Ludovica Taglieri

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 functional 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 unacceptable 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.

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

PurposeBreast cancer is a heterogeneous disease, characterized by various molecular phenotypes that correlate with different prognosis and response to treatments. Taxanes 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 experience 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 clinical parameters, such as toxicity or outcome.MethodsThe 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.ResultsWe studied the literature in order to find any possible association between the major pharmacogenomic variants and specific taxane-related toxicity and patient outcome. We found that the data of these studies are sometimes discordant, due to both the small number of enrolled patients and the heterogeneity of the examined population.ConclusionsAmong 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 experimental procedure. In the future, greater studies on genetic polymorphisms should be performed in order to identify differentiating signatures for patients with higher toxicity and with resistant or responsive outcome, before the administration of taxanes.

Breast cancer cells respond differently to docetaxel depending on their phenotype and on survivin upregulation.

Breast cancer is characterized by molecular heterogeneity, and four major breast cancer subtypes have been identified, each characterized by significant differences in survival, prognosis, and response to therapy. We have studied the effects of docetaxel treatment on apoptosis and survivin expression in four breast cancer cell lines: MCF7 (luminal A: estrogen receptor-positive and progesterone receptor-positive, ErbB2-negative), BT474 (luminal B: estrogen receptor/progesterone receptor/ErbB2-positive), SKBR3 (HER2-like: estrogen receptor/progesterone receptor-negative, ErbB2-positive), and MDA-MB231 (basal-like: estrogen receptor/progesterone receptor/ErbB2-negative). We demonstrated that docetaxel-induced apoptosis and survivin upregulation (MCF7 p = 0.002, BT474 p = 0.001, SKBR3 p = 0.001) in luminal A/B and HER2-like cells, while it induced mainly necrosis and a lower rate of survivin upregulation (MDA-MB231 p = 0.035) in basal-like cells. Wortmannin, a p-Akt inhibitor, was able to revert surviving upregulation and, at the same time, induced an increase of docetaxel-dependent apoptosis, suggesting that reduced levels of survivin can sensitize tumor cells to apoptosis. These data show that the analyzed breast cancer cell lines respond differently to docetaxel, depending on their receptor expression profile and molecular phenotype. Yet, these data confirm that one of the pathways involved in taxane-related chemoresistance is the upregulation of survivin. Further studies on the molecular mechanisms of chemoresistance and on the different modalities of apoptosis induced by chemotherapeutic agents are requested to better understand how cancer cells evade cell death, in order to design new kind of anticancer agents and survivin could represent a future target for this kind of research.

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

SummaryInhibitors 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.

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

SummaryGlioblastoma multiforme is the most common primary malignant brain tumor and its current chemotherapeutic options are limited to temozolomide. Recently, some synthetic compounds acting as inhibitors of kinesin spindle protein Eg5 have shown pronounced antitumor activity. Our group has recently demonstrated that one of these kinesin Eg5 inhibitors, named K858, exerted important antiproliferative and apoptotic effects on breast cancer cells. Since glioblastoma cells usually express high levels of kinesin Eg5, we tested the effect of K858 on two human glioblastoma cell lines (U-251 and U-87) and found that K858 inhibited cell growth, induced apoptosis, reversed epithelial-mesenchymal transition and inhibited migration in both cell lines. We also detected that, at the same time, K858 increased the expression of survivin, an anti-apoptotic molecule, and that the forced down-regulation of survivin, obtained with the specific inhibitor YM155, boosted K858-dependent apoptosis. This indicated that the anti-tumor activity of K858 on glioblastoma cells is limited by the over-expression of survivin and that the negative regulation of this protein sensitizes tumor cells to K858. These data confirmed that kinesin Eg5 is an interesting target for new therapeutic approaches for glioblastoma. We showed that K858, specifically, was a potent inhibitor of replication, an inducer of apoptosis and a negative regulator of the invasive phenotype for glioblastoma cells.

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; furthermore, 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.

