Metronomic chemotherapy preserves quality of life ensuring efficacy in elderly advanced non small cell lung cancer patients

Metastatic non small cell lung cancers (NSCLC) are diseases with poor prognosis and platinum-based doublet chemotherapy still remains their standard cure. Elderly patients often present comorbidities that limit the utilization of this chemotherapy; therefore these patients should have a first-line treatment with low toxicity and capable to preserve the quality of life (QoL) but, at the same time, to ensure the best possible response. Furthermore, a first-line treatment allows patients to be fit for further treatments, prolonging overall survival. At this regard, metronomic chemotherapy can be an optimal choice for elderly, able to improve QoL and to obtain an optimal palliation. We retrospectively studied a cohort of 41 elderly advanced NSCLC patients with different histotypes, treated with metronomic chemotherapy (weekly carbo-paclitaxel or vinorelbine as single agent) as first choice and we analyzed the tolerability, the impact on QoL and the efficacy of these schedules: no toxicity of 3 and 4 grade was observed, together to a clinical benefit of 43%. We administered FACT-L test to evaluate QoL at baseline and after 4 months and found a significant improvement in all FACT-L parameters: physical, social, emotional and functional, confirming a QoL improvement. At a median follow-up of 20.2 months the progression free survival was of 6 months and the overall survival was of 15 months. These results suggest that metronomic chemotherapy can be an effective choice of treatment for elderly NSCLC patients and further trials with more patients are needed to confirm this proposal

Circulating neuregulin-1 and galectin-3 can be prognostic markers in breast cancer

Background: It is important to identify novel plasmatic biomarkers that can contribute to assessing the prognosis and outcome of breast cancer patients. Neuregulin-1 (NRG1) and galectin-3 (Gal-3) are proteins that are involved in breast cancer development and patient survival; therefore, we studied whether the serum concentration of these 2 proteins can be correlated to breast cancer progression. Methods: Plasmatic NRG1 and Gal-3 were evaluated in 25 healthy controls and 50 breast cancer patients at baseline and at 3 and 6 months after treatment with anthracyclines and taxanes, with or without trastuzumab. Results: NRG1 and Gal-3 were significantly more elevated in cancer patients than in healthy controls; further- more, NRG1 and Gal-3 were significantly increased after chemotherapy and were predictive of mortality at 1 year. Conclusions: Circulating NRG1 and Gal-3 can be additional biomarkers indicative of prognosis and outcomes for breast cancer patients

The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

Inhibitors of kinesin spindle protein Eg5 are characterized by pronounced antitumor activity. Our group has recently synthesized and screened a library of 1,3,4-thiadiazoline analogues with the pharmacophoric structure of K858, an Eg5 inhibitor. We herein report the effects of K858 on four different breast cancer cell lines: MCF7 (luminal A), BT474 (luminal B), SKBR3 (HER2 like) and MDA-MB231 (basal like). We demonstrated that K858 displayed anti-proliferative activity on every analyzed breast cancer cell line by inducing apoptosis. However, at the same time, we showed that K858 up-regulated survivin, an anti-apoptotic molecule. We then performed a negative regulation of survivin expression, with the utilization of wortmannin, an AKT inhibitor, and obtained a significant increase of K858-dependent apoptosis. These data demonstrate that K858 is a potent inhibitor of replication and induces apoptosis in breast tumor cells, independently from the tumor phenotype. This anti-proliferative response of tumor cells to K858 can be limited by the contemporaneous over-expression of survivin; consequently, the reduction of survivin levels, obtained with AKT inhibitors, can sensitize tumor cells to K858-induced apoptosis

Design, synthesis and biological evaluation of new pyrimidine derivatives as anticancer agents

BACKGROUND: Anticancer drug resistance is a challenging phenomenon of growing concern which arises from alteration in drug targets. Despite the fast speed of new chemotherapeutic agent design, the increasing prevalence of this phenomenon requires further research and treatment development. Recently, we reported a new aminopyrimidine compound-namely RDS 344-as a potential innovative anticancer agent.METHODS: Herein, we report the design, synthesis, and anti-proliferative activity of new aminopyrimidine derivatives structurally related to RDS 3442 obtained by carrying out substitutions at position 6 of the pyrimidine core and/or on the 2-aniline ring of our hit. The ability to inhibit cell proliferation was evaluated on different types of tumors, glioblastoma, triple-negative breast cancer, oral squamous cell carcinomas and colon cancer plus on human dermal fibroblasts chosen as control of normal cells.RESULTS: The most interesting compound was the N-benzyl counterpart of RDS 3442, namely 2a, that induced a significant decrease in cell viability in all the tested tumor cell lines, with EC50s ranging from 4 and 8 muM, 4-13 times more active of hit.CONCLUSIONS: These data suggest a potential role for this class of molecules as promising tool for new approaches in treating cancers of different histotype

