C inical
`ancer
`Research
`
`\
`
`May 28, 2008
`HEALTH SCIENCES
`LIBRARIES
`
`W1C
`
`L672
`v.14
`nO.10
`May 15
`2008
`
`

`

`Clinical Cancer Research
`
`The Journal
`
`of Clinical
`
`and Translational
`
`Research
`
`Deputy Editors
`James L. Abbruzzese, Carlos L. Arteaga,
`Alexander M. M. Eggermont, Jerome Ritz,
`EricH. Rubin, Patricia S. Steeg
`senior Editor for CCR Focus
`Susan E. Bates
`
`Edltor-in-ehief: Kenneth C. Anderson
`Senior Editors
`Ronald G. Blasberg, James H. Doroshow, Lee M. Ellis,
`Jennifer Grandis, Stephen M. Hahn, Thomas C. Hamilton,
`Lee J. Helman, Bruce E. Johnson, PauJ Kleihues,
`Jonathan Licht, Massimo Loda, Owen A. O'Connor,
`Steven Piantadosi, Alex Sparreboom, Beverly A. Teicher
`
`Bharat B. Aggarwal
`Sleven Ahrendt
`joseph A. Aisner
`Kenneth D. Aldape
`Francis Ali-Osman
`Carmen J. Allegra
`Enrique Alvarez
`gebecca G. Bagley
`Frank M. Balis
`Bart Barlogie
`lose Baselga
`Robert C. Bast, Jr.
`Hector Banifora
`David C. Beer
`Michael E. Berens
`P. l..eif Bergsagel
`Irwin D. Bernstein
`Donald A. Berry
`Joseph R. Bertino
`Kapil N. Bhalla
`William Bigbee
`Michael J. Birrer
`Ernest C. Borden
`George J. Bosl
`Ruud H. Brakenhoff
`Lawrence C. Brody
`Jennifer R. Brown
`Monica R. Brown lones
`Ronald M. Bukowski
`Angelika M. Burger
`Aman U. Buzdar
`Stephen A. Cannistra
`Michael A. Carducci
`William E. Carson
`Richard E. Champlin
`Paul B. Chapman
`Paul Chiao
`R. Cho
`Kathleen
`Michaele C. Christian
`Fortunato Ciardiello
`Margie L. Clapper
`Robert Clarke
`Cary L Clayman
`Ezra E.W. Cohen
`Michael B. Cohen
`Barbara A. Conley
`Kathleen A. Cooney
`Jorge E. Cortes
`Peter V. Danenberg
`Andrew ,. Dannenberg
`Yves DeClerck
`
`8. Deisseroth
`Alben
`Sally J. Denardo
`Mark W. Dewhirst
`Robert Diasio
`Colin P. Dinney
`Robert DiPaola
`Ethan Dmitrovsky
`Ross C. Donehower
`Glenn Dranoff
`Louis Dubeau
`Raymond N. DuBois
`Alan Eastman
`J. Egorin
`Merrill
`Add K. EI-Naggar
`Francisco
`J. Esteva
`Soldano
`Ferrone
`William D. Figg
`Antonio T. Fo]o
`Kenneth A. Peon
`Arlene A. Porastiere
`David A. Frank
`Arthur E. frankel
`Paul
`frankel
`Ralph S. Freedman
`Henry S. Friedman
`Gary E. Gallick
`Varsha Gandhi
`Spiridione Garbisa
`Adi Gazdar
`Stephen
`L George
`Stanton L Gerson
`Giuseppe Giaccone
`Luca Gianni
`Bonnie S. Glisson
`I. David Goldman
`James S. Coydos
`William J. Gradishar
`Steven Grant
`Joe W. Gray
`Jean L Crem
`William E. Grizzle
`Bruce G. Haffty
`Anne W. Hamburger
`Paul M. Harari
`Adrian L. Harris
`F. Hayes
`Daniel
`Nicholas K. Hayward
`Stephen
`S. Hecht
`Roy S. Herbst
`James G. Herman
`John A. Hickman
`
`Editorial Board
`
`Manuell-lidalgo
`Walter N. Hittelman
`Samuel B. 1-10
`Robert M. Hoffman
`Monica Hollstein
`Shawn E. Holt
`Sandra
`J. Horning
`Gabriel N. Hortobagyi
`J. Houghton
`Peter
`Ralph Hruban
`Mlen-Chie Hung
`lohn T. Isaacs
`Mark A. Israel
`lean-Pierre
`lssa
`Rakesh K. lain
`C. David lames
`fin len
`William C. Kaelin
`Barton A. Kamen
`Hagop Kamarjian
`Judith E. Karp
`Scott H. Kaufmann
`Stanley B. Kaye
`Robert S. Kerbel
`J. Kerin
`Michael
`Khandan Keyomarsi
`David Khayat
`Fadlo R. Khuri
`J. Kinsella
`Timothy
`John M. Kirkwood
`Hynda K. Kleinman
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`Jason A. Koutcher
`Donald Kufe
`Rakesh Kumar
`Razelle Kurzrock
`Steven M. Larson
`Fredrick S. Leach
`He-Young Lee
`lin Soc Lee
`Stanley Lipkowitz
`Scott M. Lippman
`Paul Liu
`Philip O. Livingston
`Alben E LoBugiio
`H. Kim Lyerly
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`J. Lynch
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`E. Meyn
`Raymond
`Frank L. Meyskens
`Luka Milas
`Randall E. Millikan
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`Michael A. Morse
`Hasan Mukhtar
`Carolyn Muller
`J. Mullin
`Robert
`lames L. Mulshine
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`Frank G. Ondrey
`Michael S. O'Reilly
`Joyce A. O'Shaughnessy
`Rodney L. Page
`Klaus Pantel
`Iae-Cahb Park
`Harvey I. Pass
`Ira Pastan
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`Donald A. Podoloff
`Komelia Polyak
`Yves G. Pommier
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`Michael Reiss
`C. Patrick Reynolds
`Paul Richardson
`J. Robertson
`Michael
`Myrna R. Rosenfeld
`Miriam P. Rosin
`Eric K. Rowinsky
`lawrence Rubinstein
`Youcef M. Rustum
`David P. Ryan
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`Guido Sauter
`Stefania Scala
`David A. Scheinberg
`lohn Schiller
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`Gary K. Schwartz
`Michael V. Seiden
`Adrian M. Senderowicz
`Geoffrey Shapiro
`Laura K. Shawver
`Jerry W. Shay
`J. Shih
`Weichung
`DongM.
`Shin
`Sabina Signoretti
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`Jeffrey A. Sosman
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`Cy A. Stein
`J. Storkus
`Walter
`Roger Srrair
`leffrey G. Supko
`Sandra M. Swain
`Chris H. Takimoro
`Moshe Talpaz
`David Tarin
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`Mary 8. Todd
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`William Travis
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`Winfried S. Wels
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`Theresa L. Whiteside
`KepingXie
`Chung S. Yang
`Jin-Ming Yang
`J. Yeatman
`Timothy
`Yun Yen
`Wei Zhang
`
`~~
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`American As.sociation fur Cancer Research
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`

