies combining trastuzumab with other chemotherapeutic agents, including docetaxel, vinorelbine, platinum salts, gemcitabine and capecitabine. This article summarises the available data on trastuzumab-based combinations for breast cancer.     

Promising molecular targeted therapies in breast cancer

In recent years, there has been a significant improvement in the understanding of molecular events and critical pathways involved in breast cancer. This has led to the identification of novel targets and development of anticancer therapies referred to as targeted therapy. Targeted therapy has high specificity for the molecules involved in key molecular events that are responsible for cancer phenotype such as cell growth, survival, migration, invasion, metastasis, apoptosis, cell-cycle progression, and angiogenesis. Targeted agents that have been approved for breast cancer include trastuzumab and lapatinib, directed against human epidermal growth factor receptor 2 (HER2) and bevacizumab, directed against vascular endothelial growth factor (VEGF). Several other targeted agents currently under evaluation in preclinical and clinical trials include inhibitors of epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, VEGF/VEGFR inhibitors, and agents that interfere with crucial signaling pathways such as PI3K/AKT/mTOR and RAS/MEK/ERK; agents against other tyrosine kinases such as Src, insulin-like growth factor (IGF)/IGF-receptor (IGFR); agents that promote apoptosis such as Poly ADP ribose polymerase inhibitors; agents that target invasion and metastasis such as matrix metalloproteinases inhibitors and others. In this review, we highlight the most promising targeted agents and their combination with mainstream chemotherapeutic drugs in clinical trials.     

Chemotherapy of breast cancer: are the taxanes going to change the natural history of breast cancer?

Among the novel chemotherapeutic drugs introduced in the last decade, taxanes have emerged as the most powerful compounds and results available to date suggest that they will be remembered in the future as the breast cancer chemotherapy of the 1990s. The two taxanes (paclitaxel, Taxol, Bristol-Myers Squibb and docetaxel, Taxotere, Rh?ne-Poulenc Rorer) share some characteristics, but are also significantly different both in preclinical profile and, most importantly, in clinical characteristics. The main clinical differences are related to their different efficacy-toxicity ratio in relation to dose and schedule; the differing integrability of paclitaxel and docetaxel in anthracycline-taxane containing regimens, secondary to major differences in pharmacokinetic interactions between each taxane and the anthracyclines, and; the potential differences in level of synergism between each taxane and herceptin (HeR2Neu antibody/trastuzumab, Genentech/Roche). In clinical practice, the taxanes are now standard therapy in metastatic breast cancer after prior chemotherapy, in particular anthracyclines, has failed. Their role in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging and sheds new light on the potential role of taxanes in the adjuvant setting. However, the impact of taxanes on the natural history of breast cancer is yet to be defined, despite the trend of results suggesting that these agents have the potential for significant improvements in advanced and, most importantly, adjuvant therapy of breast cancer. The results of all completed or ongoing Phase III trials in first-line metastatic and the adjuvant setting will help determine if taxanes will further improve the outcome of breast cancer or not.     

Epigenetic events associated with breast cancer and their prevention by dietary components targeting the epigenome

Aberrant epigenetic alterations in the genome such as DNA methylation and chromatin remodeling play a significant role in breast cancer development. Since epigenetic alterations are considered to be more easily reversible compared to genetic changes, epigenetic therapy is potentially very useful in reversing some of these defects. Methylation of CpG islands is an important component of the epigenetic code, and a number of genes become abnormally methylated in breast cancer patients. Currently, several epigenetic-based synthetic drugs that can reduce DNA hypermethylation and histone deacetylation are undergoing preclinical and clinical trials. However, these chemicals are generally very toxic and do not have gene specificity. Epidemiological studies have shown that Asian women are less prone to breast cancer due to their high consumption of soy food than the Caucasian women of western countries. Moreover, complementary/and or alternative medicines are commonly used by Asian populations which are rich in bioactive ingredients known to be chemopreventive against tumorigenesis in general. Examples of such agents include dietary polyphenols, (-)-epigallocatechin-3-gallate (EGCG) from green tea, genistein from soybean, isothiocyanates from plant foods, curcumin from turmeric, resveratrol from grapes, and sulforaphane from cruciferous vegetables. These bioactive components are able to modulate epigenetic events, and their epigenetic targets are known to be associated with breast cancer prevention and therapy. This approach could facilitate the discovery and development of novel drugs for the treatment of breast cancer. In this brief review, we will summarize the epigenetic events associated with breast cancer and the potential of some of these bioactive dietary components to modulate these events and thus afford new therapeutic or preventive approaches.     