Are pharmacogenomic biomarkers an effective tool to predict taxane toxicity and outcome in breast cancer patients? Literature review

Purpose Breast cancer is a heterogeneous disease, char- acterized by various molecular phenotypes that correlate with different prognosis and response to treatments. Taxa- nes are some of the most active chemotherapeutic agents for breast cancer; however, their utilization is limited, due to hematologic and cumulative neurotoxicity on treated patients. To understand why only some patients experi- ence severe adverse effects and why patients respond and develop resistance with different rates to taxane therapy, the metabolic pathways of these drugs should be completely unraveled. The variant forms of several genes, related to taxane pharmacokinetics, can be indicative markers of clin- ical parameters, such as toxicity or outcome. Methods The search of the data has been conducted through PubMed database, presenting clinical data, clinical trials and basic research restricted to English language until June 2015. Results We studied the literature in order to find any pos- sible association between the major pharmacogenomic variants and specific taxane-related toxicity and patient outcome. We found that the data of these studies are * Susanna Scarpa [email protected] Francesca De Iuliis [email protected] Gerardo Salerno [email protected] Ludovica Taglieri [email protected] 1 Experimental Medicine Department, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy sometimes discordant, due to both the small number of enrolled patients and the heterogeneity of the examined population. Conclusions Among all analyzed genes, only CYP1B1 and ABCB1 resulted the strongest candidates to become biomarkers of clinical response to taxane therapy in breast cancer, although their utilization still remains an experi- mental procedure. In the future, greater studies on genetic polymorphisms should be performed in order to identify differentiating signatures for patients with higher toxic- ity and with resistant or responsive outcome, before the administration of taxanes

The kinesin Eg5 inhibitor K858 induces apoptosis and reverses the malignant invasive phenotype in human glioblastoma cells

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and the current chemotherapeutic options for GBM are limited to temozolomide. Recently, inhibitors of kinesin spindle protein Eg5 have shown pronounced antitumor activity and our group has demonstrated that one of these inhibitors of kinesin Eg5, named K858, exerts important anti-proliferative and apoptotic effects on breast cancer cells. Since GBM cells usually express high levels of kinesin Eg5, we tested the effect of K858 on two human GBM cell lines (U-251 and U-87) and found that K858 could inhibit cell growth, induce apoptosis, revert epithelial-mesenchymal transition and inhibit migration in both cell lines. However, at the same time, K858 increased survivin expression, an anti-apoptotic molecule; so, down-regulating survivin with the specific inhibitor YM155, we obtained an important increase of K858-dependent apoptosis. This indicated that the anti-tumor activity of K858 on GBM was limited by the over-expression of survivin and that the negative regulation of this protein could sensitize tumor cells to K858-induced apoptosis. These data support the choice of kinesin Eg5 as target of new therapeutic approaches for GBM; in particular, K858 has been demonstrated to be a potent inhibitor of replication, inducer of apoptosis and negative regulator of the invasive phenotype for GBM cells

Taxane induced neuropathy in patients affected by breast cancer: literature review

Taxane induced neuropathy (TIN) is the most limiting side effect of taxane based chemotherapy, relative to the majority of breast cancer patients undergoing therapy with both docetaxel and paclitaxel. The symptoms begin symmetrically from the toes, because the tips of the longest nerves are affected for first. The patients report sensory symptoms such as paresthesia, dysesthesia, numbness, electric shock-like sensation, motor impairment and neuropathic pain. There is a great inter-individual variability among breast cancer women treated with taxanes, in fact 20-30% of them don't develop neurotoxicity. Actually, there is no standard therapy for TIN, although many medications, antioxidants and natural substances have been tested in vitro and in vivo. We will summarize all most recent literature data on TIN prevention and treatment, in order to reach an improvement in TIN management. Further studies are needed to evaluate new therapies that restore neuronal function and improve life quality of patients

