[Show abstract][Hide abstract] ABSTRACT: Purpose: Despite its indolent nature, chronic lymphocytic leukemia (CLL) remains an incurable disease. To establish the potential pathogenic role of microRNAs (miRNAs), the identification of deregulated miRNAs in CLL is crucial. Experimental Design: We analyzed the expression of 723 mature miRNAs in 217 early stage CLL cases and in various different normal B-cell subpopulations from tonsils and peripheral blood. Results: Our analyses indicated that CLL cells exhibited a miRNA expression pattern that was most similar to the subsets of antigen-experienced and marginal zone-like B-cells. These normal subpopulations were used as reference to identify differentially expressed miRNAs in comparison with CLL. Differences related to the expression of 25 miRNAs were found to be independent from IGHV mutation status or cytogenetic aberrations. These differences, confirmed in an independent validation set, led to a novel comprehensive description of miRNAs potentially involved in CLL. We also identified miRNAs whose expression was distinctive of cases with mutated versus unmutated IGHV genes or cases with 13q, 11q, and 17p deletions and trisomy 12. Finally, analysis of clinical data in relation to miRNA expression revealed that miR-26a, miR-532-3p, miR-146-5p and miR-29c* were strongly associated with progression free survival. Conclusion: This study provides novel information on miRNAs expressed by CLL and normal B-cell subtypes, with implication on the cell of origin of CLL. In addition, our findings indicate a number of deregulated miRNAs in CLL which may play a pathogenic role and promote disease progression. Collectively, this information can be utilized for developing miRNA-based therapeutic strategies in CLL.
Clinical cancer research : an official journal of the American Association for Cancer Research. 06/2014;
[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma (MM) is due to the proliferation in the bone marrow (BM) of malignant plasmacells (PCs) and it accounts for about 10% of all hematological tumors. MM is the natural evolution of a monoclonal gammopathy of uncertain significance. Although the introduction of novel biological agents in the clinical practice has changed the natural history of the disease, MM remains incurable. MicroRNAs (miRNAs) are short non-coding RNAs that control cell functions through mRNA targeting. In the cancer setting, miRNAs have shown prognostic and predictive potentials. Several preclinical findings demonstrate their broad anticancer activities in various types of cancer, including MM. In this article, we provide an overview of the biology of miRNAs together with the scenario of miRNA deregulation in MM. These findings shine light on the use of miRNAs as anti-MM agents. We also discuss the recent findings on miRNA therapeutics of MM.
Current Pharmaceutical Biotechnology 05/2014; · 2.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Radiotherapy is one of the most therapeutic strategies for breast cancer patients, although its efficacy may be reduced by intrinsic radiation resistance of cancer cells. Recent investigations demonstrate a link between cancer cell radio-resistance and activation of sphingosine kinase (SphK1), which plays a key role in the balance of lipid signaling molecules. Sphingosine kinase (SphK1) activity can alter the sphingosine-1-phosphate (S1P)/ceramide ratio leading to an imbalance in the sphingolipid rheostat. Fingolimod (FTY720) is a novel sphingosine analog and a potent immunosuppressive drug that acts as a SphK1 antagonist, inhibits the growth, and induces apoptosis in different human cancer cell lines. We sought to investigate the in vitro radiosensitizing effects of FTY720 on the MDA-MB-361 breast cancer cell line and to assess the effects elicited by radiation and FTY720 combined treatments. We found that FTY720 significantly increased anti-proliferative and pro-apoptotic effects induced by a single dose of ionizing radiation while causing autophagosome accumulation. At the molecular level, FTY720 significantly potentiated radiation effects on perturbation of signaling pathways involved in regulation of cell cycle and apoptosis, such as PI3K/AKT and MAPK. In conclusion, our data highlight a potent radiosensitizing effect of FTY720 on breast cancer cells and provide the basis of novel therapeutic strategies for breast cancer treatment.
