New agents for the management of resistant metastatic breast cancer

Introduction: Metastatic breast cancer (MBC) is an incurable disease and treatment is directed towards symptom palliation and survival prolongation. Treatment selection in patients is based on tumor biology, age, comorbidities, performance status, tumor burden, and prior treatment history.

Areas covered: This present review summarizes the recent treatment strategies in the management of MBC, highlighting regimens after first-line therapy. Topics discussed include new strategies for endocrine therapy, anti-HER2 therapy, and promising strategies for the management of triple negative breast cancer.

Expert opinion: MBC is a heterogeneous entity and despite recent advances, there is significant room for improvement of treatment beyond first-line therapies. Combination regimens that can maximize clinical efficacy while minimizing toxicities are required. Current investigation approaches in advanced stages of clinical development include immunoconjugates, immune checkpoint blockade, novel cyclin-dependent-kinase inhibitors, and PARP inhibitors for MBC associated with germline BRCA mutations. We recommend that every patient with MBC should be evaluated for clinical trial options.     

Advances in PARP inhibitors for the treatment of breast cancer

Introduction: Poly(ADP-Ribose) polymerases (PARPs) are one of the important components of base excision repair pathway for single strand DNA breaks. Currently accepted hypothesis for the mechanism of action for PARP inhibitors in tumors with homologous recombination deficiency is synthetic lethality, as the simultaneous blockage of both pathways prevents the tumor cells from repairing DNA damage. Other proposed mechanisms include PARP trapping, defective BRCA1 and POLQ recruitment to sites of DNA repair. Breast cancer subgroups with germline BRCA mutations or non-mutational functional defects in BRCA proteins exemplify potential targets for PARP inhibitors.

Areas covered: Promising results have been achieved with PARP inhibitors in BRCA associated cancers, particularly in ovarian and breast cancer. Olaparib is the only PARP inhibitor approved by FDA in the treatment of patients with germline BRCA mutated advanced ovarian cancer pretreated with ≥3 prior lines of chemotherapy. In this article, we reviewed the current status of PARP inhibitors, completed and ongoing trials, safety and resistance issues in patients with breast cancer.

Expert opinion: PARP inhibitors show promise in cancers with BRCA mutation and in the treatment of sporadic cancers with defective homologous recombination. Predictors of response, strategies to overcome resistance, combination with other chemotherapies and targeted agents, optimum dose and schedule of administration should be investigated in future trials.     

The safety of antiangiogenic agents and PARP inhibitors in platinum-sensitive recurrent ovarian cancer

Introduction: Recurrence is a common event in endothelial ovarian cancer (EOC) patients, and the choice of the most appropriate treatment is driven by the platinum-free interval, molecular characteristics of the disease such as BRCA mutational status, previous treatments and toxicity.

Areas covered: This review focuses on the main hematologic and non-hematologic toxicities correlated with the use of licensed antiangiogenic agents and PARP inhibitors in recurrent platinum-sensitive EOC, providing recommendations for their management.

Expert opinion: The clinical research over the next years will be focused on a more precise characterization of molecular pathways underlying tumorigenesis of the five ovarian tumors, to improve the decision-making process in these rare diseases. For this purpose, new study designs and international collaborations will become mandatory. Immunotherapy, antiangiogenic agents and PARP inhibitors will be combined to build a treatment strategy algorithm which will allow patients to receive all the available treatment option, in the more appropriate sequence.     

PARP inhibitors as antitumor agents: a patent update (2013-2015)

Introduction: PARP inhibitors have been extensively explored as antitumor agents and have shown potent efficacy both in vitro and in vivo. They can be used in monotherapy under the synthetic lethality concept or in combination with radiotherapy or chemotherapy, inducing a synergistic effect.

Areas covered: This review covers relevant efforts in the development of PARP inhibitors with a particular focus on recently patented PARP inhibitors, combination therapy involving PARP inhibitors, tumor responsiveness to PARP inhibitors as detailed in reports made from 2013 – 2015, and PARP drugs in clinical trials and other novel inhibitors that emerged in 2013 – 2015.

