Susan E Bates

National Institutes of Health, Maryland, United States

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Publications (283)1648.33 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Successful cancer treatments are generally defined as those that decrease tumor quantity. In many cases, this decrease occurs exponentially, with deviations from a strict exponential being attributed to a growing fraction of drug-resistant cells. Deviations from an exponential decrease in tumor quantity can also be expected if drugs have a nonuniform spatial distribution inside the tumor, for example, because of interstitial pressure inside the tumor. Here, we examine theoretically different models of cell killing and analyze data from clinical trials based on these models. We show that the best description of clinical outcomes is by first-order kinetics with exponential decrease of tumor quantity. We analyzed the total tumor quantity in a diverse group of clinical trials with various cancers during the administration of different classes of anticancer agents and in all cases observed that the models that best fit the data describe the decrease of the sensitive tumor fraction exponentially. The exponential decrease suggests that all drug-sensitive cancer cells have a single rate-limiting step on the path to cell death. If there are intermediate steps in the path to cell death, they are not rate limiting in the observational time scale utilized in clinical trials-tumor restaging at 6- to 8-week intervals. On shorter time scales, there might be intermediate steps, but the rate-limiting step is the same. Our analysis, thus, points to a common pathway to cell death for cancer cells in patients. See all articles in this Cancer Research section, "Physics in Cancer Research." Cancer Res; 74(17); 4653-62. ©2014 AACR.
    Cancer research. 09/2014; 74(17):4653-4662.
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    ABSTRACT: ABCG2 is a potential biomarker causing multidrug resistance (MDR) in Non-Small Cell Lung Cancer (NSCLC). We conducted this study to investigate whether Icotinib, a small-molecule inhibitor of EGFR tyrosine kinase, could interact with ABCG2 transporter in NSCLC. Our results showed that Icotinib reversed ABCG2-mediated MDR by antagonizing the drug efflux function of ABCG2. Icotinib stimulated the ATPase activity in a concentration-dependent manner and inhibited the photolabeling of ABCG2 with [125I]-Iodoarylazidoprazosin, demonstrating that it interacts at the drug-binding pocket. Homology modeling predicted the binding conformation of Icotinib at Asn629 centroid-based grid of ABCG2. However, Icotinib at reversal concentration did not affect the expression levels of AKT and ABCG2. Furthermore, a combination of Icotinib and topotecan exhibited significant synergistic anticancer activity against NCI-H460/MX20 tumor xenografts. However, the inhibition of transport activity of ABCG2 was insufficient to overcome pemetrexed resistance in NCI-H460/MX20 cells, which was due to the co-upregulated thymidylate synthase (TS) and ABCG2 expression. This is the first report to show that the up-regulation of TS in ABCG2-overexpressing cell line NCI-H460/MX20 may play a role of resistance to pemetrexate. Our findings suggested different possible strategies of overcoming the resistance of topotecan and pemetrexed in the NSCLC patients.
    Oncotarget 06/2014; · 6.64 Impact Factor
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    ABSTRACT: Romidepsin and vorinostat are histone deacetylase inhibitors (HDACis) that have activity in T-cell lymphomas, but have not gained traction in solid tumors. To gain deeper insight into mechanisms of HDACi efficacy, we systematically surveyed 19 cell lines with different molecular phenotypes, comparing romidepsin and vorinostat at equipotent doses. Acetylation at H3K9 and H4K8 along with 22 other histone lysine acetylation and methylation modifications were measured by reverse phase proteomics array (RPPA), and compared with growth inhibition (IC50), and cell cycle arrest. These assays typically used to assess HDACi effect showed that acetylation and methylation of specific lysine residues in response to HDACis were consistent across cell lines, and not related to drug sensitivity. Using a treatment duration more reflective of the clinical exposure, cell death detected by annexin staining following a 6 h drug exposure identified a subset of cell lines, including the T-cell lymphoma line, that was markedly more sensitive to HDAC inhibition. Kinetic parameters (Km values) were determined for lysine acetylation and for cell cycle data and were themselves correlated following HDACi exposure, but neither parameter correlated with cell death. The impact on cell survival signaling varied with the molecular phenotype. This study suggests that cellular response to HDACis can be viewed as two distinct effects: a chromatin effect and a cell death effect. All cells undergo acetylation, which is necessary but not sufficient for cell death. Cells not primed for apoptosis will not respond with cell death to the impact of altered histone acetylation. The divergent apoptotic responses observed reflect the variable clinical outcome of HDACi treatment. These observations should change our approach to the development of therapeutic strategies that exploit the dual activities of HDACis.