Cancer biology & therapy 03/2014; 15(6). · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ovarian cancer is the leading cause of death among gynecological tumors. Carboplatin/paclitaxel represents the cornerstone of front-line treatment. Instead, there is no consensus for management of recurrent/progressive disease, in which pegylated liposomal doxorubicin (PLD) ± carboplatin is widely used. We performed a systematic review and metaanalysis to evaluate impact of PLD-based compared with no-PLD-based regimens in the ovarian cancer treatment. Data were extracted from randomized trials comparing PLD-based treatment to any other regimens in the January 2000-January 2013 time-frame. Study end-points were overall survival (OS), progression free survival (PFS), response rate (RR), CA125 response, and toxicity. Hazard ratios (HRs) of OS and PFS, with 95% CI, odds ratios (ORs) of RR and risk ratios of CA125 response and grade 3-4 toxicity, were extracted. Data were pooled using fixed and random effect models for selected endpoints. Fourteen randomized trials for a total of 5760 patients were selected and included for the final analysis, which showed no OS differences for PLD-based compared with other regimens (pooled HR: 0.94; 95% CI: 0.88-1.02; P = 0.132) and a significant PFS benefit of PLD-based schedule (HR: 0.91; 95% CI: 0.86-0.96; P = 0.001), particularly in second-line (HR: 0.85; 95% CI: 0.75-0.91) and in platinum-sensitive (HR: 0.83; 95% CI: 0.74-0.94) subgroups. This work confirmed the peculiar tolerability profile of this drug, moreover no difference was observed for common hematological toxicities and for RR, CA125 response. PLD-containing regimens do not improve OS when compared with any other schedule in all phases of disease. A marginal PFS advantage is observed only in platinum-sensitive setting and second-line treatment.
Cancer biology & therapy 03/2014; 15(6). · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma (MM) cells induce relevant angiogenic effects within the human bone marrow milieu (huBMM) by the aberrant expression of angiogenic factors. Hypoxia triggers angiogenic events within the huBMM and the transcription factor hypoxia-inducible factor-1α (HIF-1α) is over-expressed by MM cells. Since synthetic miR-199a-5p mimics negatively regulates HIF-1α, we here investigated a miRNA-based therapeutic strategy against hypoxic MM cells. We indeed found that enforced expression of miR-199a-5p led to down-modulated expression of HIF-1α as well as of other pro-angiogenic factors such as VEGF-A, IL-8, and FGFb in hypoxic MM cells in vitro. Moreover, miR-199a-5p negatively affected MM cells migration, while it increased the adhesion of MM cells to bone marrow stromal cells (BMSCs) in hypoxic conditions. Furthermore, transfection of MM cells with miR-199a-5p significantly impaired also endothelial cells migration and down-regulated the expression of endothelial adhesion molecules such as VCAM-1 and ICAM-1. Finally, we identified a hypoxia\AKT/miR-199a-5p loop as a potential molecular mechanism responsible of miR-199a-5p down-regulation in hypoxic MM cells. Taken together our results indicate that miR-199a-5p has an important role for the pathogenesis of MM and support the hypothesis that targeting angiogenesis via a miRNA/HIF-1α pathway may represent a novel potential therapeutical approach for this still lethal disease.
[Show abstract][Hide abstract] ABSTRACT: Sp1 transcription factor controls a pleiotropic group of genes and its aberrant activation has been reported in number of malignancies including multiple myeloma. Here we investigated and report its aberrant activation in Waldenstrom's macroglobulinemia (WM). Both loss of - and gain of Sp1 function studies have highlighted a potential oncogenic role of Sp1 in WM. We have further investigated effect of a small molecule inhibitor (Terameprocol-TMP) targeting Sp1 activity in WM. Treatment with TMP inhibited growth and survival and impaired NF-κB and STAT3 activity in WM cells. We next investigated and observed that TMP treatment induced further inhibition of WM cells in MYD88 knock-down WM cells. Moreover, we observed that BTK, a downstream target of MYD88 signaling pathway, is transcriptionally regulated by Sp1 in WM cells. Combined use of TMP with BTK or IRAK1/4 inhibitors resulted in significant and synergistic dose-dependent antiproliferative effect in MYD88 L265P-expressing WM cells. In summary, these results demonstrate Sp1 as an important transcription factor that regulates proliferation and survival of WM cells independent of MYD88 pathway activation and provide preclinical rationale for clinical development of TMP in WM alone or in combination with inhibitors of MYD88 pathway.