On and off metronomic oral vinorelbine in elderly women with advanced breast cancer

background: Elderly patients with metastatic breast cancer (MBC) have more problems receiving chemotherapy than younger patients, especially with the presence of multiple comorbidities, adverse drug events and function- al decline. Low-dose oral administration of cytotoxic agents such as vinorelbine, a semisynthetic vinca alkaloid that interferes with microtubule assembly, leading to arrest of cell division, is usually effective and well tolerated. Methods: From February 2010 to February 2014, 32 patients with MBC, median age 76 years (range 69-83) were treated with oral vinorelbine 30 mg (total dose), one day on and one day off, until disease progression or unac- ceptable toxicity levels were reported. Toxicity, quality of life and clinical benefit were evaluated. Matched t-tests were conducted to discern whether quality-of-life indicator (p<0.05 was considered significant) differed before and 6 months after treatment. Statistical analysis was performed using Graph Pad Prism 5.0 (GraphPad Software Inc., San Diego, CA, USA). Results: No grade 3 and 4 adverse events were reported. A clinical benefit of 50% was found in our cohort. On and off metronomic vinorelbine oral administration resulted in good tolerability and safe profile in our selected elderly population, and improved patient adherence to therapy. conclusions: The present study demonstrated that metronomic vinorelbine might be a potential treatment in elderly patients by reducing adverse effects and increasing quality of life, setting the stage for future extensive clinical trials

Thyroid hormone regulates fibronectin expression through the activation of the hypoxia inducible factor 1

Thyroid hormones regulate gene expression via both canonical and non-canonical signaling. Hyperthyroidism is associated with elevated plasma levels of fibronectin (FN): in this study we elucidate the molecular mechanism through which triiodothyronine (T3) regulates FN and demonstrate that T3 induces FN expression via a non-canonical pathway by activating hypoxia-inducible factor-1 (HIF-1). We found that T3 treatment increased cellular and secreted FN in human hepatoma cells (HepG2) and human dermal fibroblasts (HF) via the PI3K/Akt/HIF-1 pathway. The inhibition of either Akt phosphorylation with wortmannin or HIF-1 with YC1 in both cell types prevented HIF-1α synthesis and FN positive regulation upon T3 treatment. We showed that HIF-1α overexpression per se was sufficient to up-regulate FN in both cell lines as demonstrated by the transient transfection of both the constitutively active and wild-type forms of HIF-1α. Our data demonstrate the involvement of the PI3K/Akt/HIF-1 pathway in mediating T3 induced FN up-regulation

Elderly woman with triple-negative metastatic breast cancer successfully treated with metronomic capecitabine.

Triple-negative breast cancer phenotype (estrogen receptor-, progesterone receptor- and human epidermal growth receptor 2-negative) is one of the most aggressive molecular subtypes, accounting for 15-20% of all breast tumors. There is no standard treatment for this setting of patients except anthracyclines and taxanes, but not all elderly patients can tolerate these kinds of agents. We describe the case of an elderly woman affected by triple-negative breast cancer with bone and brain metastases who has been treated for five years with metronomic capecitabine. At the moment, the patient has stable disease and enjoys good quality of life. She had initially been diagnosed with a poor Karnofsky index, which has actually improved from 50 to 90. Metronomic capecitabine treatment has clearly improved her quality of life, as documented by the results of the Functional Assessment of Cancer Therapy Breast. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.Triple-negative breast cancer phenotype (estrogen receptor-, progesterone receptor- and human epidermal growth receptor 2-negative) is one of the most aggressive molecular subtypes, accounting for 15-20% of all breast tumors. There is no standard treatment for this setting of patients except anthracyclines and taxanes, but not all elderly patients can tolerate these kinds of agents. We describe the case of an elderly woman affected by triple-negative breast cancer with bone and brain metastases who has been treated for five years with metronomic capecitabine. At the moment, the patient has stable disease and enjoys good quality of life. She had initially been diagnosed with a poor Karnofsky index, which has actually improved from 50 to 90. Metronomic capecitabine treatment has clearly improved her quality of life, as documented by the results of the Functional Assessment of Cancer Therapy Breast. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved