Paraskevi Giannakakou

Weill Cornell Medical College, New York, New York, United States

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Publications (141)1126.6 Total impact

  • David M Nanus · Paraskevi Giannakakou
    Science 09/2015; 349(6254):1283-4. DOI:10.1126/science.aad2448 · 33.61 Impact Factor
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    ABSTRACT: Renal cell carcinoma (RCC) is a heterogeneous disease with regards to histology, progression, and response to treatment. Cytotoxic chemotherapy has been extensively studied in metastatic RCC (mRCC). Responses in most studies are modest and the mechanisms of resistance remain poorly understood. Targeted therapies have significantly improved outcomes in mRCC; however, most patients eventually relapse and die of their disease. Early clinical data suggest that combinations of chemotherapy and targeted agents are clinically active and are well tolerated. We reviewed the available literature for published clinical trials incorporating traditional chemotherapeutic agents in the treatment of mRCC. These papers were identified through a Medline search and were included if they employed at least one chemotherapeutic agent in the treatment of mRCC. The literature was also reviewed for information regarding mechanisms of chemotherapy resistance. The data regarding the use of cytotoxic chemotherapy in mRCC consist of small, non-randomized phase I and II studies. The major response proportions with single agent chemotherapies are low but combination regimens either with other cytotoxic agents, cytokines, or targeted agents have demonstrated moderate activity. Disparate trial designs and lack of head to head clinical trials make it difficult to compare the efficacy of chemotherapy with that of immunotherapy or targeted agents. Chemotherapy is particularly useful in patients with collecting duct histology and predominantly sarcomatoid differentiation. Chemotherapy resistance may be mediated by overexpression of p-glycoprotein efflux pumps and the dysregulation of the microtubule-hypoxia inducible factor signaling axis. The role of cytotoxic chemotherapy in the treatment for clear cell RCC remains poorly defined. Cytotoxic chemotherapy is considered a standard of care in patients with mRCC with predominantly sarcomatoid differentiation and collecting duct RCC variants (Motzer et al., 2014). Early trials combining chemotherapy with targeted therapies are generally well tolerated and show clinical activity. A better understanding of the biology of aggressive subsets of RCC and mechanisms of resistance will help elucidate the role of cytotoxic agents in the current treatment paradigm of RCC. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Critical reviews in oncology/hematology 08/2015; DOI:10.1016/j.critrevonc.2015.08.007 · 4.03 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):5096-5096. DOI:10.1158/1538-7445.AM2015-5096 · 9.33 Impact Factor
  • Prashant Khade · Paraskevi Giannakakou
    Cancer Research 08/2015; 75(15 Supplement):2121-2121. DOI:10.1158/1538-7445.AM2015-2121 · 9.33 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):3600-3600. DOI:10.1158/1538-7445.AM2015-3600 · 9.33 Impact Factor
  • Seaho Kim · Luigi Portella · Paraskevi Giannakakou
    Cancer Research 08/2015; 75(15 Supplement):3451-3451. DOI:10.1158/1538-7445.AM2015-3451 · 9.33 Impact Factor
  • Giuseppe Galletti · Cynthia Cheung · David S. Rickman · Paraskevi Giannakakou
    Cancer Research 08/2015; 75(15 Supplement):4311-4311. DOI:10.1158/1538-7445.AM2015-4311 · 9.33 Impact Factor
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    ABSTRACT: Background Single nucleotide polymorphisms (SNPs) in platelet-associated genes partly explain inherent variability in platelet counts. Patients with monoallelic Bernard Soulier syndrome due to the Bolzano mutation (GPIBA A156V) have variable platelet counts despite a common mutation for unknown reasons.Objectives We investigated the effect of the most common SNP (R307H) in the hematopoietic-specific tubulin isotype β-1 in these Bernard Soulier patients and potential microtubule-based mechanisms of worsened thrombocytopenia.Patients/Methods Ninety-four monoallelic Bolzano mutation patients were evaluated for the R307H β-1 SNP and had platelet counts measured by three methods; the Q43P SNP was also evaluated. To investigate possible mechanisms underlying this association, we used molecular modeling of β-1 tubulin with and without the R307H SNP. We transfected SNP or non-SNP β-1 tubulin into MCF-7 and CMK cell lines and measured microtubule regrowth after nocodazole-induced depolymerization.ResultsWe found that patients with at least one R307H SNP allele had significantly worse thrombocytopenia; manual platelet counting revealed a median platelet count of 124 in non-SNP and 76 in SNP patients (both x 109/L; p<0.01). The Q43P SNP had no significant association with platelet count. Molecular modeling suggested a structural relationship between the R307H SNP and microtubule stability via alterations in the M-loop of β tubulin; in vitro microtubule recovery assays revealed cells transfected with R307H SNP β-1 had significantly impaired microtubule recovery.Conclusions Our data show that the R307H SNP is significantly associated with the degree of thrombocytopenia in congenital and acquired platelet disorders, and may affect platelets by altering microtubule behavior.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 12/2014; 13(4). DOI:10.1111/jth.12824 · 5.72 Impact Factor
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    ABSTRACT: Taxanes are the only chemotherapies used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. In this study, we show that ERG overexpression in in vitro and in vivo models of CRPC is associated with decreased sensitivity to taxanes. ERG affects several parameters of microtubule dynamics and inhibits effective drug-target engagement of docetaxel or cabazitaxel with tubulin. Finally, analysis of a cohort of 34 men with metastatic CRPC treated with docetaxel chemotherapy reveals that ERG-overexpressing prostate cancers have twice the chance of docetaxel resistance than ERG-negative cancers. Our data suggest that ERG plays a role beyond regulating gene expression and functions outside the nucleus to cooperate with tubulin towards taxane insensitivity. Determining ERG rearrangement status may aid in patient selection for docetaxel or cabazitaxel therapy and/or influence co-targeting approaches.
    Nature Communications 11/2014; 5:5548. DOI:10.1038/ncomms6548 · 11.47 Impact Factor
  • Tito Fojo · Paraskevi Giannakakou
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    ABSTRACT: Over the past decade, funding for cancer research by the US government and others has stagnated, while the demand for investment has grown because of the increasing cancer incidence worldwide. We discuss how National Cancer Institute funding efforts have developed during this period, and the contemporary and future impact of these measures on cancer research in the USA.
    Nature Reviews Clinical Oncology 10/2014; 11(11). DOI:10.1038/nrclinonc.2014.173 · 14.18 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):1158-1158. DOI:10.1158/1538-7445.AM2014-1158 · 9.33 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):923-923. DOI:10.1158/1538-7445.AM2014-923 · 9.33 Impact Factor
  • Luigi Portella · Paraskevi Giannakakou
    Cancer Research 10/2014; 74(19 Supplement):2112-2112. DOI:10.1158/1538-7445.AM2014-2112 · 9.33 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):897-897. DOI:10.1158/1538-7445.AM2014-897 · 9.33 Impact Factor
  • Prashant K Khade · Paraskevi Giannakakou
    Proceedings of the National Academy of Sciences 07/2014; 111(31). DOI:10.1073/pnas.1410788111 · 9.67 Impact Factor
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    ABSTRACT: Nicotinamide adenine dinucleotide (NAD(+)) is an endogenous enzyme cofactor and cosubstrate that has effects on diverse cellular and physiologic processes, including reactive oxygen species generation, mitochondrial function, apoptosis, and axonal degeneration. A major goal is to identify the NAD(+)-regulated cellular pathways that may mediate these effects. Here we show that the dynamic assembly and disassembly of microtubules is markedly altered by NAD(+). Furthermore, we show that the disassembly of microtubule polymers elicited by microtubule depolymerizing agents is blocked by increasing intracellular NAD(+) levels. We find that these effects of NAD(+) are mediated by the activation of the mitochondrial sirtuin sirtuin-3 (SIRT3). Overexpression of SIRT3 prevents microtubule disassembly and apoptosis elicited by antimicrotubule agents and knockdown of SIRT3 prevents the protective effects of NAD(+) on microtubule polymers. Taken together, these data demonstrate that NAD(+) and SIRT3 regulate microtubule polymerization and the efficacy of antimicrotubule agents.
