Susan E Bates

NCI-Frederick, Фредерик, Maryland, United States

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Publications (316)1956.09 Total impact

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    ABSTRACT: The ATP-binding cassette (ABC) transporters of class G display a different domain organisation than P-glycoprotein/ABCB1 and bacterial homologues with a nucleotide-binding domain preceding the transmembrane domain. The linker region connecting these domains is unique and its function and structure cannot be predicted. Sequence analysis revealed that the human ABCG2 linker contains a LSGGE sequence, homologous to the canonical C-motif/ABC signature present in all ABC nucleotide-binding domains. Predictions of disorder and of secondary structures indicated that this C2-sequence was highly mobile and located between an α-helix and a loop similarly to the C-motif. Point mutations of the two first residues of the C2-sequence fully abolished the transport-coupled ATPase activity, and led to the complete loss of cell resistance to mitoxantrone. The interaction with potent, selective and non-competitive, ABCG2 inhibitors was also significantly altered upon mutation. These results suggest an important mechanistic role for the C2-sequence of the ABCG2 linker region in ATP binding and/or hydrolysis coupled to drug efflux.
    No preview · Article · Dec 2015 · Cellular and Molecular Life Sciences CMLS
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    ABSTRACT: Belinostat is a second-generation zinc-binding histone deacetylase inhibitor that is approved for peripheral T-cell lymphoma and is currently being studied in small cell lung cancer and other advanced carcinomas as a 48-hour continuous intravenous infusion. Belinostat is predominantly metabolized by UGT1A1, which is polymorphic. Preliminary analyses revealed a difference in belinostat clearance based on UGT1A1 genotype. A 2-compartment population pharmacokinetic (PK) model was developed and validated that incorporated the UGT1A1 genotype, albumin, and creatinine clearance on the clearance parameter; body weight was a significant covariate on volume. Simulated doses of 600 and 400 mg/m(2) /24 h given to patients considered extensive or impaired metabolizers, respectively, provided equivalent AUCs. This model and subsequent simulations supported additional PK/toxicity and pharmacogenomics/toxicity analyses to suggest a UGT1A1 genotype-based dose adjustment to normalize belinostat exposure and allow for more tolerable therapy. In addition, global protein lysine acetylation was modeled with PK and demonstrated a reversible belinostat exposure/response relationship, consistent with previous reports.
    No preview · Article · Dec 2015 · The Journal of Clinical Pharmacology
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    ABSTRACT: Introduction: Cutaneous T-cell lymphoma (CTCL) encompasses a rare group of hematologic malignancies, in which complete and durable responses to treatment are often elusive, with patients requiring multiple successive lines of therapy. Traditional chemotherapeutic agents do not seem to deliver lasting responses and are not without cumulative toxicity. In this context, focus has shifted to biologic and immunomodulatory agents, of which the histone deacetylase inhibitor (HDACi) romidepsin has attracted interest for its tolerability and proven efficacy in around one-third of patients in two pivotal clinical trials.Areas covered: In this review, we survey existing preclinical and clinical data for romidepsin from its discovery to use in prospective clinical trials. Pharmacology, toxicity and current market overview including potential comparators are also examined.Expert opinion: There is a clear and demonstrable role for romidepsin in the treatment of CTCL given convincing long-term Phase II efficacy data. Nonetheless, prospective data are lacking to guide selection between different biologic agents and to better identify those patients most likely to benefit from this therapy. We suggest that comparative trials between biologic agents, and ongoing research into CTCL pathogenesis and biomarkers of disease response are required to guide this decision-making process in future.
    No preview · Article · Oct 2015 · Expert Opinion on Orphan Drugs
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    ABSTRACT: Histone deacetylase inhibitors (HDIs) are under investigation for the treatment of a number of human health problems. HDIs have proven therapeutic value in refractory cases of cutaneous T-cell lymphoma. Electrocardiographic ST segment morphological changes associated with HDIs were observed during development. Because ST segment morphology is typically linked to changes in ATP sensitive potassium (KATP) channel activity, we tested the hypothesis that HDIs affect cardiac KATP channel subunit expression. Two different HDIs, romidepsin and trichostatin A, caused ~20-fold increase in SUR2 (Abcc9) subunit mRNA expression in HL-1 cardiomyocytes. The effect was specific for the SUR2 subunit as neither compound causes a marked change in SUR1 (Abcc8) expression. Moreover, the effect was cell specific as neither HDI markedly altered KATP subunit expression in MIN6 pancreatic β-cells. We observe significant enrichment of the H3K9Ac histone mark specifically at the SUR2 promoter consistent with the conclusion that chromatin remodeling at this locus plays a role in increasing SUR2 gene expression. Unexpectedly, however, we also discovered that HDI-dependent depletion of cellular cholesterol is required for the observed effects on SUR2 expression. Taken together, the data in the present study demonstrate that KATP subunit expression can be epigenetically regulated in cardiomyocytes, defines a role for cholesterol homeostasis in mediating epigenetic regulation and suggests a potential molecular basis for the cardiac effects of the HDIs.
    Full-text · Article · Aug 2015 · Frontiers in Pharmacology