Expert opinion: Clinical studies and applications of PARP inhibitors as antitumor agents have gained considerable recognition in the last few years. In addition to FDA-approved olaparib, an increasing number of new inhibitors have been designed and synthesized, some of which are under preclinical or clinical evaluation. Novel inhibitors are still required, especially new scaffold compounds or drugs with improved properties, such as higher selectivity, higher potency and lower toxicity. The development of combination therapies involving PARP inhibitors and the exploration of biomarkers to predict outcomes with PARP inhibitors would expand the applications of these inhibitors, allowing more patients to benefit from this promising class of drugs in the future.     

Directing the use of DDR kinase inhibitors in cancer treatment

Introduction: Defects in the DNA damage response (DDR) drive the development of cancer by fostering DNA mutation but also provide cancer-specific vulnerabilities that can be exploited therapeutically. The recent approval of three different PARP inhibitors for the treatment of ovarian cancer provides the impetus for further developing targeted inhibitors of many of the kinases involved in the DDR, including inhibitors of ATR, ATM, CHEK1, CHEK2, DNAPK and WEE1.

Areas covered: We summarise the current stage of development of these novel DDR kinase inhibitors, and describe which predictive biomarkers might be exploited to direct their clinical use.

Expert opinion: Novel DDR inhibitors present promising candidates in cancer treatment and have the potential to elicit synthetic lethal effects. In order to fully exploit their potential and maximize their utility, identifying highly penetrant predictive biomarkers of single agent and combinatorial DDR inhibitor sensitivity are critical. Identifying the optimal drug combination regimens that could used with DDR inhibitors is also a key objective.     

Dual inhibition of STAT1 and STAT3 activation downregulates expression of PD-L1 in human breast cancer cells

Objectives: Breast cancer is the most commonly diagnosed cancer, and it is a leading cause of cancer-related deaths in females worldwide. Triple-negative breast cancer (TNBC) constitutes 15% of breast cancer and shows distinct metastasis profiles with poor prognosis. Strong PD-L1 expression has been observed in some tumors, supporting their escape from immune surveillance. Targeting PD-L1 could be a promising therapeutic approach in breast cancer patients. We investigated potential molecular mechanisms for constitutive expression of PD-L1 by inhibiting upstream STAT1 and STAT3 signals.

Methods: PD-L1 expression in three breast cancer cell lines was measured using quantitative PCR and western blotting. Activation of STAT1 and STAT3 was blocked using pharmacological inhibitors and siRNA. The mechanism underlying the constitutive expression of PD-L1 was investigated using ChIP and co-immunoprecipitation assays.

Results: We found that individual inhibition of STAT1 and STAT3 activation partially downregulated PD-L1, while combined inhibition completely downregulated PD-L1 expression. Moreover, our results suggest that pSTAT1-pSTAT3 dimerize in cytosol and translocate to the nucleus, where they bind to PD-L1 promoter and induce PD-L1 expression.

Conclusion: These findings provide a rationale for combined targeting of STAT1 and STAT3 for the development of immune-based cancer therapies for down regulation of PD-L1 expression.     

Inflammation in Heart Failure: known knowns and unknown unknowns

Introduction: The review deals with inflammation in heart failure (HF). Many data show that systemic inflammation is frequent in HF and implicate that inflammation contributes to damage and dysfunction of the cardiovascular system.

Areas Covered: Experimental data have been mainly obtained in acute laboratory animal models. It is questionable whether animals’ data can be translated into clinical settings with patients with chronic HF who have concomitant pathologies.

The idea of a common inflammatory pathway that characterizes all different forms of clinical HF is unrealistic. It seems realistic that inflammation differs in non-cardiac and cardiac diseases.

Research therapeutic options address the use of inhibitors of cytokines, of agents antagonizing oxidative stress, of MMP and of PI3K signaling pathways.

Expert Opinion: Considering the many unknowns in our knowledge it is not surprising that early trials aimed to antagonize inflammation in HF have been disappointing. We are far away from having solid therapeutic schedules to use immunomodulation in all subtypes of HF. However, modern trials on HF due to virus infections have proven that immunomodulation is therapeutically effective.

We should wisely use the known facts and accept that we have many unknowns. By appropriate selection of the subtypes of HF we may be able to find the appropriate therapy against inflammation in HF.     

