Therapeutic targets for metastatic prostate cancer

Prostate cancer is the most commonly diagnosed non-cutaneous cancer in adult males. Although prostate cancer that is confined to the gland can be cured in many patients using surgery or radiation, these treatments are only effective for localized tumors and the long-term failure rates for these treatments suggests that prostate cancer can metastasize relatively early in the course of the disease. Once prostate cancer has metastasized there are no curative therapies. The greatest challenge in the treatment of advanced prostate cancer is to access and eliminate metastatic cells. Therefore, effective prostate cancer therapy will require novel strategies to target cancer cells both at the site of the primary tumor and at distant metastatic sites. In this article we review several therapeutic targets and approaches that may provide new treatments for metastatic prostate cancer. We discuss the use of small molecules to target specific molecular events associated with metastatic prostate cancer, the use of specific antibodies that target unique metastasis associated molecules and the use of various gene therapy strategies to achieve anti-metastatic activities.     

Vinflunine for the treatment of breast cancer

Introduction: Breast cancer is the most frequently diagnosed cancer and the highest cause of cancer mortality in females worldwide. The development of drugs improving overall survival in late-stage metastatic breast cancer remains a challenge.

Vinflunine is the most recently developed drug in the vinca alkaloid class. Its arrival has been eagerly awaited for treatment of solid tumors, and in particular, for metastatic breast cancer.

Areas covered: The pharmacological features of vinflunine are described. Its clinical development as monotherapy or in combination in metastatic breast cancer is detailed. A literature search on the topic was conducted through PubMed, clinical trials and the proceedings of the main cancer congresses.

Expert opinion: The overall results from phase III studies, and in particular those that combined vinflunine with capecitabine, have been less favorable. The combination’s effectiveness was at best moderate compared with other drugs which also target metastatic breast cancer, and complicated by significant hematological and gastrointestinal adverse effects. Its use in advanced metastatic breast cancer cannot currently be recommended.     

Capecitabine: fulfilling the promise of oral chemotherapy

Capecitabine is a synthetic oral fluoropyrimidine carbamate that is sequentially activated in a three-step process, which results in the preferential production of 5-fluorouracil in tumours, rather than in the normal surrounding tissue. Capecitabine is proven to be as effective as the combination of 5-fluorouracil and leucovorin administered on the Mayo clinic schedule in patients with metastatic colorectal cancer. It has also been proven to be effective in patients with metastatic breast cancer that has progressed despite prior anthracyclines and taxoids. More recently, it has also been shown to increase survival in combination with docetaxel in patients with metastatic breast cancer in comparison to docetaxel alone. This article reviews the pharmacology and clinical activity of capecitabine, as well as combinations of capecitabine with other chemotherapeutic agents and future directions of investigation with this convenient and widely active antitumour therapy.     

Capecitabine: fulfilling the promise of oral chemotherapy

Capecitabine is a synthetic oral fluoropyrimidine carbamate that is sequentially activated in a three-step process, which results in the preferential production of 5-fluorouracil in tumours, rather than in the normal surrounding tissue. Capecitabine is proven to be as effective as the combination of 5-fluorouracil and leucovorin administered on the Mayo clinic schedule in patients with metastatic colorectal cancer. It has also been proven to be effective in patients with metastatic breast cancer that has progressed despite prior anthracyclines and taxoids. More recently, it has also been shown to increase survival in combination with docetaxel in patients with metastatic breast cancer in comparison to docetaxel alone. This article reviews the pharmacology and clinical activity of capecitabine, as well as combinations of capecitabine with other chemotherapeutic agents and future directions of investigation with this convenient and widely active antitumour therapy.     

Chemokines and breast cancer: a gateway to revolutionary targeted cancer treatments?

Breast cancer is an example of a solid tumour which is well treated in the early stages of disease by surgical excision, but once metastatic spread has occurred, medical therapies (chemotherapy and radiotherapy) are highly toxic, expensive and palliative. It is known that certain tumours exhibit specific patterns of metastasis, chemokines may provide a molecular answer to this mystery. Chemokines and their receptors play important roles in the various stages of tumour development and metastasis. Chemokines interact with their specific receptors as well as interacting with the glycosaminoglycan (GAG) component of proteoglycan. We discuss the basic metastatic process and the involvement of chemokines in breast cancer biology. Finally, we summarize potential therapeutic applications of chemokines and chemokine/glycosaminoglycan interactions including chemokine agonists, antagonists, anti-sense therapy, immunotherapy and soluble GAGs, as well as future perspectives in this field.     