[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma (MM) is a disease with an adverse outcome and new therapeutic strategies are urgently awaited. A rising body of evidence supports the notion that microRNAs (miRNAs), master regulators of eukaryotic gene expression, may exert anti-MM activity. Here, we evaluated the activity of synthetic miR-34a in MM cells. We found that transfection of miR-34a mimics in MM cells induces a significant change of gene expression with relevant effects on multiple signal transduction pathways. We detected early inactivation of pro-survival and proliferative kinases Erk-2 and Akt followed at later time points by caspase-6 and -3 activation and apoptosis induction. To improve the in vivo delivery, we encapsulated miR-34a mimics in stable nucleic acid lipid particles (SNALPs). We found that SNALPs miR-34a were highly efficient in vitro in inhibiting growth of MM cells. Then, we investigated the activity of the SNALPs miR-34a against MM xenografts in SCID mice. We observed significant tumor growth inhibition (p<0.05) which translated in mice survival benefits (p = 0.0047). Analysis of miR-34a and NOTCH1 expression in tumor retrieved from animal demonstrated efficient delivery and gene modulation induced by SNALPs miR-34a in the absence of systemic toxicity. We here therefore provide evidence that SNALPs miR-34a may represent a promising tool for miRNA-therapeutics in MM.
PLoS ONE 01/2014; 9(2):e90005. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The GOLFIG-2 phase III trial was designed to compare the immunobiological activity and antitumor efficacy of GOLFIG chemoimmunotherapy regimen with standard FOLFOX-4 chemotherapy in frontline treatment of metastatic colorectal cancer (mCRC) patients. This trial was conceived on the basis of previous evidence of antitumor and immunomodulating activity of the GOLFIG regimen in mCRC. GOLFIG-2 is a multicentric open/label phase III trial (EUDRACT: 2005-003458-81). Chemo-naive mCRC patients were randomized in a 1:1 ratio to receive biweekly standard FOLFOX-4 or GOLFIG [gemcitabine (1000 mg/m, day 1); oxaliplatin (85 mg/m, day 2); levofolinate (100 mg/m, days 1-2), 5-fluorouracil (5-FU) (400 mg/m in bolus followed by 24 h infusion at 800 mg/m,days 1-2), sc. GM-CSF (100 μg, days 3-7); sc. aldesleukin (0·5 MIU bi-daily, days 8-14 and 17-30)] treatments. The study underwent early termination because of poor recruitment in the control arm. After a median follow-up of 43.83 months, GOLFIG regimen showed superiority over FOLFOX in terms of progression-free survival [median 9·23 (95% confidence interval (CI), 6·9-11.5) vs. median 5.70 (95% CI, 3.38-8.02) months; hazard ratio (HR): 0.52 (95% CI, 0.35-0.77), P=0·002] and response rate [66.1% (95% CI, 0.41-0.73) vs. 37·0% (95% CI, 0.28-0.59), P=0.002], with a trend to longer survival [median 21.63 (95% CI, 18.09-25.18) vs. 14.57 mo (95% CI, 9.07-20.07); HR: 0·79 (95% CI, 0.52-1.21); P=0.28]. Patients in the experimental arm showed higher incidence of non-neutropenic fever (18.5%), autoimmunity signs (18.5%), an increase in the number of monocytes, eosinophils, CD4 T lymphocytes, natural killer cells, and a decrease in immunoregulatory (CD3CD4CD25FoxP3) T cells. Taken together, these findings provide proof-of-principle that GOLFIG chemoimmunotherapy may represent a novel reliable option for first-line treatment of mCRC.
[Show abstract][Hide abstract] ABSTRACT: The miR-221/222 cluster is upregulated in malignant plasma cells from multiple myeloma (MM) patients harboring the t(4;14) translocation. We previously reported that silencing of miR-221/222 by an antisense oligonucleotide induces anti-MM activity and upregulates canonical miR-221/222 targets. The in vivo anti-tumor activity occurred when miR-221/222 inhibitors were delivered directly into MM xenografts. The aim of the present study was to evaluate the anti-MM activity of a novel phosphorothioate modified backbone 13-mer locked nucleic acid (LNA)-Inhibitor-miR-221 (LNA-i-miR-221) specifically designed for systemic delivery.
In vitro anti-MM activity of LNA-i-miR-221 was evaluated by cell proliferation and BrdU uptake assays. In vivo studies were performed with non-obese diabetic/severe combined immunodeficient (NOD.SCID) mice bearing t(4;14) MM xenografts, which were intraperitoneally or intravenously treated with naked LNA-i-miR-221. RNA extracts from retrieved tumors were analyzed for miR-221 levels and modulation of canonical targets expression. H&E staining and immunohistochemistry were performed on retrieved tumors and mouse vital organs.