Everolimus: targeted therapy on the horizon for the treatment of breast cancer

The mammalian target of rapamycin (mTOR) is a signaling kinase of the phosphatidylinositol 3-kinase/protein kinase B (also known as Akt) signaling pathway that mediates cell growth and metabolism. Dysregulation of the mTOR pathway creates a favorable environment for the development and progression of many cancers, including breast cancer, and is associated with the development of resistance to endocrine therapy and to the anti-human epidermal growth factor receptor-2 (HER2) monoclonal antibody trastuzumab. Therefore, the addition of mTOR inhibitors to conventional breast cancer therapy has the potential to enhance therapeutic efficacy and/or overcome innate or acquired resistance. Everolimus, an mTOR inhibitor with demonstrated preclinical activity against breast cancer cell lines, has been shown to reverse Akt-induced resistance to hormonal therapy and trastuzumab. Phase I-II clinical trials have demonstrated that everolimus has promising clinical activity in women with HER2-positive, HER2-negative, and estrogen receptor-positive breast cancer when combined with HER2-targeted therapy, cytotoxic chemotherapy, and hormonal therapy, respectively. Everolimus is generally well tolerated; hematologic abnormalities and stomatitis are most common adverse events when this drug is combined with cytotoxic chemotherapy. Based on these promising results, everolimus is currently under evaluation in a series of phase III Breast Cancer Trials of Oral Everolimus (BOLERO) trials of women with HER2-positive and estrogen receptor-positive breast cancer. Results of these trials will help to establish the role of everolimus in the treatment of clinically important breast cancer subtypes.     

Anticancer drug discovery from the marine environment

Discovery, isolation, biochemical/pharmacological characterization, pre-clinical and clinical trials of drugs derived from the marine environment are continuously developing and increasing. One of the most promising area is cancer therapy. Currently, there are two drugs approved by the Food and Drug Administration (FDA) and European Agency for the Evaluation of Medicinal Products (EMA) in cancer treatment, namely Cytarabine (Cytosar-U1?) and Eribulin (E7389 or Halaven?). Trabectedin (ET-743 or Yondelis1?), approved by EMA, is completing key Phase III studies in the U.S. for final approval. It was estimated that 118 marine natural products (MNPs) are currently in preclinical trials, 22 MNPs in clinical trials and 3 MNPs on the market. The characteristics and selectivity profiles of new drugs for cancer therapy, as well as drugs disclosed in related patent applications, will be the focus of this review, providing a brief and ready to use reference.     

复方苦参注射液联合醋酸甲地孕酮治疗子宫内膜癌的疗效观察

目的探讨复方苦参注射液联合醋酸甲地孕酮治疗子宫内膜癌的临床疗效。方法选取2013年4月—2015年8月在临高县人民医院妇产科接受治疗的子宫内膜癌患者88例,根据治疗方案的差别分为对照组和治疗组,每组各44例。两组患者均给予必要的基础治疗。对照组口服醋酸甲地孕酮片,160 mg/次,1次/d。治疗组在对照组基础上静脉滴注复方苦参注射液,20 mL加入0.9%生理盐水250 mL中,1次/d。两组患者均连续治疗4周。治疗后比较两组患者近期疗效,观察生存质量的改善和不良反应发生情况。结果治疗后,对照组客观缓解率(ORR)为43.18%,临床获益率(CBR)为70.45%,治疗组ORR为65.91%,CBR为88.64%,两组ORR、CBR比较差异有统计学意义(P0.05)。治疗后,对照组和治疗组生存质量改善率分别为75.00%和90.91%,差异具有统计学意义(P0.05)。治疗过程中,对照组不良反应例数明显高于治疗组,差异具有统计学意义(P0.05)。结论复方苦参注射液联合醋酸甲地孕酮治疗子宫内膜癌效果显著,可显著改善患者生活质量,具有一定的临床推广应用价值。     