Novel chemotherapeutic agents for the treatment of brain cancer

Brain cancer encompasses both primary and metastatic brain tumours and accounts for over 120,000 new patients each year. Despite aggressive therapy, the majority of patients with brain cancer have poor prognosis and have brief survival intervals. Current chemotherapy drugs, used alone or in combination, have minimal or only modest activity. Novel agents that have recently been applied to brain cancer include temozolomide, irinotecan and paclitaxel. Temozolomide is a DNA alkylating agent, irinotecan inhibits DNA topoisomerase I and paclitaxel binds to microtubules and induces polymerisation. Neoplastic angiogenesis and brain tumour invasion are also targets for therapeutic intervention with new agents such as thalidomide, suramin and marimastat. All of these agents have demonstrated activity against brain cancer in vitro. Several of the drugs, in particular temozolomide, paclitaxel and irinotecan, have entered preliminary clinical trials and have demonstrated some efficacy. However, chemotherapy for primary brain tumours remains rather non-specific and mostly ineffective. The use of chemotherapy may be more effective against selected metastatic brain tumours. Continued basic research is needed to further elucidate the genetic basis of transformation, tumour invasion and angiogenesis. It is hoped that this research will lead to new therapeutic targets for drug design and development. In addition, new strategies must be developed to overcome the problem of chemotherapy resistance.     

Novel chemotherapeutic agents for the treatment of brain cancer

Brain cancer encompasses both primary and metastatic brain tumours and accounts for over 120,000 new patients each year. Despite aggressive therapy, the majority of patients with brain cancer have poor prognosis and have brief survival intervals. Current chemotherapy drugs, used alone or in combination, have minimal or only modest activity. Novel agents that have recently been applied to brain cancer include temozolomide, irinotecan and paclitaxel. Temozolomide is a DNA alkylating agent, irinotecan inhibits DNA topoisomerase I and paclitaxel binds to microtubules and induces polymerisation. Neoplastic angiogenesis and brain tumour invasion are also targets for therapeutic intervention with new agents such as thalidomide, suramin and marimastat. All of these agents have demonstrated activity against brain cancer in vitro. Several of the drugs, in particular temozolomide, paclitaxel and irinotecan, have entered preliminary clinical trials and have demonstrated some efficacy. However, chemotherapy for primary brain tumours remains rather non-specific and mostly ineffective. The use of chemotherapy may be more effective against selected metastatic brain tumours. Continued basic research is needed to further elucidate the genetic basis of transformation, tumour invasion and angiogenesis. It is hoped that this research will lead to new therapeutic targets for drug design and development. In addition, new strategies must be developed to overcome the problem of chemotherapy resistance.     

HER2阳性乳腺癌靶向治疗药物的临床研究进展

乳腺癌已成为全球最常见的癌症,人表皮生长因子受体2（HER2）阳性乳腺癌恶性程度较高,早期易复发和转移,总体预后较差。HER2阳性乳腺癌的治疗因靶向药物的不断问世而呈现更多可能,这类药物包括单克隆抗体（曲妥珠单抗、帕妥珠单抗）、酪氨酸激酶抑制剂（奈拉替尼、拉帕替尼、吡咯替尼、图卡替尼）、抗体药物偶联物（T-DM1、DS-8201）。对HER2阳性乳腺癌靶向治疗药物的最新临床试验结果进行综述,以期为该类乳腺癌的临床用药提供参考。     

Advanced breast cancer: chemotherapy phase III trials that change a standard

At the present time, there is not a standard regimen in upfront metastatic setting for breast cancer. A wide variety of regimens which includes anthracyclines, taxanes, gemcitabine or capecitabine are currently used, however, there is evidence to support the use of many of these drugs in early breast cancer and consequently limiting their use in first line treatment. The aim of this review is to evaluate every randomized phase III trials conducted in first line metastatic breast cancer. For this reason, all randomized studies that evaluated the role of chemotherapy in advanced breast cancer were analyzed and classified according to their protocol design. So far, sixteen major randomized clinical trials have evaluated the role of chemotherapy as front line in metastatic breast cancer. Some of them have analyzed a different anthracyclines-based regimen as the control arm versus new combinations or new drugs. In others, the aim is to evaluate the most effective therapy after progression to an adjuvant anthracyclines-containing regimen. The suitability of the control arm, the prospective definition of patient's subgroups as well as the statistical methodology have been taken into account.     

Trastuzumab: new indication. Metastatic breast cancer, in combination with docetaxel: promising, but more evaluation is needed

(1) There is no consensus on the optimal chemotherapy for metastatic breast cancer. Patients who have never previously received chemotherapy are generally given an anthracycline-based combination of cytotoxic agents. Options for patients who have already received an anthracycline include a taxane such as paclitaxel or docetaxel. The median survival time with these treatments is only about 2 to 2.5 years. (2) Trastuzumab is a monoclonal antibody directed against HER-2, a protein overexpressed by certain tumours, including about 25% of breast tumours. In 2000, the approved indications included first-line treatment of metastatic breast cancer in combination with paclitaxel. One clinical trial had shown, albeit with a low level of evidence, a median increase in survival of about 4 to 5 months. Trastuzumab is now approved for first-line treatment of metastatic breast cancer, in combination with docetaxel. (3) Evaluation data include the results of an open-label trial comparing docetaxel + trastuzumab with docetaxel monotherapy in 186 patients. The median survival time was significantly longer with the combination (31.2 versus 22.7 months). There are no relevant comparisons with other widely used cytotoxic drugs. Indirect comparison suggests that survival is similar with docetaxel + trastuzumab and paclitaxel + trastuzumab. (4) Data on the trastuzumab-docetaxel combination confirm the known adverse effects of trastuzumab, which include heart failure and diarrhea. Trastuzumab increases the frequency of docetaxel-induced neutropenia, which carries a risk of infections. (5) In summary, the results of clinical trials show that median survival time is increased by a few months when trastuzumab is added to a cytotoxic drug. However, the best cytotoxic agent is not known, and adverse effects are poorly documented. (6) In practice, trastuzumab has only been shown to benefit a minority of women with breast cancer, namely those whose tumours overexpress HER-2. Trastuzumab therapy is an option for metastatic breast cancer treatment, provided patients are enrolled in studies designed to answer the many outstanding questions.     

Should aromatase inhibitors replace tamoxifen?

Six years ago, we reviewed the selective aromatase inhibitors, anastrozole and letrozole, for the treatment of women with breast cancer. We concluded that anastrozole was at least as effective as megestrol (the standard treatment at that time for women with advanced postmenopausal breast cancer in whom tamoxifen had failed), but that there was insufficient published evidence to decide the place of letrozole in therapy. Since then, these drugs have become standard second-line treatment options for postmenopausal women with locally advanced or metastatic, hormone-receptor-positive breast cancer, and a third selective aromatase inhibitor, [symbol: see text] exemestane (pronounced eks-ee-mes-tane), has been added to the market. Here we consider whether the aromatase inhibitors should replace tamoxifen as first-line therapy.     

Recent developments in treatment stratification for metastatic breast cancer

The modern approach to management of metastatic breast cancer (MBC) is centred on individualizing treatment to best suit the patient's breast cancer characteristics (molecular subtype, disease burden and prognostic markers), as well as the patient's clinical history (co-morbidities, prior therapies and social factors). The wealth of treatments available has heightened the complexity of tailored patient care that in turn allows better optimization of treatment efficacy and quality of life. There are promising developments in the management of estrogen receptor (ER)-positive breast cancer, particularly with respect to overcoming resistance with dual targeting of the phosphoinositide-3 kinase/AKT/mammalian target of rapamycin and ER-signalling pathways. A central focus in the management of triple negative breast cancer has been through efforts to identify novel therapeutic targets in this disease subgroup. Next-generation sequencing approaches have begun to reveal how breast cancer somatic mutational heterogeneity between tumours with the same histopathological subtype is likely to impede efforts to identify novel common therapeutic targets. The most successful example of targeted therapy in MBC is the targeting of human epidermal growth factor receptor 2 (HER2) by trastuzumab. Dual and irreversible HER2/epidermal growth factor receptor targeting and attenuation of downstream resistance pathways also appear promising in HER2-positive trastuzumab-refractory breast cancer. Targeted therapy with antiangiogenic agents shows clinical activity, but the balance between efficacy, toxicity and cost remains a topic of debate, emphasizing the unmet need for a predictive biomarker of response to this class of drug. Poly(ADP ribose) polymerase(PARP) inhibitors appear to have clinically meaningful activity in BRCA germline mutant breast cancer. Activity of PARP inhibitors in other breast cancer subgroups is yet to be clearly defined. Novel chemotherapy agents show marginally superior efficacy, at a cost of a moderate increase in toxicity. Bone-modifying drugs expand supportive care options; again, better permitting individualization of treatment choice. The future management of MBC will increasingly focus on stratifying therapeutics based on individualized-tumour molecular aberrations.     

