Niki Karachaliou

Catalan Institute of Oncology, Badalona, Catalonia, Spain

Are you Niki Karachaliou?

Claim your profile

Publications (38)144.65 Total impact

  • Rafael Rosell, Niki Karachaliou
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer is a genetic disease occurring through a multi-step process. Many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified and the pathways through which they act characterized. One question that remains unanswered is whether the development of new, more specific therapeutic agents is the best way to minimize cancer morbidity and mortality in the long-term. Metastasis is the relentless pursuit of cancer to escape its primary site and colonize distant organs. Phenotypic changes during cancer progression reflect the sequential accumulation of genetic alterations, which endow cancer cells with the ability to undergo their own divergent evolution and create distinct metastatic species. In order to understand this process, it is crucial to identify genes whose alterations accumulate during cancer progression and correlate with metastatic phenotypes of cancer cells.
    CANCER AND METASTASIS REVIEW 05/2015; DOI:10.1007/s10555-015-9557-1 · 6.45 Impact Factor
  • 03/2015; 3(3):36. DOI:10.3978/j.issn.2305-5839.2015.01.16
  • [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the safety and efficacy of metronomic vinorelbine in combination with cisplatin as first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). A total of 41 patients with inoperable stage IIIb or stage IV NSCLC (14 with adenocarcinomas, 19 with squamous cell carcinoma and eight with other types), PS = 0-2, were treated with cisplatin (80 mg/m(2)) in combination with oral metronomic vinorelbine (60 mg total dose, every other day) in cycles of 21 days. A total of 35 patients who received at least one cycle of chemotherapy were evaluable for toxicity and response. Partial response was achieved in 13 patients (ORR 37.1 %; CI 21.1-53.1 %) and stable disease in 10 (28.6 %). After a median follow-up period of 26.2 months (range 0.5-33.4 months), the median progression-free survival was 4.2 months and the median overall survival 12.0 months. The 1-year survival rate was 52.6 %. Myelosuppression was the main adverse event with grade 3 and 4 neutropenia occurring in five (14.3 %) and six (17.1 %) patients, respectively. Three of these patients presented with febrile neutropenia and there was one death due to sepsis. Non-hematologic toxicities were mild. Cisplatin in combination with metronomic vinorelbine is an active, although myelotoxic, therapeutic option in the first-line setting for the treatment of patients with locally advanced and metastatic non-small cell lung cancer, which merits further evaluation in randomized trials.
    Cancer Chemotherapy and Pharmacology 02/2015; 75(4). DOI:10.1007/s00280-015-2707-x · 2.57 Impact Factor
  • Source
    Niki Karachaliou, Rafael Rosell
    02/2015; 269. DOI:10.1016/j.ebiom.2015.02.010
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Resistance to RAF- and MEK-targeted therapy is a major clinical challenge. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Malignant gliomas, such as glioblastoma multiforme (GBM), present some of the greatest challenges in the management of cancer patients worldwide. Even with aggressive surgical resections and recent advances in radiotherapy and chemotherapy, the prognosis for GBM patients remains dismal and quality of life is poor. Although new molecular pathways crucial to the biology and invasive ability of GBM are coming to light, translation of basic science achievements into clinical practice is slow. Optimal management requires a multidisciplinary approach and knowledge of potential complications arising from both disease and treatment. To help illustrate "where we are going" with GBM, we here include a detailed depiction of the molecular alterations underlying this fatal disease, as well as intensive research over the past two decades that has led to considerable advances in the understanding of basic GBM biology, pathogenesis and therapeutic approaches.
  • Rafael Rosell, Niki Karachaliou
