Susan E Bates

National Cancer Institute (USA), 베서스다, Maryland, United States

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Publications (285)1744.96 Total impact

  • [Show abstract] [Hide abstract]
    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.
    British Journal of Haematology 04/2015; DOI:10.1111/bjh.13400 · 4.96 Impact Factor
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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: journals.permissions@oup.com.
    Annals of Oncology 03/2015; 26(suppl 2):ii20. DOI:10.1093/annonc/mdv091.1 · 6.58 Impact Factor
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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.
  • Susan E Bates
    The Oncologist 12/2014; 20(1). DOI:10.1634/theoncologist.2014-0469 · 4.54 Impact Factor
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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.
    Clinical Cancer Research 12/2014; 21(4). DOI:10.1158/1078-0432.CCR-14-1333 · 8.19 Impact Factor
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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.
    Clinical Cancer Research 10/2014; 20(20):5240-54. DOI:10.1158/1078-0432.CCR-14-2020 · 8.19 Impact Factor
  • Susan E Bates
    Clinical Cancer Research 10/2014; 20(20):5172. DOI:10.1158/1078-0432.CCR-14-1257 · 8.19 Impact Factor
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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.
    Cancer Research 09/2014; 74(17):4653-4662. DOI:10.1158/0008-5472.CAN-14-0420 · 9.28 Impact Factor
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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; · 6.63 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; 8(8). DOI:10.1016/j.molonc.2014.05.001 · 5.94 Impact Factor
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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; 51. DOI:10.1016/j.biocel.2014.03.026 · 4.24 Impact Factor
  • Cancer Research 03/2014; 73(24 Supplement):P4-01-09-P4-01-09. DOI:10.1158/0008-5472.SABCS13-P4-01-09 · 9.28 Impact Factor
  • Antonio Tito Fojo, Susan E Bates
    The Oncologist 03/2014; 19(4). DOI:10.1634/theoncologist.2014-0091 · 4.54 Impact Factor
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    ABSTRACT: Advances in understanding the biology of cancer, as well as advances in diagnostic technologies, such as the advent of affordable high-resolution DNA sequencing, have had a major impact on the approach to identification of specific alterations in a given patient's cancer that could be used as a basis for treatment selection, and hence the development of companion diagnostics. Although there are now several examples of successful development of companion diagnostics that allow identification of patients who will achieve the greatest benefit from a new therapeutic, the path to coapproval of a diagnostic test along with a new therapeutic is complex and often inefficient. This review and the accompanying articles examine the current state of companion diagnostic development in the United States and Europe from academic, industry, regulatory, and economic perspectives. See all articles in this CCR Focus section, "The Precision Medicine Conundrum: Approaches to Companion Diagnostic Co-development." Clin Cancer Res; 20(6); 1419-27. ©2014 AACR.
    Clinical Cancer Research 03/2014; 20(6):1419-27. DOI:10.1158/1078-0432.CCR-14-0091 · 8.19 Impact Factor
  • Susan E Bates
    Clinical Cancer Research 03/2014; 20(6):1418. DOI:10.1158/1078-0432.CCR-14-0223 · 8.19 Impact Factor
  • Susan E Bates
    Clinical Cancer Research 12/2013; 19(23):6352. DOI:10.1158/1078-0432.CCR-13-2847 · 8.19 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 10/2013; 3:261. DOI:10.3389/fonc.2013.00261
  • Cancer Research 08/2013; 73(8 Supplement):3399-3399. DOI:10.1158/1538-7445.AM2013-3399 · 9.28 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):2193-2193. DOI:10.1158/1538-7445.AM2013-2193 · 9.28 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). DOI:10.4161/cc.25914 · 5.01 Impact Factor

Publication Stats

18k Citations
1,744.96 Total Impact Points

Institutions

  • 1986–2015
    • National Cancer Institute (USA)
      • • Developmental Therapeutics Program
      • • Center for Cancer Research
      • • Medical Oncology Branch and Affiliates
      • • Cancer Therapy Evaluation Program
      • • Pediatric Oncology Branch
      • • Community Clinical Oncology Program (CCOP)
      베서스다, Maryland, United States
  • 2000–2014
    • NCI-Frederick
      Фредерик, Maryland, United States
  • 1990–2014
    • National Institutes of Health
      • • Center for Cancer Research
      • • Laboratory of Molecular Pharmacology
      • • Program of Developmental Therapeutics
      • • Branch of Medical Genetics
      • • Laboratory of Cell Biology
      Maryland, United States
  • 2013
    • Texas Tech University
      • Department of Biological Sciences
      Lubbock, TX, United States
  • 2012
    • Cancer Research and Biostatistics
      Seattle, Washington, United States
  • 2011
    • The Chinese University of Hong Kong
      • Department of Pharmacy
      Hong Kong, Hong Kong
  • 2002–2011
    • Cancer Research Institute
      New York, New York, United States
    • McGill University
      Montréal, Quebec, Canada
    • University of Maryland, Baltimore
      • Department of Medicine
      Baltimore, Maryland, United States
  • 2009
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
    • University of Melbourne
      Melbourne, Victoria, Australia
  • 2003–2009
    • Hebrew University of Jerusalem
      • • Department of Oncology
      • • Department of Biological Chemistry
      Yerushalayim, Jerusalem, Israel
  • 1989–2008
    • Georgetown University
      • Lombardi Cancer Center
      Washington, Washington, D.C., United States
  • 2007
    • St. John's University
      • Department of Pharmaceutical Sciences
      New York City, NY, United States
  • 2005
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 1997–2004
    • Northern Inyo Hospital
      BIH, California, United States
  • 1998
    • Pontifical Catholic University of Chile
      • Departamento de Hematología-Oncología
      Santiago, Region Metropolitana de Santiago, Chile
  • 1996
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      Роквилл, Maryland, United States
  • 1991
    • U.S. Food and Drug Administration
      Washington, Washington, D.C., United States