白蛋白纳米粒药物传递系统的研究进展

目的综述白蛋白纳米粒作为药物传递系统的最新研究进展。方法依据国内外研究文章及专利文献共63篇,将白蛋白的性质及功能、白蛋白纳米粒的制备工艺、靶向肿瘤作用机理、上市药物及其临床前和临床实验结果进行了概括。结果白蛋白是一种良好的药物载体,显示独特的靶向肿瘤机理;白蛋白纳米粒的制备方法中二硫键形成法相对于其他制备方法具有显著优点,避免了很多基于溶剂传递的传统剂型中存在的潜在问题,由其制备的上市药物紫杉醇白蛋白纳米粒(Abraxane)具有较好的临床疗效。结论白蛋白纳米粒给药系统的研究有着重要的临床意义及发展前景。     

Effects of natural and novel synthetic jasmonates in experimental metastatic melanoma

BACKGROUND AND PURPOSE: No current treatment reliably affects the course of metastatic melanoma. Consequently, novel approaches to the control of metastasis are actively sought. The overall goal of the present study was to identify new anti-metastatic agents active against melanoma cells. EXPERIMENTAL APPROACH: Two directions were taken: 1. To determine whether the natural plant hormone methyl jasmonate, which kills cancer cells selectively, can suppress the characteristic metastatic behavior of B16-F10 melanoma cells; 2. To synthesize and identify novel jasmonate derivatives with better cytotoxic and anti-metastatic activities than methyl jasmonate. KEY RESULTS: We found that methyl jasmonate suppressed B16-F10 cell motility and inhibited the development of experimental lung metastases of these cells. Furthermore, methyl jasmonate suppressed the motility of a sub-clone of these cells over-expressing P-glycoprotein and exhibiting multidrug resistance. The synthetic derivative Compound I (5,7,9,10-tetrabromo derivative of methyl jasmonate, the most active derivative) had greater cytotoxic potency (IC(50), 0.04 mM) than methyl jasmonate (IC(50), 2.6mM). Compound I prevented B16-F10 cell adhesion efficiently and inhibited the development of lung metastases at a much lower dose than methyl jasmonate. CONCLUSIONS AND IMPLICATIONS: Natural and synthetic jasmonates have anti-metastatic actions. Further development of these agents for the suppression of metastasis in melanoma and other types of cancer is warranted.     

晚期乳腺癌药物研究与治疗进展

目的:综述晚期乳腺癌药物研究与治疗进展。方法:收集相关最新发表的文章,对晚期乳腺癌药物和治疗进展进行分析总结。结果与结论:晚期乳腺癌属于不可治愈的疾病。临床实践证明,以紫杉类药物、曲妥珠单抗、第三代芳香化酶抑制剂等为新一代抗癌新药应用于临床,显著改善患者的生存和生活质量,晚期乳腺癌逐渐演变成为一种慢性病。近年来,一些具有全新作用机制的新型抗肿瘤药物如帕妥珠单抗、曲妥珠单抗emtansine、氟维司群注射液、依维莫司等的出现,将改变晚期乳腺癌的治疗策略。     

Anti-metastatic effects of curcusone B, a diterpene from Jatropha curcas

A new approach to cancer therapy in recent years has been to target the metastatic process. The anti-metastatic potential of curcusone B, a diterpene isolated from Jatropha curcas Linn. (Euphorbiaceae), a herbal plant that has been used in traditional folk medicine in many tropical countries, was investigated against 4 human cancer cell lines. Treatment with non-cytotoxic doses of curcusone B resulted in a strong reduction of in vitro invasion, motility and secretion of matrix-metalloproteinases (MMP) of the cancer cells, whereas the ability to adhere to a Matrigel-coated surface was variably sensitive to curcusone B treatment. Curcusone B, thus, effectively suppresses the metastatic processes at doses that are non-toxic to cells, which may be of therapeutic benefit for the treatment of metastatic cancers.     

Monoclonal antibody-based targeted therapy in breast cancer

Advances in molecular biology have identified tumor markers that not only predict prognosis and therapeutic response but may also function as potential therapeutic targets. Activated growth factor receptors induce breast cancer cells to proliferate, invade, and metastasize in experimental models. Overexpression of growth factor receptors has been associated with a poor clinical outcome in breast cancer patients. Biological therapy with monoclonal antibody directed against growth factor receptor pathways became important targeted therapy in breast cancer and is being pursued on various fronts. The anti-HER2 antibody trastuzumab is approved in the metastatic setting and is now trying to find the place in the adjuvant setting. Phase II and III studies with antibodies directed against VEGF and EGFR are also ongoing.     

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.