    Molecular oncology. 05/2014;
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    ABSTRACT: In this study we investigated the effect of linsitinib on the reversal of multidrug resistance (MDR) mediated by the overexpression of the ATP-binding cassette (ABC) subfamily members ABCB1, ABCG2, ABCC1 and ABCC10. Our results indicate for the first time that linsitinib significantly potentiate the effect of anti-neoplastic drugs mitoxantrone (MX) and SN-38, which are substrates of ABCG2 and paclitaxel, docetaxel and vinblastine which are substrates of ABCC10. Linsitinib moderately enhanced the cytotoxicity of vincristine in cell lines overexpressing ABCB1, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, linsitinib significantly increased the intracellular concentration and significantly decreased the efflux of [(3)H]-MX in ABCG2-overexpressing cells and [(3)H]-paclitaxel in ABCC10-overexpressing cells. However, linsitinib, at a concentration that reversed MDR, did not significantly alter the expression levels of either the ABCG2 or ABCC10 transporter proteins. Furthermore, linsitinib did not significantly alter the intracellular localization of ABCG2 or ABCC10. Moreover, linsitinib stimulates the ATPase activity of ABCG2 in a concentration-dependent manner. Overall, our study suggests that linsitinib could attenuate ABCG2- and ABCC10-mediated MDR by directly inhibiting their function as opposed to altering ABCG2 or ABCC10 protein expression.
    The international journal of biochemistry & cell biology 04/2014; · 4.89 Impact Factor
  • Antonio Tito Fojo, Susan E Bates
    The Oncologist 03/2014; · 4.10 Impact Factor
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    ABSTRACT: The US FDA and the EMA have approved seven agents for the treatment of renal cell carcinoma, primarily based on differences in progression-free survival (PFS). Because PFS is an arbitrary endpoint we hypothesized that an analysis would demonstrate the growth rate of tumors remained constant at the time of RECIST-defined disease progression. We previously estimated the growth (g) and regression (d) rates and the stability of g using data from the Phase III trial comparing sunitinib and interferon. Sufficient data were available and rate constants statistically valid in 321 of 374 patients randomized to sunitinib. Median d was 0•0052 days-1; in 53 patients no tumor growth was recorded. Median g was 0•00082 days-1 and was stable for a median of 275 days on therapy, remaining stable beyond 300, 600 and 900 days in 122, 65 and 27 patients, respectively. A possible increase in g while receiving sunitinib could be discerned in only 18 of 321 patients. Given a median g of 0•00082 days-1 the estimated median time to a second progression were sunitinib continued past RECIST-defined progression was 7.3 months. At 100, 200, and 300 days after starting therapy, an estimated 47%, 27%, and 13% of tumor remains sunitinib sensitive and could explain a RECIST-defined response to a new TKI. Prolonged stability of g with sunitinib suggests continued sunitinib beyond RECIST-defined progression may provide a beneficial outcome. Randomized trials in patients whose disease has "progressed" on sunitinib are needed to test this hypothesis.
    PLoS ONE 01/2014; 9(5):e96316. · 3.53 Impact Factor
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    ABSTRACT: Burkitt lymphoma is characterized by deregulation of c-myc, and therapies targeting c-myc are under investigation as treatments. Histone deacetylase inhibitors are known to abrogate c-myc expression, leading us to examine their effect in a series of Burkitt lymphoma cell lines. While treatment with romidepsin, panobinostat, vorinostat, or belinostat for 48 h resulted in complete cell death in the Ramos and ST486 lines, CA46 and DG75 cells were resistant. In parallel studies, CA46 and DG75 cells were also insensitive to 48 h treatment with the Aurora kinase inhibitors (AKIs) MLN8237 (alisertib), VX-680 (tozasertib), or ZM447439. Bax knockdown is known to lead to HDI resistance, and we found that loss of Bax or both Bak and Bax correlated with resistance to both AKIs and HDIs in the Burkitt cell lines. As proof-of-concept to evaluate the contribution of Bax and Bak to HDI-mediated apoptosis, we found that apoptosis was unaffected in HCT-116 colon carcinoma cells lacking Bak, blunted in cells lacking Bax, and nearly completely abrogated in cells lacking both Bak and Bax compared with wild-type cells. To explore potential clinical variations in Bak and Bax expression, a series of samples from 16 patients diagnosed with Burkitt lymphoma was examined. While the majority of samples were positive for both Bak and Bax, some (3/16) expressed low levels of both proteins. We thus conclude that HDI-mediated and AKI-mediated apoptosis requires mitochondrial engagement, and that baseline Bax and Bak expression may serve as biomarkers for patients with Burkitt lymphoma likely to respond to HDI treatment.