  • No preview · Article · Aug 2015 · Cancer Research

  • No preview · Article · Aug 2015 · Cancer Research
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    ABSTRACT: The histone deacetylase inhibitor belinostat is eliminated through glucuronidation by UGT1A1. Polymorphisms that reduce UGT1A1 function could result in increased belinostat exposure and toxicities. We wanted to determine which SNPs alter belinostat exposure and toxicity. In a phase I (BPE) trial belinostat (400, 500, 600 or 800 mg/m(2) /24 h, 48 h continuous infusion) was administered to patients with cancer in combination with cisplatin and etoposide (n = 25). Patients were genotyped for UGT1A1 variants associated with reduced function: UGT1A1*6, UGT1A1*28 and UGT1A1*60. Endpoints were associations between UGT1A1 genotype and belinostat pharmacokinetics (PK), toxicities and global protein lysine acetylation (AcK). Belinostat AUC was increased (P = 0.003) and t1/2 increased (P = 0.0009) in UGT1A1*28 and *60 carriers, that received more than 400 mg/m(2) /24 h. The incidence of grade 3-4 thrombocytopenia (P = 0.0081) was associated with UGT1A1 polymorphisms. The FDA approved package insert recommends dose adjustment of belinostat for UGT1A1*28. However, our data suggest dose adjustment is also necessary for UGT1A1*60. UGT1A1 polymorphisms were associated with increased systemic belinostat exposure, increased AcK and increased incidence of toxicities, particularly at doses > 400 mg/m(2) /24 h. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Aug 2015 · The Journal of Clinical Pharmacology
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    Susan E Bates · Robert W Robey · Richard L Piekarz
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    ABSTRACT: Epigenetic targets have emerged as an exciting area for drug discovery. The discovery that histone deacetylase (HDAC) inhibitors had marked anticancer activity in T-cell lymphoma gave impetus to the field. In a phase I study published in Clinical Cancer Research in March 2002, romidepsin (depsipeptide), a potent HDAC inhibitor, was found to be tolerable, with a side effect profile that was later understood to be characteristic of this class of agents. Evidence of activity in this key phase I trial provided momentum for the further study of epigenetic agents. Clin Cancer Res; 21(10); 2195-7. ©2015 AACR. See related article by Sandor et al., Clin Cancer Res 2002;8(3) Mar 2002;718-28. ©2015 American Association for Cancer Research.
    Preview · Article · May 2015 · Clinical Cancer Research
  • Susan E Bates

    No preview · Article · May 2015 · Clinical Cancer Research
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    ABSTRACT: Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3·5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action. © 2015 John Wiley & Sons Ltd.
    Full-text · Article · Apr 2015 · British Journal of Haematology
  • Susan E Bates

    No preview · Article · Apr 2015 · Clinical Cancer Research
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    ABSTRACT: ANG1005 (formerly GRN1005) is a novel drug conjugate consisting of 3 paclitaxel molecules covalently linked to Angiopep-2 designed to cross the blood brain barrier via endocytosis after binding the low-density lipoprotein (LDL) receptor-related protein (LRP). In development for taxane-sensitive brain metastases, a multi-center, single-arm study with the primary endpoint of intra-cranial overall response rate in patients with brain metastases from breast cancer is ongoing. Since MRI detection of brain metastases utilizes gadolinium leakage rather than actual tumor volume, new assessment methods are needed. A pilot study at the NCI enrolled patients to evaluate the utility of 18F-FLT (3'-fluoro-3' deoxythymidine)-PET. Patients with measurable brain metastases from breast cancer were eligible. ANG1005 was administered IV at 550 mg/m2 q 21 days. MRI imaging with gadolinium was used to determine clinical response, and compared to 18F-FLT PET/CT imaging performed before and after cycle 1. FLT incorporation reflects DNA synthesis. Dynamic scans were obtained over 30 min and a static whole body PET image at 1 hour. The % change in standard uptake value (SUV) before and after ANG1005 was determined, considering a significant change > 20%. Eighteen metastatic brain lesions in eight patients were analyzed with FLT PET. The maximum (SUVmax) ranged from 0.8 to 4.0 at baseline, mean 1.8. Tumor to normal (T:N) ratios ranged from 2.9 to 22.3, mean 7.7. Twelve of the 18 lesions showed a >20% decrease post-therapy. The average % change in SUVmax was -24.8% (11 to -66.8%), and T:N ratios -7.7%. The FLT-PET response was frequently discordant with the MRI result. Two patients had confirmed partial responses with durations of response of 6 and 13 cycles. One patient had an unconfirmed PR, with progression after 6 cycles. Two patients had stable disease, receiving 6 and 8 cycles. Therapy for CNS metastases from breast cancer is an important unmet need, as is assessment of therapeutic outcome. ANG1005 is a paclitaxel conjugate with demonstrated activity designed to cross the blood-brain barrier. Pilot evaluations of FLT-PET imaging of brain metastases suggest it is a promising tool for detection and measurement of CNS disease. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
    Full-text · Article · Mar 2015 · Annals of Oncology
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    ABSTRACT: Purpose:T-cell lymphomas (TCLs) are aggressive diseases, which carry a poor prognosis. The emergence of new drugs for TCL has created a need to survey these agents in a rapid and reproducible fashion, in order to prioritize combinations which should be prioritized for clinical study. Mouse models of TCL that can be used for screening novel agents and their combinations are lacking. Developments in non-invasive imaging modalities like surface bioluminescence (SBL) and 3-dimensional-ultrasound are challenging conventional approaches in xenograft modeling relying on caliper measurements. The recent approval of pralatrexate and romidepsin creates an obvious combination that could produce meaningful activity in TCL, which has yet to be studied in combination. Experimental Design:High-throughput screening (cHTS) and multi-modality imaging approach of SBL and 3D-US in a xenograft NOG mouse model of TCL were used to explore the in vitro and in vivo activity of pralatrexate and romidepsin in combination. Corresponding mass spectrometry based pharmacokinetic and immunohistochemistry based pharmacodynamic analysis of xenograft tumors were performed to better understand a mechanistic basis for the drug: drug interaction. Results:In vitro, pralatrexate and romidepsin exhibited concentration-dependent synergism in combination against a panel of TCL cell lines. In a NOG murine model of TCL, the combination of pralatrexate and romidepsin exhibited enhanced efficacy compared with either drug alone across a spectrum of tumors using complimentary imaging modalities such as SBL and 3D-US. Conclusions:Collectively, these data strongly suggest that the combination of pralatrexate and romidepsin merit clinical study in patients with TCLs. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · Feb 2015 · Clinical Cancer Research
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    Susan E Bates
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    ABSTRACT: The development of new treatment options for central nervous system (CNS) metastases from breast cancer and fromother solid tumors lags far behindprogress in otherareasofoncology.Despite this lag, a series of paradigm shifts have made it possible to renew our efforts to make progress.
    Preview · Article · Dec 2014 · The Oncologist
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    ABSTRACT: Purpose: DMS612 is a dimethane sulfonate analog with bifunctional alkylating activity and preferential cytotoxicity to human renal cell carcinoma (RCC) in the NCI-60 cell panel. This first-in-human phase I study aimed to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of DMS612 administered by 10-min intravenous infusion on days 1, 8, and 15 every 28 days. Experimental Design: Patients with advanced solid malignancies were eligible. Enrollment followed a 3+3 design. Pharmacokinetics of DMS612 and metabolites were assessed by mass spectroscopy and pharmacodynamics by γ-H2AX immunofluorescence. Results: A total of 31 patients with colorectal (11), RCC (4), cervical (2), and urothelial (1) cancers were enrolled. Six dose levels were studied, from 1.5 mg/m2 to 12 mg/m2. DLTs of grade 4 neutropenia and prolonged grade 3 thrombocytopenia were observed at 12 mg/m2. The MTD was determined to be 9 mg/m2 with a single DLT of grade 4 thrombocytopenia in 1 of 12 patients. Two patients had a confirmed partial response at the 9 mg/m2 dose level, in renal (1) and cervical (1) cancer. DMS612 was rapidly converted into active metabolites. γ-H2AX immunofluorescence revealed dose-dependent DNA damage in both peripheral blood lymphocytes and scalp hairs. Conclusions: The MTD of DMS12 on days 1, 8, and 15 every 28 days was 9 mg/m2. DMS612 appears to be an alkylating agent with unique tissue specificities. Dose-dependent pharmacodynamic signals and 2 partial responses at the MTD support further evaluation of DMS612 in phase II trials. Copyright © 2014, American Association for Cancer Research.
    No preview · Article · Dec 2014 · Clinical Cancer Research
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    ABSTRACT: Despite enormous advances in our understanding of aggressive lymphomas, it is clear that progress in the peripheral T-cell lymphomas (PTCL) has lagged well behind other B-cell malignancies. Although there are many reasons for this, the one commonly cited notes that the paradigms for diffuse large B-cell lymphoma (DLBCL) were merely applied to all patients with PTCL, the classic "one-size-fits-all" approach. Despite these challenges, progress is being made. Recently, the FDA has approved four drugs for patients with relapsed/refractory PTCL over the past 5 years, and if one counts the recent Japanese approval of the anti-CCR4 monoclonal antibody for patients with adult T-cell leukemia/lymphoma, five drugs have been approved worldwide. These efforts have led to the initiation of no fewer than four randomized clinical studies exploring the integration of these new agents into standard CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone)-based chemotherapy regimens for patients with newly diagnosed PTCL. In addition, a new wave of studies are exploring the merits of novel drug combinations in the disease, an effort to build on the obvious single-agent successes. What has emerged most recently is the recognition that the PTCL may be a disease-characterized by epigenetic dysregulation, which may help explain its sensitivity to histone deacetylase (HDAC) inhibitors, and open the door for even more creative combination approaches. Nonetheless, advances made over a relatively short period of time are changing how we now view these diseases and, hopefully, have poised us to finally improve its prognosis. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma." Clin Cancer Res; 20(20); 5240-54. ©2014 AACR.
    No preview · Article · Oct 2014 · Clinical Cancer Research
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    Susan E Bates

    Preview · Article · Oct 2014 · Clinical Cancer Research

  • No preview · Article · Oct 2014 · Cancer Research
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    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.
    Preview · Article · Sep 2014 · Cancer Research
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    ABSTRACT: ABCG2 was first identified due to its unusual phenotype, as several groups began reporting non-P-glycoprotein (Pgp), non-MRP1-mediated drug resistance in cell lines selected with mitoxantrone. Subsequent to the cloning of BCRP/ABCP/MXR, the Human Genome Nomenclature Committee assigned the name ABCG2. ABCG2 expression is complex and regulated in a tissue-specific, disease stage-specific, and tumor-specific way. ABCG2, composed of 655 amino acids, runs as a 72 kDa protein on SDS-PAGE and is organized into two main structural elements: an N-terminal ATP-binding domain (NBD) and a C-terminal transmembrane domain (TMD). ABCG2 appears to play a role in the physiologic efflux of multiple endogenous substrates. Porphyrin/heme was identified as the first endogenous ABCG2 substrate in ABCG2 knockout mice. Kinase inhibitors are an ever-growing class of compounds that act as ABCG2 inhibitors. Several studies have documented the expression of ABCG2 in multiple tissues, in a pattern consistent with multiple roles in xenobiotic protection.
    No preview · Chapter · Aug 2014

Publication Stats

22k Citations
1,956.09 Total Impact Points


  • 1995-2015
    • NCI-Frederick
      • Laboratory of Pathology
      Фредерик, Maryland, United States
  • 1986-2015
    • National Institutes of Health
      • • Center for Cancer Research
      • • Branch of Medical Oncology Branch and Affiliates
      • • Branch of Medical Genetics
      • • Program of Developmental Therapeutics
      • • Laboratory of Cell Biology
      베서스다, Maryland, United States
    • National Cancer Institute (USA)
      • • Developmental Therapeutics Program
      • • Center for Cancer Research
      • • Medical Oncology Branch and Affiliates
      • • Pediatric Oncology Branch
      • • Community Clinical Oncology Program (CCOP)
      베서스다, Maryland, United States
  • 2012
    • Cancer Research and Biostatistics
      Seattle, Washington, United States
  • 2011
    • Cancer Research Institute
      New York, New York, United States
    • The Chinese University of Hong Kong
      • Department of Pharmacy
      Hong Kong, Hong Kong
  • 2009
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
    • University of Melbourne
      Melbourne, Victoria, Australia
  • 2004-2009
    • Hebrew University of Jerusalem
      • Department of Oncology
      Yerushalayim, Jerusalem, Israel
  • 2007
    • St. John's University
      • Department of Pharmaceutical Sciences
      New York City, NY, United States
  • 2006
    • Albert Einstein College of Medicine
      New York City, New York, United States
  • 2005
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2001-2004
    • Northern Inyo Hospital
      BIH, California, United States
  • 2002
    • New York Medical College
      New York, New York, United States
    • McGill University
      Montréal, Quebec, Canada