Hyaluronic acid modified daunorubicin plus honokiol cationic liposomes for the treatment of breast cancer along with the elimination vasculogenic mimicry channels

Background: Breast cancer is an alarming global public health problem and a main cause of cancer-related death in women. Systemic chemotherapy is the most widely used treatment for breast cancer. However, current chemotherapy treatments are far from desirable due to poor targeting specificity, severe side effects and vasculogenic mimicry (VM).

Purpose: Hyaluronic acid (HA)-modified daunorubicin plus honokiol (HNK) cationic liposomes were prepared and characterised for treatment of breast cancer by eliminating VM.

Methods: HA-modified daunorubicin plus HNK cationic liposomes were prepared by a thin-film hydration method. Evaluations were performed on MCF-7 cells and MDA-MB-435S cells, which are human breast cancer cells, and xenografts of MDA-MB-435S cells.

Results: In vitro results revealed that the HA-modified daunorubicin plus HNK cationic liposomes enhanced the cellular uptake and destroyed VM channels. In vivo results demonstrated that the liposomes prolonged the circulation time in the blood, obviously accumulated in the tumour region, and enhanced the overall anticancer effects. Action mechanisms were related to down-regulation of VM protein indicators including FAK, EphA2, MMP-2 and MMP-9.

Conclusions: The prepared HA-modified daunorubicin plus HNK cationic liposomes may serve as a promising therapeutic strategy for the treatment of breast cancer.     

Therapeutic potential of investigational CHK-1 inhibitors for the treatment of solid tumors

Introduction: For several decades’ cancer treatment targeting DNA repair pathways incorporated both chemo- and radiotherapy only. However, over the last decade improved knowledge of DNA repair processes has paved the way for the development of novel targeted drugs abrogating DNA repair signaling. Checkpoint kinase inhibitors are exciting molecules and hold promise in the treatment of both solid and hematologic malignancies. Herein, we discuss preclinical and clinical studies with this class of molecules.

Areas covered: In this review, we discuss the role of check point kinase 1 (CHK-1) in DNA repair and provide a comprehensive summary of pre-clinical and early phase clinical trials with CHK-1 inhibitors. We also provide molecular structural basis of CHK-1inhibitors binding to CHK-1.

Expert opinion: Available data from both pre-clinical and early clinical studies illustrates potential efficacy of this class of molecules when combined with antimetabolites in treating both solid and hematologic malignancies. In addition, there might be an additive role in combining this class of molecules to PARP inhibitors, platinum chemotherapy, or radiation therapy in p53 or BRCA mutated tumors. The safety of the aforementioned combination needs to be closely evaluated in the ongoing clinical trials.     

Lactoferrin-decorated vs PEGylated zein nanospheres for combined aromatase inhibitor and herbal therapy of breast cancer

Objectives: Herein, we propose combined aromatase inhibitor and herbal therapy of breast cancer as a synergistic therapeutic modality.

Methods: Zein nanospheres were prepared by phase separation for co-delivery of exemestane and luteolin. To enhance their tumor-targeting capability, the nanospheres were coated with PEGylated phospholipids and lactoferrin for passive and active targeting, respectively.

Results: The developed nanospheres demonstrated a small particle size and controlled drug release. In addition, the nanospheres revealed high serum stability, acceptable hemocompatibility, and good physical stability. Moreover, a 5-fold scale-up of zein nanospheres could be enabled followed by spray-drying using 2.5% mannitol as a drying adjuvant. PEGylated and lactoferrin-targeted nanospheres showed enhanced cytotoxicity against MCF-7 and 4T1 breast cancer cells with higher selectivity to cancer cells rather than normal fibroblasts. The in-vivo pharmacokinetics and anti-tumor efficacy confirmed the superiority of zein nanospheres particularly after PEGylation compared to free drug(s). The enhanced anti-cancer activity of nanocarriers was revealed as prolonged circulation half-life, lower % change in tumor volume, reduced expression of aromatase, Cyclin D1 and VEGF markers as well as amplified apoptosis and necrosis.