    Nature Reviews Clinical Oncology 12/2014; DOI:10.1038/nrclinonc.2014.225 · 15.70 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Designing molecular targeted therapy with high specificity based on novel tumor biomarkers is a high priority in lung cancer research. Several molecular aberrations have been already identified in non-small cell lung cancer (NSCLC), with subsequent development of drugs targeted to these aberrations. A more recent actionable target is MET, a multifaceted receptor tyrosine kinase which frequently interacts with other key oncogenic tyrosine kinases including epidermal growth factor receptor (EGFR) and ERBB3 leading to resistance to anti-EGFR therapies. However a phase III trial enrolling only patients with MET-positive tumors was stopped in early March due to futility since there was no evidence that the addition of onartuzumab to erlotinib has any positive effect. From the results of the MET lung phase III trial, we provide new pieces of information that can contribute to further preclinical validation and also be part of the armamentarium for clinical translational research.
    12/2014; 3(6):384-8. DOI:10.3978/j.issn.2218-6751.2014.08.10
  • The Lancet Respiratory Medicine 11/2014; 2(12). DOI:10.1016/S2213-2600(14)70259-0
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In a Spanish Lung Cancer Group (SLCG) phase II trial, the combination of BRCA1 and RAP80 expression was significantly associated with outcome in Caucasian patients with non-small-cell lung cancer (NSCLC). The SLCG therefore undertook an industry-independent collaborative randomized phase III trial comparing non-selected cisplatin-based chemotherapy with therapy customized according to BRCA1/RAP80 expression. An analogous randomized phase II trial was carried out in China under the auspices of the SLCG to evaluate the effect of BRCA1/RAP80 expression in Asian patients.
    Annals of Oncology 08/2014; DOI:10.1093/annonc/mdu389 · 6.58 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Activation of bypass signaling pathways, impairment of apoptosis and mutation of epidermal growth factor receptor (EGFR) to a drug-resistant state are well known mechanisms of resistance to singleagent erlotinib therapy in non-small-cell lung cancer (NSCLC) driven by EGFR mutations. Orphan receptor 1 (ROR1) knockdown inhibited the growth of NCI-H1975 cells (harboring EGFR L858R and T790M mutations). A pro-survival function for ROR1/MEK/ERK signaling in cooperation with AKT has been demonstrated. Methods: We have assessed ROR1 expression in 45 patients from the EURTAC trial (clinicaltrials.gov NCT00446225), 27 of whom harbored pretreatment concomitant EGFR T790M mutations, and correlated results with outcome. Results: Progression-free survival (PFS) was 11.8 months for erlotinib-treated patients with low/ intermediate and 5.8 months for those with high ROR1 levels. PFS for chemotherapy-treated patients was 5.6 and 9 months, respectively (P=0.0165). A total of 15 erlotinib-treated patients harbored concomitant T790M mutations; for these patients, PFS was 10.8 months for those with low/intermediate compared to 2.7 months for those with high ROR1 levels. In contrast, among 12 chemotherapy-treated patients with concomitant T790M mutations, PFS was 5.8 months for those with low/intermediate, compared to 14.2 months for those with high ROR1 levels (P=0.0138). Conclusions: ROR1 expression has a differential effect on outcome to erlotinib and chemotherapy in EGFR-mutant NSCLC patients. High ROR1 expression significantly limits PFS in erlotinib-treated patients with T790M mutations and ROR1-directed therapies can enhance the efficacy of treatment. In contrast, high ROR1 expression confers longer PFS to chemotherapy in the same group of patients. The role of chemotherapy and erlotinib in EGFR-mutant NSCLC patients with high ROR1 expression warrants further investigation.
    06/2014; 3(3):122-130. DOI:10.3978/j.issn.2218-6751.2014.03.02
  • Source
    Rafael Rosell, Bartomeu Massuti, Niki Karachaliou
  • [Show abstract] [Hide abstract]