    Cell cycle (Georgetown, Tex.) 08/2013; 12(17). · 5.24 Impact Factor
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    ABSTRACT: ABCG2 (also known as breast cancer resistance protein; BCRP) is an ATP-binding cassette (ABC) transporter localized to the plasma membrane where it mediates the efflux of xenobiotics, including potential therapeutics. Studies investigating Abcg2 function at the blood-brain-barrier in mouse models are often compared to human ABCG2 function. It is critical to understand the nature of species differences between mouse and human ABCG2, since extrapolations are made from murine data to humans. Two independent drug-selected cell line pairs expressing human or mouse ABCG2 were compared for efflux of fluorescent substrates using flow cytometry. To this end, we developed and characterized a new mouse Abcg2-expressing subline that demonstrated efflux of known fluorescent ABCG2 substrates and increased resistance to mitoxantrone, which is reduced in the presence of the ABCG2 inhibitor Ko143. Our results indicate that the substrate specificity of human and mouse ABCG2 is very similar. We identified a new human and mouse ABCG2 substrate, a porphyrin analog, purpurin-18 (Pp-18), which is not a substrate for P-gp or MRP1. The ability of inhibitors to block efflux activity of ABCG2 was assessed using Pp-18. Inhibitors also demonstrated similar effects on human and mouse ABCG2. Chrysin, benzoflavone, and cyclosporin A inhibited Pp-18 efflux in both human and mouse ABCG2. The similarity of the substrate and inhibitor specificity of human and mouse ABCG2 supports interpretation of mouse models in understanding the clinical, pharmacological and physiological roles of ABCG2.
    Drug metabolism and disposition: the biological fate of chemicals 07/2013; · 3.74 Impact Factor
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    ABSTRACT: Romidepsin is a potent histone deacetylase inhibitor (HDI) with activity in T-cell lymphoma. Given preclinical data demonstrating greater induction of gene expression with longer exposures to HDIs, a phase I study of a days 1, 3, and 5 romidepsin schedule was evaluated. A secondary objective was to assess the effect of romidepsin on radioactive iodine (RAI) uptake in thyroid cancers. Open label, single arm, phase I, 3 + 3 dose escalation study. Romidepsin was administered as a four-hour infusion on days 1, 3 and 5 of a 21-day cycle. Pharmacokinetics (PK) and pharmacodynamics (PD) were assessed, including histone acetylation in peripheral blood mononuclear cells (PBMCs); RAI uptake in refractory thyroid cancer; and HDI-related ECG changes. 28 patients with solid tumors, including eleven patients with thyroid cancer were enrolled. Six dose levels were explored and 7 mg/m2 on days 1, 3, and 5 was identified as tolerable. No RECIST-defined objective responses were recorded although nine patients had stable disease a median 30 weeks (range 21 - 112) including six with thyroid cancer a median of 33 weeks. PD studies detected acetylated histones in PBMCs and ECG changes beginning at low dose levels. Follow-up RAI scans in patients with RAI refractory thyroid cancer did not detect meaningful increases. A romidepsin dose of 7 mg/m2 administered on days 1, 3, and 5 was found tolerable and resulted in histone acetylation in PBMCs. Although there were no objective responses with romidepsin alone, this schedule may be useful for developing combination studies in solid tumors.
    Clinical Cancer Research 06/2013; · 7.84 Impact Factor
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    ABSTRACT: PURPOSE: Romidepsin is a histone deacetylase inhibitor (HDI) approved for the treatment of both cutaneous and peripheral T cell lymphoma (CTCL and PTCL). During development, a thorough assessment of cardiac toxicity was performed. EXPERIMENTAL DESIGN: A phase II single-agent non-randomized study of romidepsin was performed in patients with CTCL and PTCL who had progressed after at least one prior systemic therapy. RESULTS: Results for the first 42 patients enrolled on the NCI 1312 Phase II study of romidepsin in CTCL or PTCL demonstrated no cardiac toxicity based on serial electrocardiograms, troponins and MUGA scans/echocardiograms. The cardiac assessments reported herein confirm the safety of romidepsin among 131 enrolled patients, while supporting a role for electrolyte replacement. Heart rate increased an average 11 bpm following romidepsin infusion; there was no evidence of increased arrhythmia. Criteria for potassium/magnesium replacement were met prior to 55% of 1365 romidepsin doses; an association with hypoalbuminemia was confirmed. We propose a mechanism for ST segment flattening and depression, the most common electrocardiogram abnormalities observed: HDI-induced alteration of the activity or expression of KATP channels. In addition, examination of the variants of the active transporter of romidepsin, ABCB1, demonstrated a trend towards smaller heart rate changes in the peri-infusion period among wild type compared to variant diplotypes. CONCLUSIONS: We conclude that in the context of appropriate attention to electrolyte levels, the data support the cardiac safety of romidepsin.
    Clinical Cancer Research 04/2013; · 7.84 Impact Factor
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    ABSTRACT: Key points MAPK pathway activation and Bim loss may represent a fundamental mechanism of resistance to histone deacetylase inhibitors.Combination of romidepsin with a MEK inhibitor may lead to greater responses in cancers where the MAPK pathway is active.
    Blood 03/2013; · 9.78 Impact Factor
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    ABSTRACT: We present and analyze tumor growth data from prostate and brain cancer. Scaling the data from different patients shows that early stage prostate tumors show non-exponential growth while advanced prostate and brain tumors enter a stage of exponential growth. The scaling analysis points to the existence of cancer stem cells and/or massive apoptosis in early stage prostate cancer and that late stage cancer growth is not dominated by cancer stem cells. Statistical models of these two growth modes are discussed.
    03/2013;
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    ABSTRACT: Preclinical studies have suggested that sunitinib accelerates metastases in animals, ascribing this to inhibition of the vascular endothelial growth factor receptor or the tumor's adaptation. To address whether sunitinib accelerates tumors in humans, we analyzed data from the pivotal randomized phase III trial comparing sunitinib and interferon alfa in patients with metastatic renal cell carcinoma. The evidence clearly shows that sunitinib was not harmful, did not accelerate tumor growth, and did not shorten survival. Specifically, neither longer sunitinib treatment nor a greater effect of sunitinib on tumors reduced survival. Sunitinib did reduce the tumor's growth rate while administered, thereby improving survival, without appearing to alter tumor biology after discontinuation. Concerns arising from animal models do not apply to patients receiving sunitinib and likely will not apply to similar agents.
    Cell Reports 02/2013; · 7.21 Impact Factor
  • Tito Fojo, Susan Bates
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    ABSTRACT: Given the malleable nature of cancer cells, we should expect, and do see, the development of resistance to any new chemotherapeutic agent. Models that help us understand how this happens are a first step to better and more effective chemotherapeutics. Cancer Discov; 3(1); 20-3. ©2012 AACR.