Anthracycline-Free Neoadjuvant Chemotherapy Ensures Higher Rates of Pathologic Complete Response in Breast Cancer

Micro‐Abstract We describe a study of anthracycline‐free taxane/carboplatin‐based neoadjuvant chemotherapy in patients with initially inoperable breast cancer. The primary endpoint of pathologic complete response was 64% with a high tolerability and no grade 4 toxicity. Therefore, we propose this schedule of therapy as the best in terms of efficacy and low toxicity for this kind of patient. Purpose: Neoadjuvant chemotherapy (NCT) is a standard of care for locally advanced and initially inoperable breast cancer. NCT can test chemotherapy efficacy and can be followed by breast‐conserving surgery. Considering taxanes as one of the most effective agents, we analyzed the efficacy of a neoadjuvant schedule without anthracyclines and based only on taxanes and carboplatin, trying to avoid cardiotoxicity, which is the most serious side effect correlated with anthracyclines. Patients and Methods: We enrolled 61 patients with breast cancer, belonging to 4 subgroups, according to molecular phenotypes: 24 triple‐negative/basal‐like, 13 HER2‐like, 20 luminal B, and 4 luminal A. All patients underwent weekly chemotherapy with carboplatin AUC2, paclitaxel 80 mg/m2, with trastuzumab (in case of HER2 positivity) 2 mg/kg, except for luminal A patients, who underwent only hormonal therapy. Among 61 patients, 26 (43%) received modified radical mastectomy and 35 (57%) received breast‐conserving surgery. Results: The patients obtaining pathologic complete response (pCR) were 20 (83%) of 24 triple‐negative/basal‐like, 10 (76%) of 13 HER2‐like, 6 (30%) of 20 luminal B, and 3 (75%) of 4 luminal A. All the patients were evaluated for toxicity: no grade 4 was detected, 5 patients experienced grade 3 neuropathy, then reverted to G2 after chemotherapy discontinuation. At a minimum follow‐up of 5 years, median overall survival was 48 months. Conclusion: Taxane/carboplatin‐based/anthracycline‐free NCT is the best treatment for inoperable breast cancer in terms of efficacy and toxicity, because this approach avoids cardiotoxicity and obtains an optimal rate (64%) of pCR, with an important impact on survival.

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.

Resistance to the mTOR inhibitor everolimus is reversed by the downregulation of survivin in breast cancer cells

Everolimus (RAD001) is an inhibitor of mammalian target of rapamycin used in combination with exemestane to treat hormone receptor-positive advanced breast cancer. However, not all patients are equally sensitive to RAD001 and certain patients develop resistance. Therefore, the present study analyzed the mechanisms involved in the resistance of breast cancer cells to RAD001 in order to identify a potential tool to overcome it. The effects of RAD001 on the inhibition of cell viability, on the induction of apoptosis and autophagy and on the regulation of survivin, an anti-apoptotic protein, were evaluated in two breast cancer cell lines: BT474 (luminal B) and MCF7 (luminal A). RAD001 was demonstrated to induce autophagy in the two cell lines at following a short period of treatment (4 h) and to induce apoptosis exclusively in BT474 cells following longer periods of treatment (48 h). RAD001 induced the downregulation of survivin in BT474 cells and its upregulation in MCF7 cells. Consequently, inhibiting survivin with YM155 resulted in the acquired resistance of MCF7 cells to RAD001 being reverted, restoring RAD001-induced apoptosis. These data demonstrated that RAD001 exerted anti-proliferative and pro-apoptotic effects on breast cancer cells, but that these effects were repressed by the simultaneous up-regulation of survivin. Finally, the results demonstrated that inhibiting the expression of survivin resulted in the restoration of the anti-neoplastic activity of RAD001.

Unexpected Vocal Cord Paralysis and Myasthenia Gravis in a Patient with Squamous Cell Lung Cancer

Vocal cord paralysis is a voice disorder that occurs when one or both the vocal cords don’t open or don’t close properly. This often determines difficulty in swallowing and coughing by the patient, because food or liquids slip into the trachea and the lungs. Vocal cord paralysis may be caused by trauma, cancer, surgery, or intubation and it has been sometimes described to follow vinca alkaloid treatment. Myasthenia gravis is an autoimmune disorder that can represent a paraneoplastic syndrome in cancer patients. We report a 55-years-old male with an advanced squamous cell lung carcinoma, presenting a unilateral vocal cord paralysis immediately after the treatment with gemcitabine, and myasthenia gravis one week after. To date, there aren’t any data in the literature describing causal relationship between non small cell lung cancer and myasthenia gravis; here we suggest that myasthenia gravis simultaneous to lung cancer might be a rare form of paraneoplastic syndrome. It is impossible to find a single cause for our patient vocal cord paralysis: it could in fact have a multifactorial pathogenesis, not excluding the possibility of a single rare paraneoplastic syndrome, which includes both myasthenia gravis and vocal cord paralysis.