From targeted therapy in ovarian cancer to personalizing therapy for ovarian cancer

Epithelial ovarian carcinoma (EOC) is the most important cause of gynecological cancer-related mortality in Western societies. The majority of patients with ovarian cancer present with advanced disease, and in this group of patients, the median survival time is only 3 years. New treatment approaches are, therefore, required to improve outcome in this disease. Two strategies have emerged with promising results: poly ADP-ribose polymerase enzyme (PARP) inhibitors and targeting angiogenesis. The challenge remains to develop a convenient and accurate method to identify patients likely to benefit from targeted therapy.     

From targeted therapy in ovarian cancer to personalizing therapy for ovarian cancer

Epithelial ovarian carcinoma (EOC) is the most important cause of gynecological cancer-related mortality in Western societies. The majority of patients with ovarian cancer present with advanced disease, and in this group of patients, the median survival time is only 3 years. New treatment approaches are, therefore, required to improve outcome in this disease. Two strategies have emerged with promising results: poly ADP-ribose polymerase enzyme (PARP) inhibitors and targeting angiogenesis. The challenge remains to develop a convenient and accurate method to identify patients likely to benefit from targeted therapy.     

Kidney cancer therapy: new perspectives and avenues

Immunotherapy with interleukin-2 and interferon-α has been the only viable option in metastatic renal cell cancer for almost two decades. In the last several years, significant advances in the understanding of the underlying biological and molecular mechanisms of renal cell carcinoma, particularly the role of tumour angiogenesis, have led to the identification of rational therapeutic targets and permitted the design of molecularly targeted therapeutics. At present, new compounds targeting specific signalling pathways are available and have successfully passed clinical testing. The use of small molecules, such as multitargeted tyrosine kinase inhibitors, the mTOR inhibitors and monoclonal antibodies, is dramatically changing the existing concepts of systemic treatment for metastatic kidney cancer.     

Kidney cancer therapy: new perspectives and avenues

Immunotherapy with interleukin-2 and interferon-alpha has been the only viable option in metastatic renal cell cancer for almost two decades. In the last several years, significant advances in the understanding of the underlying biological and molecular mechanisms of renal cell carcinoma, particularly the role of tumour angiogenesis, have led to the identification of rational therapeutic targets and permitted the design of molecularly targeted therapeutics. At present, new compounds targeting specific signalling pathways are available and have successfully passed clinical testing. The use of small molecules, such as multitargeted tyrosine kinase inhibitors, the mTOR inhibitors and monoclonal antibodies, is dramatically changing the existing concepts of systemic treatment for metastatic kidney cancer.     

Targeted therapy for epithelial ovarian cancer

Ovarian cancer is the leading cause of death in women with gynecological malignancies and overall survival for patients with advanced epithelial ovarian cancer (EOC) remains poor. The majority of patients recur after initial treatment. A strategy for improving outcome is to minimise recurrence via targeted therapy in patients after front-line therapy, or more appropriately as consolidation therapy. EOC represents an attractive target because of the biology of the disease and that the bulk of disease occurs in the peritoneal cavity. To initiate targeted therapy, a candidate target must be identified. Innovative approaches via targeted therapy to control metastatic residual EOC are currently under investigation. The targets are molecules and pathways, on which cancer cells depend to proliferate, invade, metastasise and prevent apoptosis. Potential targeted therapies include: proapoptototic therapy, suicide gene therapy, signal transduction, antiangiogenesis, immunotherapy and cytokine therapy. The utilisation of these targets in the clinic demands carefully conducted, well-coordinated but discovery-oriented translational research in the form of clinical trials that can quickly assess alternative strategies or combination of strategies that could result in clinical benefit. Therefore, targeted therapy for epithelial ovarian cancer, especially after complete response to standard regimens, represents a paradigm whose time has come to be nurtured.     

Targeted therapy for epithelial ovarian cancer

Ovarian cancer is the leading cause of death in women with gynecological malignancies and overall survival for patients with advanced epithelial ovarian cancer (EOC) remains poor. The majority of patients recur after initial treatment. A strategy for improving outcome is to minimise recurrence via targeted therapy in patients after front-line therapy, or more appropriately as consolidation therapy. EOC represents an attractive target because of the biology of the disease and that the bulk of disease occurs in the peritoneal cavity. To initiate targeted therapy, a candidate target must be identified. Innovative approaches via targeted therapy to control metastatic residual EOC are currently under investigation. The targets are molecules and pathways, on which cancer cells depend to proliferate, invade, metastasise and prevent apoptosis. Potential targeted therapies include: proapoptototic therapy, suicide gene therapy, signal transduction, antiangiogenesis, immunotherapy and cytokine therapy. The utilisation of these targets in the clinic demands carefully conducted, well-coordinated but discovery-oriented translational research in the form of clinical trials that can quickly assess alternative strategies or combination of strategies that could result in clinical benefit. Therefore, targeted therapy for epithelial ovarian cancer, especially after complete response to standard regi-mens, represents a paradigm whose time has come to be nurtured.     

Clinical translation of immunoliposomes for cancer therapy: recent perspectives

Introduction: Liposomes have been extensively investigated as drug delivery vehicles. Immunoliposomes (ILs) are antibody-conjugated liposomes designed to selectively target antigen-expressing cells. ILs can be used to deliver drugs to tumor cells for improving efficacy and reducing toxicity. In addition, ILs can be used in immunoassays, immunotherapy, and imaging. Although there has been extensive coverage on ILs in the literature, only a limited number of clinical trials have been reported and no IL drug has been approved by the FDA.

Areas covered: Factors to consider in developing ILs are discussed, including the choice of antibody or antibody fragment, the formulation of liposomes, and the conjugation chemistry. In addition, challenges and opportunities in clinical development of ILs are discussed. The purpose of this review is to provide an overview on the state of the art of ILs and to discuss potential future developments.

Expert opinion: IL research has had a lengthy history and numerous preclinical studies have yielded encouraging results. However, there are a number of obstacles to clinical translation of ILs. Given the unique capabilities of ILs, its potential for clinical application is underexplored. There is great potential for expanded role for ILs in the clinic and further efforts to this end are warranted.

Abbreviations: Ab: antibody; ADCs: antibody-drug conjugates; API: active pharmaceutical ingredient; ADCC: antibody-dependent cellular cytotoxicity; CR: complete remission; cGMP: current good manufacturing practice; DSPE: distearoyl phosphatidylethanolamine; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; EPR: enhanced permeability and retention; Fc: fragment crystalline; Tf: transferrin; HACA: human-anti-chimeric antibody; HAHA: human-anti-human antibody; HAMA: human-anti-mouse antibody; HER2: human epidermal growth factor 2; IL: immunoliposome; LNPs: lipid nanoparticles; MRI: magnetic resonance imaging; MTD: maximum tolerated dose; PEG: polyethylene glycol; PET: positron emission tomography; PR: partial response; PSMA: prostate-specific membrane antigen; scFv: single-chain variable fragment; SPECT: single photon emission computed tomography; TTR: transthyretin     

Bacteriochlorophyll a, and its derivatives: chemistry and perspectives for cancer therapy

The review summarizes the chemistry of the third generation of photosensitizers, namely, the derivatives of natural bacteriochlorophyll a, for photodynamic treatment of cancer. The compounds of this class strongly absorb light at lambda=770-850 nm. This unique property opens new therapeutic opportunities due to deeper tissue penetration of light, thereby increasing the photodamage for tumor eradication. Analyzed are the modifications of bacteriochlorophyll a, that improve physico-chemical characteristics of compounds and enhance accumulation in tumors. Focusing on the delivery of photosensitizers to the tumor site and to specific intracellular compartments, we describe the conjugates of bacteriochlorophyll a, derivatives with carbohydrate and protein carriers. Boronated bacteriochlorins can be used in both photodynamic and boron neutron capture therapy.     

紫杉醇联合卡铂化疗治疗卵巢癌的临床观察

目的观察紫杉醇联合卡铂化疗方案治疗卵巢癌的疗效和毒副反应。方法40例卵巢癌患者用“紫杉醇＋卡铂”全身化疗或“紫杉醇＋卡铂”腹腔化疗,观察其疗效及不良反应。结果40例中,CR12例,PR18例,SD6例,PD4例,总有效率75％,主要不良反应为骨髓抑制、脱发、恶心、呕吐,但均可耐受。结论紫杉醇联合卡铂化疗方案治疗卵巢癌有较好疗效,不良反应可耐受。     

From randomised clinical trials to clinical practice : a pragmatic cost-effectiveness analysis of Paclitaxel in first-line therapy for advanced ovarian cancer

INTRODUCTION: Paclitaxel plus cisplatin is considered to be the standard first-line therapy for advanced ovarian cancer. Previous to this study, economic data on this combination resulted from randomised clinical trials (RCTs). Therefore, the objective of this study was to compare the clinical and economic outcomes associated with paclitaxel-cisplatin (PC) and cyclophosphamide-cisplatin (CC) regimens using a pragmatic perspective based on daily clinical practice in a French university hospital. METHOD: A retrospective cost-effectiveness analysis, from the hospital-payer perspective, was carried out as a before-after case study in fifty-nine consecutive women with verified International Federation of Gynaecology and Obstetrics (FIGO) stage II, III or IV ovarian cancer treated between 1995 and 2000. Median overall survival (OS) was used as the primary endpoint. The quality-adjusted time was assessed by the quality-adjusted time without symptoms or toxicity (Q-TWiST) method. Direct medical costs were collected for each patient. Monetary values for French prices in the year 2000 were used and converted to US dollars using an exchange rate of USD 1 = 7 French francs. Several univariate sensitivity analyses were carried out varying unit costs, medical practices and administration of paclitaxel. RESULTS: The incremental cost of the PC regimen was USD 10,716 per patient. OS and quality-adjusted time were improved by 10.8 and 9.3 months with the PC regimen. The cost per life-year gained and per added QALY were USD 11,907 and USD 13,827, respectively. The robustness of the results was confirmed in sensitivity analyses. CONCLUSION: Our study suggests that PC may be a cost-effective regimen for advanced ovarian cancer in a French university hospital setting. We reported higher incremental costs and lower clinical benefits than RCT-based findings, suggesting that RCT-based findings were clearly balanced by our pragmatic approach based on clinical practices. Observational studies can provide complementary and balanced data for decision making.     

Differences between opioids: pharmacological,experimental, clinical and economical perspectives

Clinical studies comparing the response and side effects of various opioids have not been able to show robust differences between drugs. Hence, recommendations of the regulatory authorities have been driven by costs with a general tendency in many countries to restrict physician''s use of opioids to morphine. Although this approach is recognized as cost-effective in most cases there is solid evidence that, on an individual patient basis, opioids are not all equal. Therefore it is important to have an armamentarium of strong analgesics in clinical practice to ensure a personalized approach in patients who do not respond to standard treatment. In this review we highlight differences between opioids in human studies from a pharmacological, experimental, clinical and health economics point of view. We provide evidence that individuals respond differently to opioids, and that general differences between classes of opioids exist. We recommend that this recognition is used to individualize treatment in difficult cases allowing physicians to have a wide range of treatment options. In the end this will reduce pain and side effects, leading to improved quality of life for the patient and reduce the exploding pain related costs.     

卵巢癌基因治疗的新进展

卵巢癌是恶性度最高的妇科肿瘤之一，由于手术和化疗的不尽人意，基因治疗是当今肿瘤研究的热点。卵巢癌的基因治疗载体主要分为病毒载体系统和非病毒载体系统。其中，腺病毒载体转染效率较高，是目前基因治疗的主要手段和最有前途的载体。卵巢癌的基因治疗策略有分子化学治疗，基因替代和免疫系统的基因调控。由于这一领域的迅速发展，卵巢癌的基因治疗有着光明的前景。     

Ferroptosis-based nano delivery systems targeted therapy for colorectal cancer: Insights and future perspectives

There are limited options for patients who develop liver metastasis from colorectal cancer (CRC), the leading cause of cancer-related mortality worldwide. Emerging evidence has provided insights into iron deficiency and excess in CRC. Ferroptosis is an iron-dependent form of programmed cell death characterized by aberrant iron and lipid metabolism, which play crucial roles in tumorigenesis, tumor progression, and treatment options. A better understanding of the underlying molecular mechanism of ferroptosis has shed light on the current findings of ferroptosis-based nanodrug targeting strategies, such as driving ferroptosis in tumor cells and the tumor microenvironment, emerging combination therapy and against multidrug resistance. Furthermore, this review highlights the challenge and perspective of a ferroptosis-driven nanodrug delivery system for CRC-targeted therapy.     

复发性上皮性卵巢癌的药物治疗及进展

卵巢癌是妇科恶性肿瘤中预后最差的肿瘤,80%的上皮性卵巢癌患者会复发。根据卵巢癌对铂类的敏感性不同将复发性卵巢癌分为:铂类敏感、铂类部分敏感、铂类耐药及难治性,对铂类敏感性的不同是影响复发性卵巢癌(ROC)治疗选择的重要特征。以贝伐单抗(Bevacizumab)为代表药物的抗血管生成药物是在复发性卵巢癌治疗中研究最多的靶向药物,而对于存在生殖系或体系BRCA突变的卵巢癌患者,可通过使用PARP抑制剂作为维持治疗直到进展来优化化疗效果并延长无进展生存期(PFS)。复发性卵巢癌患者可通过二次减瘤术、常用化疗药物联合抗血管生成剂或PARP抑制剂的"个性化"方法整合,延长复发性卵巢癌患者的PFS。     

Translational dermatology in drug discovery: perspectives for integrating humanized xenograft models and experimental clinical studies

Application of humanized xenotransplantation disease models and experimental clinical studies in the context of translational research in drug discovery in dermatology is an opportunity to reduce failure due to lack of efficacy in clinical development stage.     

Pharmacogenetics of EGFR in lung cancer: perspectives and clinical applications

Lung cancer is a lethal disease, and most cases have already disseminated at the time of diagnosis. Driver mutations in the EGFR tyrosine kinase domain (mainly deletions in exon 19 and L858R mutation in exon 21) have been identified in lung adenocarcinomas, mostly in never smokers, at frequencies of 20-60%. The EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib attain a response rate of 70% and progression-free survival of 9-13 months, although there are subgroups of patients with long-lasting remissions. No significant correlation between EGFR overexpression and response to treatment has been found, while controversial results have been reported regarding EGFR gene amplification. The pretreatment presence of the T790M mutation, initially identified as an acquired resistance mutation to treatment with EGFR TKIs, has also been reported and may indicate a genetically distinct disease. Finally, other genetic factors, such as mRNA expression of BRCA1 and components of the NF-κB pathway, can modulate response to EGFR TKIs in EGFR-mutated patients.     

基于AMPK/mTOR通路的天然产物抗大肠癌研究进展

大肠癌是严重危害人类健康的常见恶性消化系统肿瘤之一,目前临床上大肠癌的主要治疗手段是手术结合放化疗,但往往伴随着多种副作用。与此同时,越来越多的天然产物表现出良好的抗大肠癌活性,有望成为新型大肠癌治疗候选药物。AMP依赖的蛋白激酶(AMPK)是细胞内能量代谢的中心枢纽,可以通过抑制其下游靶标哺乳动物雷帕霉素靶蛋白(mTOR)而调控肿瘤细胞生长、增殖等。近年来,越来越多的研究显示一些天然产物能够通过调控AMPK/mTOR通路而发挥其抗大肠癌活性。围绕AMPK/mTOR信号通路在大肠癌中的作用及基于此通路的抗大肠癌天然产物的研究进展进行综述。

     

Anti-vascular tumor therapy: recent advances, pitfalls and clinical perspectives.

Anti-vascular tumor therapy represents a promising new strategy for cancer treatment. Anti-vascular treatment may be divided in anti-angiogenic and vascular targeting therapy. Whereas anti-angiogenic drugs aim on the inhibition of new vessel formation, vascular targeting compounds are designed to selectively destruct preexisting tumor blood vessels leading to secondary tumor cell death. Both anti-angiogenic drugs and vascular targeting agents have proven effective anti-tumoral activity in numerous preclinical studies over the last decade. In vivo, a combination with anti-vascular tumor therapy enhances the effects of other treatment modalities as chemo- and radiotherapy. Phase I clinical studies revealed a number of well-tolerated candidates. As monotherapy, however, anti-angiogenic treatment lacked efficacy in randomized clinical studies so far. In contrast, combination of anti-angiogenic therapy with chemotherapy was highly effective in an encouraging, large randomized phase III trial on metastatic colorectal cancer. This review will outline recent advances in the preclinical and clinical development of anti-vascular therapy with focus on vascular targeting. Conceptual differences between anti-angiogenic and vascular targeting therapies will be discussed with emphasis on specific problems and pitfalls in the conversion into the clinic.     

EphA2 as a target for ovarian cancer therapy

EphA2 is a receptor tyrosine kinase that is overexpressed by many human cancers, and is often associated with poor prognostic features. It is involved in many processes crucial to malignant progression, such as migration, invasion, metastasis, proliferation, survival and angiogenesis. Inducing EphA2 downregulation by any one of several mechanisms (antibody-mediated inhibition of signalling, antibody-mediated downregulation of total EphA2 expression and siRNA-mediated inhibition of expression) has been shown to decrease tumour growth, prolong survival and inhibit angiogenesis in multiple preclinical models of ovarian, breast and pancreatic cancer. Targeting EphA2 is especially attractive in ovarian cancer, in which overexpression is present in > 75% of cases. This disease is highly responsive to chemotherapy, and EphA2 inhibition is especially effective in combination with taxanes. This demonstrated efficacy, along with the low expression of EphA2 by normal adult tissues and lack of demonstrable toxicities in preclinical models, suggest that long-term treatment with EphA2-targeting agents is an attractive approach for ovarian cancer therapy.