    Cancer Discovery 01/2013; 3(1):20-3. · 10.14 Impact Factor
  • The Oncologist 01/2013; 18(7):779. · 4.10 Impact Factor
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    ABSTRACT: Epigenetic aberrations offer dynamic and reversible targets for cancer therapy; increasingly, alteration via overexpression, mutation, or rearrangement is found in genes that control the epigenome. Such alterations suggest a fundamental role in carcinogenesis. Here, we consider three epigenetic mechanisms: DNA methylation, histone tail modification and non-coding, microRNA regulation. Evidence for each of these in lung cancer origin or progression has been gathered, along with evidence that epigenetic alterations might be useful in early detection. DNA hypermethylation of tumor suppressor promoters has been observed, along with global hypomethylation and hypoacetylation, suggesting an important role for tumor suppressor gene silencing. These features have been linked as prognostic markers with poor outcome in lung cancer. Several lines of evidence have also suggested a role for miRNA in carcinogenesis and in outcome. Cigarette smoke downregulates miR-487b, which targets both RAS and MYC; RAS is also a target of miR-let-7, again downregulated in lung cancer. Together the evidence implicates epigenetic aberration in lung cancer and suggests that targeting these aberrations should be carefully explored. To date, DNA methyltransferase and histone deacetylase inhibitors have had minimal clinical activity. Explanations include the possibility that the agents are not sufficiently potent to invoke epigenetic reversion to a more normal state; that insufficient time elapses in most clinical trials to observe true epigenetic reversion; and that doses often used may provoke off-target effects such as DNA damage that prevent epigenetic reversion. Combinations of epigenetic therapies may address those problems. When epigenetic agents are used in combination with chemotherapy or targeted therapy it is hoped that downstream biological effects will provoke synergistic cytotoxicity. This review evaluates the challenges of exploiting the epigenome in the treatment of lung cancer.
    Frontiers in Oncology 01/2013; 3:261.
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    ABSTRACT: The stromal cell-derived factor-1α SDF-1α (CXCL12)/CXCR4 axis has been linked to poor prognosis in some cancers. As histone deacetylase inhibitors (HDIs) exert antitumor effects by targeting proteins affecting cell migration, we sought to evaluate the effects of the HDIs apicidin, vorinostat, entinostat (MS-275) and romidepsin on the expression and function of CXCR4 in human cancer cell lines. After treatment with romidepsin, CXCR4 mRNA expression increased 12-fold in UOK121 renal cancer cells, 16-fold in H460 non-small cell cancer cells and 4-fold in SF295 glioma cells; treatment with other HDIs yielded similar effects. CXCR4 induction was not observed in MCF7 breast cancer cells or SW620 colon cancer cells. To evaluate the corresponding functional increase, the effect of CXCR4 ligand, CXCL12, on ERK1/2, STAT3 and c-SRC activation and cell migration was examined in UOK121, SF295 and H460 cells. Alone, the HDIs increased pERK1/2, while reducing pSTAT-3 and pSRC. Following CXCL12 exposure, pERK1/2 induction was maintained, but STAT3 and SRC phosphorylation was impaired. These findings resulted in reduced basal and CXCL12-mediated cell migration. In conclusion, HDIs upregulated CXCR4 mRNA expression but impaired CXCL12-dependent signaling cascades through STAT3 and c-SRC, suggesting a potential role for HDIs in delaying or preventing metastatic processes in solid tumors.
    Cancer biology & therapy 11/2012; 14(2). · 3.29 Impact Factor
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    ABSTRACT: Romidepsin (Istodax(®), depsipeptide, FR901228, FK228, NSC 630176) is a cyclic peptide, broad-spectrum, potent histone deacetylase inhibitor, with activity mainly against class I histone deacetylase enzymes. In this article, we give an overview of the putative modes of action, such as effects on gene expression, cell cycle regulation, apoptosis induction, DNA repair, protein acetylation and induction of autophagy. Romidepsin has mainly been developed as a therapy for hematologic malignancies and is approved by the US FDA for the treatment of cutaneous T-cell lymphomas. This report outlines the laboratory and clinical development of the compound as a single agent that has more recently been evaluated in combination with other anticancer therapeutics, such as proteasome inhibitors.
    Epigenomics 10/2012; 4(5):571-89. · 2.43 Impact Factor
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    ABSTRACT: Cigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophageal cancers, yet the underlying mechanisms remain unknown. In this study, we observed that exposure of esophageal cancer cells to cigarette smoke condensate (CSC) led to upregulation of the xenobiotic pump ABCG2, which is expressed in cancer stem cells and confers treatment resistance in lung and esophageal carcinomas. Furthermore, CSC increased the side population of lung cancer cells containing cancer stem cells. Upregulation of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor, Sp1, and Nrf2 within the ABCG2 promoter, and deletion of xenobiotic response elements and/or Sp1 sites markedly attenuated ABCG2 induction. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AhR, Sp1, and Nrf2 levels within the ABCG2 promoter, markedly downregulated ABCG2, and inhibited proliferation and tumorigenicity of lung and esophageal cancer cells. Microarray analyses revealed that mithramycin targeted multiple stem cell-related pathways in vitro and in vivo. Collectively, our findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical use of mithramycin for repressing ABCG2 and inhibiting stem cell signaling in thoracic malignancies.