Conclusion: Overall, combined delivery of aromatase inhibitors and herbal drugs via tumor-targeted zein nanospheres could serve as a promising strategy for breast cancer therapy.     

Overcoming platinum resistance in ovarian cancer treatment: from clinical practice to emerging chemical therapies

Introduction: The objective of this review is to summarize results from clinical trials that tested cytotoxic drugs and target strategies for the treatment of platinum resistant (PR) recurrent ovarian cancer (ROC) with particular attention to Phase III and ongoing trials.

Areas covered: Since platinum free interval (PFI) represents the most important predictive factor for response to platinum re-treatment in ROC, non-platinum regimens are conventionally considered the most appropriate approaches.

Impressive progress has been made in recent decades, resulting in the identification of most effective cytotoxic agents and in the development of new target strategies.

However, the efficacy of most of these drugs for the treatment of PR disease is still limited.

Expert opinion: The most favorable benefit for the treatment of PR disease, has been described by the AURELIA trial that showed a 3.3 months increase in progression free survival (PFS) when bevacizumab was combined with non-platinum single agent chemotherapy in bevacizumab-naïve patients.

Nevertheless, the use of novel agents is associated to important costs for just little gains in survival.

Thus, in our opinion the economic evaluation, such as the incorporation of quality of life into the clinical studies is crucial for the development of future trials for PR-ROC.     

Role of osteopontin as a predictive biomarker for anti-EGFR therapy in triple-negative breast cancer

Objective: Effective targeted therapies for patients with triple-negative breast cancer (TNBC) present an unmet clinical need. There is evidence that TNBCs often have increased expression of the epidermal growth factor receptor (EGFR) and of osteopontin (OPN). OPN-mediated signaling can activate EGFR-dependent signaling pathways. Here, we assessed OPN as a potential predictive biomarker for response to anti-EGFR therapy in TNBC.

Research design and methods: Using two different TNBC cell lines, MDA-MB-468 and MDA-MB-231, we investigated the impact of stable expression of OPN on efficacy of the EGFR inhibitor erlotinib in vitro.

Results: We observed that breast cancer cells engineered to overexpress OPN are more sensitive to growth inhibition by erlotinib than control cells. The level of response was related to the level of OPN expression, possibly due to increased phosphorylation status of EGFR Tyr1068.

Conclusions: These results indicate that OPN expression levels are related to sensitivity of TNBC cells to growth inhibition by erlotinib. OPN thus is a promising predictive biomarker for anti-EGFR therapy in breast cancer.     

Inhibitors of α-glucosidase and α-amylase from Cyperus rotundus

Context: A methanol extract of Cyperus rotundus L. (Cyperaceae) rhizomes showed inhibitory activity against α-glucosidase and α-amylase, two enzymes involve in carbohydrate digestion.

Objective: Identification of compounds from C. rotundus rhizomes responsible for the inhibition of α-glucosidase and α-amylase.

Materials and methods: Compounds were identified by a phytochemical investigation using combined chromatographic and spectroscopic methods. α-glucosidase and α-amylase inhibitory activities were evaluated by in vitro enzyme inhibition assays.

Results: A new (2RS,3SR)-3,4′,5,6,7,8-hexahydroxyflavane (1), together with three known stilbene dimers cassigarol E (2), scirpusin A (3) and B (4) were isolated. Compound 2 inhibited both α-glucosidase and α-amylase activities while the flavane 1 only showed effect on α-amylase, and compounds 3 and 4 were active on α-glucosidase. All four compounds showed significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity.

Discussion: The inhibitory activities against α-amylase and α-glucosidase of the C. rotundus rhizomes were reported for the first time. Stilbene dimers are considered as potent inhibitors of α-glucosidase and promising antihyperglycemic agents.

Conclusion: The isolated compounds may contribute to the antidiabetic property of C. rotundus.     

Impact of bodyweight/body mass index on the effectiveness of emergency contraception with levonorgestrel: a pooled-analysis of three randomized controlled trials

Objective:

A pooled analysis of two randomized controlled trials (RCTs) suggested that increased bodyweight and body mass index (BMI) may be associated with a greater probability of pregnancy. To address this issue we investigated whether higher bodyweight and/or BMI negatively impacted the risk of pregnancy in women receiving LNG-EC (levonorgestrel – emergency contraception) after unprotected sexual intercourse in a pooled analysis of three large multinational RCTs conducted by the World Health Organization (WHO).