    ABSTRACT: Epidermal growth factor receptor (EGFR) mutations occur in 17% of non-small-cell lung cancer (NSCLC) patients with notable response to single agent therapy but with low complete remission rate and, eventually, disease progression. Priming BIM, a pro-apoptotic signaling BH3-only protein, induces sensitivity to erlotinib in EGFR-mutant cell lines. Synthetic lethal approaches and preemptive therapies based on the initial expression of BIM may significantly improve the treatment outcome. EGFR mutations result in transient pro-death imbalance of survival and apoptotic signaling in response to EGFR inhibition. SHP2 is essential to the balance between ERK and the phosphoinositide-3-kinase (PI3K)/AKT and signal transducer activator of transcription (STAT) activity, while mTOR can be an additional marker for patients with high BIM expression. Furthermore, stromal hepatocyte growth factor (HGF) confers EGFR tyrosine kinase inhibitor (TKI) resistance and induces interreceptor crosstalk with integrin-b4, Eph2, CUB domain-containing protein-1 (CDCP1), AXL and JAK1. Only by understanding better, and in more depth, complex cancer molecular biology will we have the information that will help us to design strategies to augment efficacy of EGFR TKIs and offer our patients the best, most correct therapeutic option.
    04/2014; 3(2):107-15. DOI:10.3978/j.issn.2218-6751.2014.02.04
  • [Show abstract] [Hide abstract]
    ABSTRACT: The echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) has emerged as the second most important driver oncogene in lung cancer and the first targetable fusion oncokinase to be identified in 4-6% of lung adenocarcinomas. Crizotinib, along with a diagnostic test-the Vysis ALK Break Apart fluorescence in situ hybridization (FISH) Probe Kit-is approved for the treatment of ALK positive advanced non-small cell lung cancer (NSCLC). However, the success of a targeted drug is critically dependent on a sensitive and specific screening assay to detect the molecular drug target. In our experience, reverse transcription polymerase chain reaction (RT-PCR)-based detection of EML4-ALK is a more sensitive and reliable approach compared to FISH and immunohistochemistry (IHC). Although ALK FISH is clinically validated, the assay can be technically challenging and other diagnostic modalities, including IHC and RT-PCR should be further explored.
    04/2014; 3(2):70-4. DOI:10.3978/j.issn.2218-6751.2014.02.02
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Over a short period of time, translational research has described a new clinically relevant molecular subset of non-small-cell lung cancer (NSCLC) that is defined by EGFR mutations or EML4-ALK fusions. Today, patients with metastatic disease can achieve survival rates at least double that of patients with wild-type tumors. Through the rational dissection of the mechanisms of drug sensitivity and resistance, promising strategies have been defined to further improve the outcomes of patients with NCSLC. This review adds to a growing body of knowledge into mechanisms of resistance that can be interrogated in NSCLC patients with EGFR mutations or EML4-ALK fusions, as well as strategies to overcome resistance to TKIs.
    Expert Review of Anti-infective Therapy 03/2014; DOI:10.1586/14737140.2014.896210 · 2.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Concomitant genetic alterations could account for transient clinical responses to tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) in patients harboring activating EGFR mutations. We have evaluated the impact of pretreatment somatic EGFR T790M mutations, TP53 mutations and BIM mRNA expression in 95 patients with EGFR-mutant NSCLC included in the EURTAC trial (trial registration: NCT00446225). T790M mutations were detected in 65.26% of patients using our highly sensitive method based on laser microdissection and PNA-clamping PCR, which can detect the mutation at an allelic dilution of 1 in 5000. Progression-free survival (PFS) to erlotinib was 9.7 months for those with T790M mutations and 15.8 months for those without, while among patients receiving chemotherapy, it was 6 and 5.1 months, respectively (P<0.0001). PFS to erlotinib was 12.9 months for those with high and 7.2 months for those with low/intermediate BIM expression levels, while among chemotherapy-treated patients, it was 5.8 and 5.5 months, respectively (P=0.0003). Overall survival was 28.6 months for patients with high BIM expression and 22.1 months for those with low/intermediate BIM expression (P=0.0364). Multivariate analyses showed that erlotinib was a marker of longer PFS (hazard ratio [HR]=0.35; P=0.0003), while high BIM expression was a marker of longer PFS (HR=0.49; P=0.0122) and overall survival (HR=0.53; P=0.0323). Low-level pretreatment T790M mutations can frequently be detected and can be used for customizing treatment with T790M-specific inhibitors. BIM mRNA expression is a biomarker of survival in EGFR-mutant NSCLC and can potentially be used for synthetic lethality therapies.