The role of taxanes in the treatment of breast cancer

Among the novel chemotherapeutic agents introduced in the last decade, the taxanes have emerged as the most powerful group of compounds, and results available so far confirm that they will be remembered in the future as the breast cancer chemotherapy of the 1990s. Two taxanes are available (paclitaxel and docetaxel) and they share some characteristics, although they do have some significant differences both in terms of their preclinical profile and, most importantly, their clinical characteristics. There are three main clinical differences: different efficacy-toxicity ratio in relation to dose and schedule; different integrability in anthracycline- and taxane-containing regimens, secondary to differences in pharmacokinetic interactions with anthracyclines; and different level of synergism between each taxane and trastuzumab. In clinical practice, the taxanes are now standard therapy in metastatic breast cancer. Their role as monochemotherapy or in combination with anthracyclines in advanced breast cancer has suggested their potential therapeutic impact in the treatment of patients with early breast cancer. Recent results in the adjuvant setting show that taxanes, used either in combination or in sequential therapy, possess the capability to induce significant improvements, in particular in terms of survival; thus confirming the positive impact of taxanes on the natural history of breast cancer. However, further results of all completed or ongoing Phase III trials in the early setting will help define the optimal use of taxanes and maximise the induced benefits for breast cancer patients.     

聚腺苷二磷酸核糖聚合酶抑制剂rucaparib

近年来乳腺癌、卵巢癌、胰腺癌等实体瘤的发病率逐年增加,临床上还缺乏有效的治疗药物。作为第1个用于人类癌症疗法的聚腺苷二磷酸核糖聚合酶(PARP)抑制剂,临床前研究表明rucaparib可明显抑制乳腺癌、卵巢癌等实体瘤。临床研究显示rucaparib具有良好的安全性和有效性。主要从rucaparib的药物概况、相关背景、合成路线、临床前研究和临床研究方面进行介绍。     

Preclinical and clinical studies of NK012, an SN-38-incorporating polymeric micelles, which is designed based on EPR effect

Polymeric micelles are ideally suited to exploit the EPR effect, and they have been used for the delivery of a range of anticancer drugs in preclinical and clinical studies.NK012 is an SN-38-loaded polymeric micelle constructed in an aqueous milieu by the self-assembly of an amphiphilic block copolymer, PEG-PGlu(SN-38). The antitumor activity was evaluated in several orthotopic tumor models including glioma, renal cancer, stomach cancer, and pancreatic cancer. Two independent phase I clinical trials were conducted in Japan and the USA.In the preclinical studies, it was demonstrated that NK012 exerted significantly more potent antitumor activity with no intestinal toxicity against various orthotopic human tumor xenografts than CPT-11. In clinical trials, predominant toxicity was neutropenia. Non-hematologic toxicity, especially diarrhea, was mostly Grade 1 or 2 during study treatments. Total 8 partial responses were obtained.According to data of preclinical studies, NK012 showing enhanced distribution with prolonged SN-38 release may be ideal for cancer treatment because the antitumor activity of SN-38 is time dependent. Clinical studies showed that NK012 was well tolerated and had antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing in patients with colorectal cancer in Japan and in patients with triple negative breast cancer and small cell lung cancer in the USA.     

Drugs targeted against protein kinases

Current treatments for cancer (surgery, radiation and chemotherapy) are successful for early stage localised disease but have severe side effects. New treatments are needed to increase the cure rate and life expectancy of patients. With the discovery of oncogenes, tumour suppressor genes and an understanding of their role in the development of the malignant disease, a new era of therapy has begun. Cancer is a manifestation of deregulated signalling pathways that mediate cell growth and programmed cell death. Protein kinases are essential elements in these signalling pathways. In the US, Novartis launched Gleevec (imantinib, STI-571) in May 2001 as the first anticancer drug whose mechanism of action is kinase inhibition. In Phase I trials, 23/24 patients with chronic myelogenous leukaemia (CML) had complete remissions and the drug is relatively non-toxic. Herceptin (trastuzumab) is a monoclonal antibody (mAb) against a member of the growth factor receptor family (HER-2/neu) that was launched in 1998 by Genentech for the treatment of breast cancer. Trastuzumab has an excellent antitumour profile, particularly when used in combination with doxorubicin and paclitaxol. These drugs are pioneering the treatment of cancer based on the molecular understanding of the disease. Numerous drugs that target growth factor receptors and their signalling pathways are in advanced clinical trials. Herein, antibodies against receptors and small molecule inhibitors of kinases in signalling pathways will be summarised. Inter-disciplinary preclinical studies have identified chemicals that target specific kinases. We believe that clinical studies of these agents will yield new anticancer agents that target specific diseases and that are less toxic than current agents.     