    Proceedings of the National Academy of Sciences 06/2014; 111(24):E2443-52. DOI:10.1073/pnas.1404269111 · 9.67 Impact Factor
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    ABSTRACT: Circulating tumor cells (CTCs) have emerged as a viable solution to the lack of tumor tissue availability for patients with a variety of solid tumors, including prostate cancer. Different approaches have been used to capture this tumor cell population and several of these techniques have been used to assess the potential role of CTCs as a biological marker to predict treatment efficacy and clinical outcome. CTCs are now considered a strong tool to understand the molecular characteristics of prostate cancer, and to be used and analyzed as a 'liquid biopsy' in the attempt to grasp the biological portrait of the disease in the individual patient.
    05/2014; 18(4). DOI:10.1007/s40291-014-0101-8
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    ABSTRACT: Prostate cancer growth depends on androgen receptor (AR) signaling. Androgen ablation therapy induces expression of constitutively active AR splice variants which drive disease progression. Taxanes are a standard of care therapy in castration-resistant prostate cancer (CRPC), however, mechanisms underlying the clinical activity of taxanes are poorly understood. Recent work suggests that the microtubule network of prostate cells is critical for AR nuclear translocation and activity. In this study, we employed a set of AR deletion mutants to identify the microtubule-binding domain of AR, which encompasses the DNA binding domain plus hinge region. We report that two clinically relevant AR splice variants, ARv567 and ARv7, differentially associate with microtubules and dynein motor protein, thereby resulting in differential taxane sensitivity in vitro and in vivo. ARv7, which lacks the hinge region, did not co-sediment with microtubules or co-precipitate with dynein motor protein, unlike ARv567. Mechanistic investigations revealed that the nuclear accumulation and transcriptional activity of ARv7 was unaffected by taxane treatment. In contrast, the microtubule-interacting splice variant ARv567 was sensitive to taxane-induced microtubule stabilization. In ARv567-expressing LuCap86.2 tumor xenografts, docetaxel treatment was highly efficacious, whereas ARv7-expressing LuCap23.1 tumors xenografts displayed docetaxel resistance. Our results suggest that AR variants which accumulate in CRPC cells utilize distinct pathways of nuclear import that affect the antitumor efficacy of taxanes, suggesting a mechanistic rationale to customize treatments for CRPC patients which might improve outcomes.
    Cancer Research 02/2014; 74(8). DOI:10.1158/0008-5472.CAN-13-2876 · 9.33 Impact Factor
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    ABSTRACT: Hematogenous metastasis accounts for the majority of cancer-related deaths, yet the mechanism remains unclear. Circulating tumor cells (CTCs) in blood may employ different pathways to cross blood endothelial barrier and establish a metastatic niche. Several studies provide evidence that prostate cancer (PCa) cell tethering and rolling on microvascular endothelium via E-selectin/E-selectin ligand interactions under shear flow theoretically promote extravasation and contribute to the development of metastases. However, it is unknown if CTCs from PCa patients interact with E-selectin expressed on endothelium, initiating a route for tumor metastases. Here we report that CTCs derived from PCa patients showed interactions with E-selectin and E-selectin expressing endothelial cells. To examine E-selectin-mediated interactions of PCa cell lines and CTCs derived from metastatic PCa patients, we used fluorescently-labeled anti-prostate specific membrane antigen (PSMA) monoclonal antibody J591-488 which is internalized following cell-surface binding. We employed a microscale flow device consisting of E-selectin-coated microtubes and human umbilical vein endothelial cells (HUVECs) on parallel-plate flow chamber simulating vascular endothelium. We observed that J591-488 did not significantly alter the rolling behavior in PCa cells at shear stresses below 3 dyn/cm(2). CTCs obtained from 31 PCa patient samples showed that CTCs tether and stably interact with E-selectin and E-selectin expressing HUVECs at physiological shear stress. Interestingly, samples collected during disease progression demonstrated significantly more CTC/E-selectin interactions than samples during times of therapeutic response (p=0.016). Analysis of the expression of sialyl Lewis X (sLe(x)) in patient samples showed that a small subset comprising 1.9-18.8% of CTCs possess high sLe(x) expression. Furthermore, E-selectin-mediated interactions between prostate CTCs and HUVECs were diminished in the presence of anti-E-selectin neutralizing antibody. CTC-Endothelial interactions provide a novel insight into potential adhesive mechanisms of prostate CTCs as a means to initiate metastasis.
    PLoS ONE 12/2013; 8(12):e85143. DOI:10.1371/journal.pone.0085143 · 3.23 Impact Factor
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    ABSTRACT: Circulating tumor cells (CTCs) have emerged as a reliable source of tumor cells, and their concentration has prognostic implications. CTC capture offers real-time access to cancer tissue without the need of an invasive biopsy, while their phenotypic and molecular interrogation can provide insight into the biological changes of the tumor that occur during treatment. The majority of the CTC capture methods are based on EpCAM expression as a surface marker of tumor-derived cells. However, EpCAM protein expression levels can be significantly down regulated during cancer progression as a consequence of the process of epithelial to mesenchymal transition. In this paper, we describe a novel HER2 (Human Epidermal Receptor 2)-based microfluidic device for the isolation of CTCs from peripheral blood of patients with HER2-expressing solid tumors. We selected HER2 as an alternative to EpCAM as the receptor is biologically and therapeutically relevant in several solid tumors, like breast cancer (BC), where it is overexpressed in 30% of the patients and expressed in 90%, and gastric cancer (GC), in which HER2 presence is identified in more than 60% of the cases. We tested the performance of various anti HER2 antibodies in a panel of nine different BC cell lines with varying HER2 protein expression levels, using immunoblotting, confocal microscopy, live cells imaging and flow cytometry analyses. The antibody associated with the highest capture efficiency and sensitivity for HER2 expressing cells on the microfluidic device was the one that performed best in live cells imaging and flow cytometry assays as opposed to the fixed cell analyses, suggesting that recognition of the native conformation of the HER2 extracellular epitope on living cells was essential for specificity and sensitivity of CTC capture. Next, we tested the performance of the HER2 microfluidic device using blood from metastatic breast and gastric cancer patients. The HER2 microfluidic device exhibited CTC capture in 9/9 blood samples. Thus, the described HER2-based microfluidic device can be considered as a valid clinically relevant method for CTC capture in HER2 expressing solid cancers.
    Lab on a Chip 11/2013; 14(1). DOI:10.1039/c3lc51039e · 6.12 Impact Factor

Publication Stats

6k Citations
1,126.60 Total Impact Points


  • 2007–2015
    • Weill Cornell Medical College
      • • Division of Hematology/Medical Oncology
      • • Department of Medicine
      New York, New York, United States
  • 2006–2014
    • Cornell University
      Итак, New York, United States
  • 2011
    • Victoria University of Wellington
      • School of Biological Sciences
      Wellington, Wellington, New Zealand
  • 2005–2008
    • Georgia Institute of Technology
      • School of Electrical & Computer Engineering
      Atlanta, GA, United States
  • 2001–2006
    • Emory University
      • Winship Cancer Institute
      Atlanta, GA, United States
    • Mario Negri Institute for Pharmacological Research
      • Department of Oncology
      Milano, Lombardy, Italy
    • The Scripps Research Institute
      • Skaggs Institute for Chemical Biology
      La Jolla, CA, United States
  • 2002
    • Indian Institute of Technology Bombay
      • Department of Biosciences & Bioengineering
      Mumbai, Maharashtra, India
  • 1997–2001
    • National Cancer Institute (USA)
      • Developmental Therapeutics Program
      베서스다, Maryland, United States
  • 2000
    • NCI-Frederick
      Фредерик, Maryland, United States
  • 1997–1999
    • National Institutes of Health
      • Branch of Medical Genetics
      Bethesda, MD, United States