    Clinical Cancer Research 02/2014; 20(7). DOI:10.1158/1078-0432.CCR-13-2233 · 8.19 Impact Factor
  • Molecular Cancer Therapeutics 01/2014; 12(11_Supplement):C41-C41. DOI:10.1158/1535-7163.TARG-13-C41 · 6.11 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the study was to evaluate the predictive value of genes involved in the action of cisplatin-etoposide in Small Cell Lung Cancer (SCLC). 184 SCLC patients' primary tumour samples were analyzed for ERCCI, BRCA1, ATP7B, PKM2 TOPOI, TOPOIIA, TOPOIIB and C-MYC mRNA expression. All patients were treated with cisplatin-etoposide. The patients' median age was 63 years and 120 (65%) had extended stage, 75 (41%) had increased LDH serum levels and 131 (71%) an ECOG performance status was 0-1. Patients with limited stage, whose tumours expressed high ERCC1 (p=0.028), PKM2 (p=0.046), TOPOI (p=0.008), TOPOIIA (p=0.002) and TOPOIIB (p<0.001) mRNA had a shorter Progression Free Survival (PFS). In limited stage patients, high expression of ERCC1 (p=0.014), PKM2 (p=0.026), TOPOIIA (p=0.021) and TOPOIIB (p=0.019) was correlated with decreased median overall survival (mOS) while in patients with extended stage, only high TOPOIIB expression had a negative impact on Os (p=0.035). The favorable expression signature expression signature (low expression of ERCC1, PKM2, TOPOIIA and TOPOIIB) was correlated with significantly better PFS and Os in both LS-SCLC (p<0.001 and p=0.007, respectively) and ES-SCLC (p=0.007 and (p=0.011, respectively) group. The unfavorable expression signature was an independent predictor for poor PFS (HR: 3.18; p=0.002 and HR: 3.14; p=0.021) and Os (HR: 4.35; p=0.001and HR: 3.32; p=0.019) in both limited and extended stage, respectively. Single gene's expression analysis as well as the integrated analysis of ERCC1, PKM2, TOPOIIA and TOPOIIB may predict treatment outcome in patients with SCLC. These findings should be further validated in a prospective study.
    PLoS ONE 09/2013; 8(9):e74611. DOI:10.1371/journal.pone.0074611 · 3.53 Impact Factor
  • Rafael Rosell, Trever G Bivona, Niki Karachaliou
    [Show abstract] [Hide abstract]
    ABSTRACT: Non-small-cell lung cancer is often diagnosed at the metastatic stage, with median survival of just 1 year. The identification of driver mutations in the epidermal growth factor receptor (EGFR) as the primary oncogenic event in a subset of lung adenocarcinomas led to a model of targeted treatment and genetic profiling of the disease. EGFR tyrosine kinase inhibitors confer remission in 60% of patients, but responses are short-lived. The pre-existing EGFR Thr790Met mutation could be a subclonal driver responsible for these transient responses. Overexpression of AXL and reduced MED12 function are hallmarks of resistance to tyrosine kinase inhibitors in EGFR-mutant non-small-cell lung cancer. Crosstalk between signalling pathways is another mechanism of resistance; therefore, identification of the molecular components involved could lead to the development of combination therapies cotargeting these molecules instead of EGFR tyrosine kinase inhibitor monotherapy. Additionally, novel biomarkers could be identified through deep sequencing analysis of serial rebiopsies before and during treatment.
    The Lancet 08/2013; 382(9893):720-31. DOI:10.1016/S0140-6736(13)61715-8 · 39.21 Impact Factor
  • Rafael Rosell, Niki Karachaliou
    Nature Reviews Clinical Oncology 08/2013; DOI:10.1038/nrclinonc.2013.152 · 15.70 Impact Factor

Publication Stats

115 Citations
144.65 Total Impact Points

Institutions

  • 2013–2015
    • Catalan Institute of Oncology
      • Department of Medical Oncology
      Badalona, Catalonia, Spain
    • Hospital Universitari Germans Trias i Pujol
      • Department of Medical Oncology
      Badalona, Catalonia, Spain
    • Universidad Autónoma de Madrid
      Madrid, Madrid, Spain
    • University of Crete
      • School of Medicine
      Retimo, Crete, Greece
    • Instituto Universitario USP Dexeus
      Barcino, Catalonia, Spain
  • 2014
    • Fundació Institut Investigació Germans Trias i Pujol
      Badalona, Catalonia, Spain
  • 2012–2013
    • Pangaea Biotech
      Barcino, Catalonia, Spain
    • University Hospital of Heraklion
      • Department of Gastroenterology
      Irákleio, Attica, Greece