In vitro, LNA-i-miR-221 exerted strong antagonistic activity against miR-221 and induced upregulation of the endogenous target p27Kip1. It had a marked anti-proliferative effect on t(4;14)-translocated MM cells but not on MM cells not carrying the translocation and not overexpressing miR-221. In vivo, systemic treatment with LNA-i-miR-221 triggered significant anti-tumor activity against t(4;14) MM xenografts; it also induced miR-221 downregulation, upregulated p27Kip1 and reduced Ki-67. No behavioral changes or organ-related toxicity were observed in mice as a consequence of treatments.
LNA-i-miR-221 is a highly stable, effective agent against t(4;14) MM cells, and is suitable for systemic use. These data provide the rationale for the clinical development of LNA-i-miR-221 for the treatment of MM.
PLoS ONE 01/2014; 9(2):e89659. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Stable nucleic acid lipid vesicles (SNALPs) encapsulating miR-34a to treat multiple myeloma (MM) were developed. Wild type or completely 2'-O-methylated (OMet) MiR-34a was used in this study. Moreover, SNALPs were conjugated with transferrin (Tf) in order to target MM cells overexpressing transferrin receptors (TfRs). The type of miR-34a chemical backbone did not significantly affect the characteristics of SNALPs in terms of mean size, polydispersity index, and zeta potential, while the encapsulation of an OMet miR-34a resulted in a significant increase of miRNA encapsulation into the SNALPs. On the other hand, the chemical conjugation of SNALPs with Tf resulted in a significant decrease of the zeta potential, while size characteristics and miR-34a encapsulation into SNALPs were not significantly affected. In an experimental model of MM, all the animals treated with SNALPs encapsulating miR-34a showed a significant inhibition of the tumor growth. However, the use of SNALPs conjugated with Tf and encapsulating OMet miR-34a resulted in the highest increase of mice survival. These results may represent the proof of concept for the use of SNALPs encapsulating miR-34a for the treatment of MM.
BioMed research international. 01/2014; 2014:217365.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was the evaluation of the effects of two emulsifiers on the physicochemical and technological properties of low molecular weight chitosan/poly (D,L-lactide-co-glycolide) (PLGA) nanoplexes and their transfection efficiency. Nanospheres were prepared using the nanoprecipitation method of the preformed polymer. The mean diameter and surface charge of the nanospheres were investigated by photocorrelation spectroscopy. The degree of binding of the plasmid with the nanoplexes was qualitatively and quantitatively determined. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) testing was performed using HeLa, RPMI8226, and SKMM1 cell lines. Flow cytometry and confocal laser scanning microscopy were used to determine the degree of cellular transfection and internalization of the nanoplexes into cells, respectively. The nanoplexes had a positive zeta potential, and low amounts of PLGA and poloxamer 188 showed a mean colloidal size of ~200 nm with a polydispersity index of ~0.14. The nanoplexes had suitable entrapment efficiency (80%). In vitro experiments showed that the colloidal nanodevices did not induce significant cytotoxicity. The nanoplexes investigated in this study could represent efficient and useful nonviral devices for gene delivery. Use of low amounts of PLGA and poloxamer 188 enabled development of a nanosphere able to transfect cells efficiently. These nanosystems are a helpful platform for delivery of genetic material while preserving therapeutic efficacy.
International Journal of Nanomedicine 01/2014; 9:2359-72. · 4.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Glycosylation is a posttranslational modification of proteins playing a major role in cell signalling, immune recognition, and cell-cell interaction because of their glycan branches conferring structure variability and binding specificity to lectin ligands. Aberrant expression of glycan structures as well as occurrence of truncated structures, precursors, or novel structures of glycan may affect ligand-receptor interactions and thus interfere with regulation of cell adhesion, migration, and proliferation. Indeed, aberrant glycosylation represents a hallmark of cancer, reflecting cancer-specific changes in glycan biosynthesis pathways such as the altered expression of glycosyltransferases and glycosidases. Most studies have been carried out to identify changes in serum glycan structures. In most cancers, fucosylation and sialylation are significantly modified. Thus, aberrations in glycan structures can be used as targets to improve existing serum cancer biomarkers. The ability to distinguish differences in the glycosylation of proteins between cancer and control patients emphasizes glycobiology as a promising field for potential biomarker identification. In this review, we discuss the aberrant protein glycosylation associated with human cancer and the identification of protein glycoforms as cancer biomarkers. In particular, we will focus on the aberrant CD43 glycosylation as cancer biomarker and the potential to exploit the UN1 monoclonal antibody (UN1 mAb) to identify aberrant CD43 glycoforms.