Alogliptin benzoate for the treatment of type 2 diabetes

Docetaxel (Taxotere?, Aventis Pharma), a semisynthetic taxane targeting the β-subunit of tubulin, has broad spectrum anticancer activity including non-small cell lung cancer (NSCLC). It is synergistic with platinum and radiation in preclinical models and has been tested clinically in every stage of NSCLC. Docetaxel–platinum combinations have an efficacy comparable to other newer-agent platinum doublets as first-line therapy in advanced NSCLC, and has been approved for use in this setting. Docetaxel was initially approved for NSCLC in the second-line setting following two Phase III trials demonstrating improved survival and quality of life. Ongoing clinical trials are investigating how best to combine docetaxel with thoracic radiotherapy in locally advanced disease. Preliminary studies evaluating docetaxel in the pre-operative setting have also been completed. Ongoing studies are focused on confirming the results observed with consolidation docetaxel in locally advanced NSCLC (SWOG 9504) and docetaxel in combination with molecularly targeted agents. This paper will review the pharmacology, preclinical, clinical and pharmacoeconomic data supporting the use of docetaxel in the treatment NSCLC.     

Development of new cancer therapeutic agents targeting mitosis

Targeting cellular proliferation persists as a mainstay of cancer therapeutic strategy. Although microtubule-targeting drugs (such as taxanes and vinca alkaloids) have been used successfully in the clinic to treat a variety of cancers, they carry substantial liabilities that have spurred drug companies to aggressively pursue new tubulin-targeting drug candidates with improved efficacy and toxicity profiles. The recent discoveries of new mitotic targets for cancer therapy (such as kinesin spindle protein, Aurora kinases and Polo-like kinase-1) have also stimulated intense work focused on identifying novel antimitotic drugs directed at these new targets. A number of novel antimitotic drugs have demonstrated encouraging activity in preclinical models and have progressed into clinical development. This review focuses on selected new antimitotic drugs under evaluation in clinical trials.     

抗肿瘤药培美曲塞的临床应用研究近况

抗肿瘤药培美曲塞能抑制叶酸代谢所依赖的几个关键酶的活性,从而多靶点、多方位地抑制肿瘤细胞的生长。临床前研究与临床试验都表明,培美曲塞能抗多种肿瘤,且与许多其它抗癌药有协同增效作用。虽然目前该药仅被批准用于恶性胸膜间皮瘤和非小细胞肺癌,但其在临床上还有更大的潜力。介绍近年来培美曲塞的临床应用研究情况,包括与铂络合物、吉西他滨、长春瑞滨、紫杉醇和伊立替康等药物联用的临床疗效以及单独或与其它抗癌药联用于治疗头颈部癌、乳腺癌、胃癌、肠癌及膀胱癌等的初步临床研究结果。     

Non platinum metal complexes as anti-cancer drugs

The development of metal complexes with platinum central atoms such as cisplatin or carboplatin had an enormous impact on current cancer chemotherapy. However, the spectrum of cancers that can be treated with platinum agents is narrow and treatment efficacy suffers from side effects and resistance phenomena. These unresolved problems in platinum-based anti-cancer therapy have stimulated increased research efforts in the search for novel non platinum-containing metal species as cytostatic agents. Preclinical and clinical investigations showed that the development of new metal agents with modes of action different from cisplatin is possible. Thus, complexes with iron, cobalt, or gold central atoms have shown promising results in preclinical studies and compounds with titanium, ruthenium, or gallium central atoms have already been evaluated in phase I and phase II trials. This review covers some relevant examples of preclinical and clinical research on novel non platinum metal complexes.