Methods:

A pooled analysis of three double-blind, multinational RCTs conducted by the WHO to investigate the efficacy of LNG-EC in the general population. All analyses were done on the per-protocol set (PPS) which included 5812 women who received LNG-EC within 72 hours following unprotected sexual intercourse. The analysis was based on logistic regression, with pregnancy as the outcome. BMI and weight were represented in the same model.

Results:

A total of 56 pregnancies were available for analysis in the PPS. Increasing bodyweight and BMI were not correlated with an increased risk of pregnancy in the studied population. A limitation of this study is that despite the large study population in the pooled analysis there were relatively small numbers of women in the high-BMI and high-bodyweight subgroups.

Conclusion:

LNG-EC is effective for preventing pregnancy after unprotected intercourse or contraceptive failure and no evidence was found to support the hypothesis of a loss of EC efficacy in subjects with high BMI or bodyweight. Therefore, access to LNG-EC should not be limited only to women of lower bodyweight or BMI.     

The role of Cediranib in ovarian cancer

Introduction: Treatment options for relapsed ovarian cancer have increased over the decade with the addition of targeted agents, such as PARP inhibitors and antiangiogenic agents. Bevacizumab, a monoclonal antibody binding vascular endothelial growth factor (VEGF), was the first anti-angiogenic agent to be incorporated in the ovarian cancer treatment landscape. Other molecules utilising different mechanisms of action to target angiogenesis have been developed, including cediranib, an oral potent inhibitor of VEGF Tyrosine Kinase Inhibitor that has demonstrated activity in both phase II and phase III studies.

Areas covered: Herein we will review cediranib as well as the evidence for its use in ovarian cancer, both as monotherapy and in combination with chemotherapy, PARP inhibitors and immunotherapy. A literature search was made in PubMed and on ClinicalTrials.gov for clinical trials with cediranib.

Expert opinion: The addition of cediranib for the treatment of ovarian cancer is promising, and has demonstrated a significant improvement in progression free survival in a phase III trial in combination with chemotherapy and maintenance treatment. Cediranib is currently being explored in ovarian cancer and other gynaecological malignancies aiming to improve patient care; further research will help define its role in standard clinical practice for patients with ovarian cancer.     

Niraparib for the treatment of ovarian cancer

Introduction: Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are being developed in maintenance and recurrence treatment settings in ovarian cancer. They inhibit single-stranded DNA repair, inducing synthetic lethality in cells with underlying homologous recombination deficiency (HRD). Marked responses are seen in ovarian cancers with breast cancer gene 1 (BRCA1) or 2 (BRCA2) mutation, although up to 50% of high-grade serous ovarian cancers (HGSOC) have HRD may also benefit.

Areas covered: This review focuses on niraparib (oral PARP I and II inhibitor), its clinical testing in ovarian cancer, including the Myriad MyChoice HRD test as a potential companion diagnostic. Future directions plus ongoing trials, including novel combinations are highlighted.

Expert opinion: There is now level 1 evidence of efficacy from the first randomized placebo-controlled phase III trial using niraparib maintenance in women with platinum-sensitive recurrent HGSOC with complete or partial response post platinum-based chemotherapy. Niraparib improved progression free survival over placebo in all groups of women. The benefit was greatest in patients with germline BRCA1/2 mutation, followed by HRD positive tumors; however, absence of either does not exclude the possibility of benefit from niraparib maintenance. Additional studies are underway with niraparib in the first line maintenance, and 4^th/5^th line recurrence treatment settings.     

Taurine reduces blue light-induced retinal neuronal cell apoptosis in vitro

Background: The massive uptake of organic compatible osmolytes is a self-protective response to multiple stressors.

Objective: This study aimed to determine the protective effects of the osmolyte taurine against blue light-induced apoptosis in retinal neuronal cells in vitro.