BioMed research international. 01/2014; 2014:742831.
[Show abstract][Hide abstract] ABSTRACT: Epigenetic silencing of tumor suppressor genes frequently occurs and may account for their inactivation in cancer cells. We previously demonstrated that miR-29b is a tumor suppressor microRNA (miRNA) that targets de novo DNA methyltransferases and reduces the global DNA methylation of multiple myeloma (MM) cells. Here, we provide evidence that epigenetic activity of miR-29b leads to promoter demethylation of suppressor of cytokine signaling-1 (SOCS-1), a hypermethylated tumor suppressor gene. Enforced expression of synthetic miR-29b mimics in MM cell lines resulted in SOCS-1 gene promoter demethylation, as assessed by Sequenom MassARRAY EpiTYPER analysis, and SOCS-1 protein upregulation. miR-29b-induced SOCS-1 demethylation was associated with reduced STAT3 phosphorylation and impaired NFκB activity. Downregulation of VEGF-A and IL-8 mRNAs could be detected in MM cells transfected with miR-29b mimics as well as in endothelial (HUVEC) or stromal (HS-5) cells treated with conditioned medium from miR-29b-transfected MM cells. Notably, enforced expression of miR-29b mimics increased adhesion of MM cells to HS-5 and reduced migration of both MM and HUVEC cells. These findings suggest that miR-29b is a negative regulator of either MM or endothelial cell migration. Finally, the proteasome inhibitor bortezomib, which induces the expression of miR-29b, decreased global DNA methylation by a miR-29b-dependent mechanism and induced SOCS-1 promoter demethylation and protein upregulation. In conclusion, our data indicate that miR-29b is endowed with epigenetic activity and mediates previously unknown functions of bortezomib in MM cells.
[Show abstract][Hide abstract] ABSTRACT: To investigate the incidence and clinical relevance of classic and new prognostic markers, IGHV gene mutational status, and chromosomal abnormalities in cMBLs compared to Rai stage 0 chronic lymphocytic leukemia (Rai0-CLL).
A group of 136 clinical monoclonal B lymphocytosis (cMBL) patients and a group of 216 Rai0-CLL cases were investigated prospectively.
IGHV mutated cases were significantly more frequent among cMBLs (P=0.005), while the distribution of CD38 and ZAP-70 positive cases, of patients with NOTCH1 and SF3B1 mutations or exhibiting the major CLL cytogenetic abnormalities was similar in the two groups. Moreover, no significant differences were found neither in IGHV/IGHD/IGHJ gene usage nor in the overall prevalence of stereotyped IGHV gene sequences. Cells from cMBL and Rai0-CLL exhibited similar gene and miRNA signatures; in addition, when grouped according to the IGHV mutational status, IGHV unmutated cases showed different transcriptional signatures compared to IGHV mutated patients, irrespectively of the cMBL or Rai0-CLL classification. cMBL diagnosis per se was predictive of longer progression free survival.
Our study based on a prospective series of patients indicates that no major differences exist between the circulating cells from cMBL and Rai0-CLL, at least based on a comparison of the markers utilized in the study. This possibly suggests that the two conditions mainly differ in the initial size of the monoclonal cell population, which may influence the subsequent timing of clonal expansion and clinical manifestations.
Clinical Cancer Research 09/2013; · 7.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Small nucleolar RNAs (snoRNAs) and small Cajal body-specific RNAs are non-coding RNAs involved in the maturation of other RNA molecules. Alterations of sno/scaRNA expression may play a role in cancerogenesis. This study elucidates the patterns of sno/scaRNA expression in 211 chronic lymphocytic leukemia (CLL) patients (Binet stage A) also in comparison with those of different normal B-cell subsets.
The patterns of sno/scaRNA expression in highly purified CD19+ B-cells of 211 CLL patients and in 18 normal B-cell samples - 6 from peripheral blood, and 12 from tonsils (4 germinal center, 2 marginal zone, 3 switched memory and 3 naive B-cells) - were analyzed on the Affymetrix GeneChip(R) Human Gene 1.0 ST array.