    Cancer Research 07/2012; 72(16):4178-92. · 9.28 Impact Factor
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    ABSTRACT: Histone deacetylase inhibitors (HDI) have exhibited some efficacy in clinical trials, but it is clear that their most effective applications have yet to be fully determined. In this study, we show that HDIs influence the expression of a common polymorphic variant of the chemotherapy drug efflux transporter ABCG2, which contributes to normal tissue protection. As one of the most frequent variants in human ABCG2, the polymorphism Q141K impairs expression, localization, and function, thereby reducing drug clearance and increasing chemotherapy toxicity. Mechanistic investigations revealed that the ABCG2 Q141K variant was fully processed but retained in the aggresome, a perinuclear structure, where misfolded proteins aggregate. In screening for compounds that could correct its expression, localization, and function, we found that the microtubule-disrupting agent colchicine could induce relocalization of the variant from the aggresome to the cell surface. More strikingly, we found that HDIs could produce a similar effect but also restore protein expression to wild-type levels, yielding a restoration of ABCG2-mediated specific drug efflux activity. Notably, HDIs did not modify aggresome structures but instead rescued newly synthesized protein and prevented aggresome targeting, suggesting that HDIs disturbed trafficking along microtubules by eliciting changes in motor protein expression. Together, these results showed how HDIs are able to restore wild-type functions of the common Q141K polymorphic isoform of ABCG2. More broadly, our findings expand the potential uses of HDIs in the clinic.
    Cancer Research 04/2012; 72(14):3642-51. · 9.28 Impact Factor

Publication Stats

16k Citations
1,648.33 Total Impact Points

Institutions

  • 1990–2014
    • National Institutes of Health
      • • Center for Cancer Research
      • • Branch of Medical Oncology Branch and Affiliates
      • • Program of Developmental Therapeutics
      • • Branch of Medical Genetics
      • • Laboratory of Pathology
      Maryland, United States
  • 1989–2014
    • National Cancer Institute (USA)
      • • Center for Cancer Research
      • • Medical Oncology Branch and Affiliates
      Maryland, United States
  • 2013
    • University of Zagreb
      Zagrabia, Grad Zagreb, Croatia
    • Texas Tech University
      • Department of Biological Sciences
      Lubbock, TX, United States
  • 2012
    • Cancer Research and Biostatistics
      Seattle, Washington, United States
    • Leidos Biomedical Research
      Maryland, United States
  • 2009–2011
    • The Chinese University of Hong Kong
      • Department of Pharmacy
      Hong Kong, Hong Kong
    • University of Melbourne
      Melbourne, Victoria, Australia
  • 2007–2011
    • St. John's University
      • Department of Pharmaceutical Sciences
      New York City, NY, United States
  • 2000–2010
    • NCI-Frederick
      Maryland, United States
  • 2003–2009
    • West Virginia University
      Morgantown, West Virginia, United States
  • 1989–2009
    • Georgetown University
      • Lombardi Cancer Center
      Washington, Washington, D.C., United States
  • 2003–2007
    • Hebrew University of Jerusalem
      • Department of Biological Chemistry
      Jerusalem, Jerusalem District, Israel
  • 2006
    • Albert Einstein College of Medicine
      New York City, New York, United States
  • 2005
    • New York Medical College
      New York City, New York, United States
  • 2002
    • McGill University
      Montréal, Quebec, Canada
    • University of Copenhagen Herlev Hospital
      Herlev, Capital Region, Denmark
    • Cancer Research Institute
      New York City, New York, United States
  • 2001
    • Kagoshima University
      • Faculty of Medicine
      Kagosima, Kagoshima, Japan
    • University of Copenhagen
      København, Capital Region, Denmark
  • 1998
    • Pontifical Catholic University of Chile
      • Departamento de Hematología-Oncología
      Santiago, Region Metropolitana de Santiago, Chile
  • 1991
    • U.S. Food and Drug Administration
      Washington, Washington, D.C., United States