Methods: Real-time PCR was used to measure osmolyte transport. Radioimmunoassays were performed to measure osmolyte uptake. Cell Counting Kit-8 assays were conducted to measure cellular viability. Flow cytometry analysis was used to measure apoptosis.

Results: Compared with normotonic stress, hypertonic stress-induced uptake of osmolytes, including betaine, myoinositol, and taurine, into the retinal neuronal cells. Blue light increased osmolyte transporter mRNA expression together with osmolyte uptake. Furthermore, taurine significantly suppressed blue light-induced retinal neuronal cell apoptosis.

Conclusion: The compatible osmolyte taurine may have an important role in cell resistance to blue light and cell survival.     

Taurine prevents ultraviolet B induced apoptosis in retinal ganglion cells

Background: Compatible osmolytes accumulation is an active resistance response in retina under ultraviolet (UV) radiation and hypertonicity conditions.

Objective: The purpose of this research is to investigate the protective role of taurine on retina under UVB radiation.

Methods: Osmolytes transporters were measured by quantitative realtime PCR. Osmolytes uptake was estimated by radioimmunoassay. Cell viability was calculated by MTT assay. Cell apoptosis was measured by flow cytometry analysis.

Results: Hypertonicity accelerated osmolytes uptake into retinal ganglion cells (RGCs) including taurine, betadine, and myoinositol. UVB radiation increased osmolytes transporter expression and osmolytes uptake. In addition, osmolyte taurine remarkably prevented UVB radiation induced cell apoptosis in RGCs.

Conclusions: The effect of compatible osmolyte taurine on cell survival rate may play an important role in cell resistance and adaption to UVB exposure.     

Efficacy of buparlisib in treating breast cancer

Introduction: Breast cancer is the most frequent cancer in women. Despite a decline in breast cancer mortality, prognosis of advanced breast cancer remains poor. In a desperate need to improve breast cancer outcomes, newer agents that target molecular pathways are being tested. Deregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) is frequently found in breast cancer. This can lead to resistance of endocrine therapy and anti-HER2 therapies. Targeting this pathway may restore sensitivity to these compounds. Buparlisib (BKM-120) is an orally active pan-PI3K inhibitor evaluated in different tumor types.

Areas covered: Buparlisib is one of the most investigated PI3K inhibitors. Preclinical and clinical studies of buparlisib in breast cancer are analyzed and discussed. This article reviews the status of buparlisib, completed and ongoing trials, and its safety.

Expert opinion: PI3K inhibitors show promising results in breast cancer. However, we raise a number of issues including the identification of biomarkers to predict treatment response and strategies to counteract resistance. Moreover, its toxicity profile could limit its extensive use.     

Clinical trial transparency update: an assessment of the disclosure of results of company-sponsored trials associated with new medicines approved in Europe in 2012

Background:

The objective of this study was to assess the timely disclosure of results of company-sponsored clinical trials related to all new medicines approved by the European Medicines Agency (EMA) during 2012. This is an extension of the previously reported study of trials related to all new medicines approved in Europe in 2009, 2010 and 2011, which found that over three-quarters of all these trials were disclosed within 12 months and almost 90% were disclosed by the end of the study.

Methods:

The methodology used was exactly as previously reported. Various publicly available information sources were searched for both clinical trial registration and disclosure of results. All completed company-sponsored trials related to each new medicine approved for marketing by the EMA in 2012, carried out in patients and recorded on a clinical trials registry and/or included in an EMA European Public Assessment Report (EPAR), were included. Information sources were searched between 1 May and 31 July 2014.

Outcome measures and results:

The main outcome measure was the proportion of trials for which results had been disclosed on a registry or in the scientific literature either within 12 months of the later of either first regulatory approval or trial completion, or by 31 July 2014 (end of survey). Of the completed trials associated with 23 new medicines licensed to 17 different companies in 2012, results of 90% (307/340) had been disclosed within 12 months, and results of 92% (312/340) had been disclosed by 31 July 2014.

Conclusions:

The disclosure rate within 12 months of 90% suggests the industry is now achieving disclosure in a timely manner more consistently than before. The overall disclosure rate at study end of 92% indicates that the improvement in transparency amongst company-sponsored trials has been maintained in the trials associated with new medicines approved in 2012.