CLLs display a sno/scaRNAs expression profile similar to normal memory, naive and marginal-zone B-cells, with the exception of a few down-regulated transcripts (SNORA31, -6, -62, and -71C). Our analyses also suggest some heterogeneity in the pattern of sno/scaRNAs expression which is apparently unrelated to the major biological (ZAP-70 and CD38), molecular (IGHV mutation) and cytogenetic markers. Moreover, we found that SNORA70F was significantly down-regulated in poor prognostic subgroups and this phenomenon was associated with the down-regulation of its host gene COBLL1. Finally, we generated an independent model based on SNORA74A and SNORD116-18 expression, which appears to distinguish two different prognostic CLL groups.
These data extend the view of sno/scaRNAs deregulation in cancer and may contribute to discover novel biomarkers associated with the disease and potentially useful to predict the clinical outcome of early stage CLL patients.
BMC Medical Genomics 09/2013; 6(1):27. · 3.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The progress in the understanding of biological events underlying multiple myeloma (MM) development and progression has allowed the design of molecularly targeted therapies (MTTs) for this disease and several new compounds are presently under investigation in the preclinical and clinical settings. The recent discovery that miRNAs, and short non coding RNAs in general, are involved in the pathogenesis of cancer has raised the issue whether a novel therapeutic approach should be provided by selective interference with miRNA network. This review will focus on the rationale of miRNA-based therapeutics, providing the most relevant information on biogenesis and technical issues in miRNA analysis. Finally, a detailed overview of the recent findings on miRNA therapeutics of MM will be discussed.
Current drug targets 07/2013; · 3.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction: Multiple myeloma (MM) is an incurable plasma cell malignancy, which causes significant morbidity due to organ damage and bone tissue destruction. In recent years, novel drugs have become available for MM therapy thanks to the growing knowledge of disease pathobiology. Areas covered: Intrinsic genetic lesions, as well as the bone marrow microenvironment, contribute to the activation of proliferation and survival pathways, impairment of cell death mechanisms and drug resistance. The phosphatidylinositol 3-kinase (PI3K) and the Ras/mitogen-activated protein kinase (MAPK) cascades are the signaling pathways mainly involved in the MM development. In the last decade, several molecules interfering with growth and survival promoting signaling have been developed. Expert opinion: Despite the availability of novel therapeutics, MM still evolves into a drug-resistant phase and most patients die of progressive disease. Therefore, there is an urgent need of novel therapeutic strategies. Among a plethora of new investigational agents, microRNA (miRNA) represents the basis for the design of novel therapeutic strategies which basically rely on miRNA inhibition or miRNA replacement approaches and take benefit respectively from the use of miRNA inhibitors or synthetic miRNAs as well as from lipid-based nanoparticles as carriers for in vivo delivery.
Expert opinion on biological therapy 06/2013; · 3.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bevacizumab is a humanized anti-VEGF monoclonal antibody able to produce clinical benefit in advanced non-squamous non-small-cell lung cancer (NSCLC) patients when combined to chemotherapy. At present, while there is a rising attention to bevacizumab-related adverse events and costs, no clinical or biological markers have been identified and validated for baseline patient selection. Preclinical findings suggest an important role for myeloid-derived inflammatory cells, such as neutrophils and monocytes, in the development of VEGF-independent angiogenesis. We conducted a retrospective analysis to investigate the role of peripheral blood cells count and of an inflammatory index, the neutrophil-to-lymphocyte ratio (NLR), as predictors of clinical outcome in NSCLC patients treated with bevacizumab plus chemotherapy. One hundred and twelve NSCLC patients treated with chemotherapy ± bevacizumab were retrospectively evaluated for the predictive value of clinical or laboratory parameters correlated with inflammatory status. Univariate analysis revealed that a high number of circulating neutrophils and monocytes as well as a high NLR were associated with shorter progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients only. We have thus developed a model based on the absence or the presence of at least one of the above-mentioned inflammatory parameters. We found that the absence of all variables strongly correlated with longer PFS and OS (9.0 vs. 7.0 mo, HR: 0.39, p = 0.002; and 20.0 vs. 12.0 mo, HR: 0.29, p < 0.001 respectively) only in NSCLC patients treated with bevacizumab plus chemotherapy. Our results suggest that a baseline systemic inflammatory status is marker of resistance to bevacizumab treatment in NSCLC patients.
Cancer biology & therapy 06/2013; 14(6):469-75. · 3.29 Impact Factor