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`Clinical Cancer Research
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`

`

`Clinical
`Research Highlights
`Cancer
`
`Selected Articles from This Issue
`
`May 15,2008
`
`ClinicalActivity of GM-CSF and Thalidomide
`in Prostrate Cancer
`Garcia et al.
`
`Page 3052
`
`Managing Hypertension Induced by VEGF
`Signaling Inhibitors
`Curwen et al.
`
`'Page 3124
`
`Granulocyte macrophage
`colony-stimulating
`factor
`(GM-CSF) and the
`agent
`immunomodulatory
`thalidomide
`have clinical
`activity in advanced prostate cancer. To determine
`the
`biological and clinical effects of this combination
`before
`to radical prostatectomy, Garcia and coworkers conducted
`a phase II study. They found that
`the combination was
`safe and did not
`impact on the perioperative morbidity
`of radical prostatectomy. Although pathologic
`responses
`were not observed, most patients achieved a reduction in
`prostate-specific antigen. Further, they found that the
`administration of GM-CSF and thalidomide
`induces the
`infiltration of dendritic cells and T cells into tumor
`tissue,
`showing that the clinical activity of GM-CSF and
`thalidomide in prostate cancer is immune mediated.
`
`RRM1 Polymorphisms Predict
`Gemcitabine Response
`Kim et al.
`
`Page 3083
`
`patients with high tumoral
`Gemcitabine-treated
`expression of ribonucleotide
`reductase M1 (RRM1)
`generally have poor prognosis, due to a decreased
`in
`efficacy of gemcitabine
`therapy. Two polymorphisms
`the promoter sequence of RRM 1 have been previously
`shown to regulate RRM 1 expression. Here, Kim and
`colleagues investigated whether
`these polymorph isms
`are correlated with the efficacy of gemcitabine-based
`chemotherapy in lung cancer patients. They detected
`significant differences in response rates to gemcitabine
`according to the allelotypes of the RRM 1 promoter
`sequence. These polymorph isms, which can be
`determined using germline DNA, may be useful as
`predictive markers of gemcitabine-based
`therapy.
`
`Hypertension is frequently encountered when inhibitors
`of vascular endothelial growth factor (VEGF) signaling
`are administered to cancer patients. Here, Curwen and
`colleagues report on a preclinical examination of
`hypertension induced by a VEGFsignaling inhibitor,
`cediranib,
`in rats. They found that moderate blood
`pressure increases induced by cediranib were managed
`by coadministration
`of an angiotensin-converting
`enzyme
`inhibitor. A calcium antagonist was required, however, to
`reverse more severe hypertensive responses. Importantly,
`coadministration
`of the calcium antagonist did not affect
`the antitumor activity of cediranib. These data indicate
`that hypertension is a consequence of inhibiting
`physiologic VEGFsignaling and show that it can be
`controlled with appropriately selected antihypertensive
`medication.
`
`Interaction of Imatinib with Human
`Organic Ion Carriers
`Hu et al.
`
`Page 3141
`
`The activity of imatinib in leukemia has recently
`I (Ocrl)
`been linked to the organic cation transporter
`gene SLC22Al. To further understand mechanisms
`involved in the drug's cellular entry, Hu and colleagues
`characterized the interaction of imatinib with
`15 transporters
`in amphibian
`and mammalian models.
`They found that
`imatinib could be transported by
`various ABC transporters
`and by OATPIA2, but not by
`ocr!. An expression microarray, however, showed that
`SLC22A1 provides a composite surrogate for the
`expression of multiple transporters
`relevant to imatinib.
`Given that
`it is highly expressed in the intestine,
`gliomas, and leukemia cells, these findings suggest
`that OATPIA2 may playa key role in imatinib
`pharmacokinetics
`and pharmacodynamics.
`
`

`

`Clinical
`Cancer
`
`Research Contents
`
`Molecular Pathways
`Medlanisms of Acquired Resistance to Epidermal Growth factor Receptor Tyrosine Kinase
`Inhibitors
`In Non-Small Cell Lung Cancer. Jeffrey A. Engelman
`and Pasi A. Ianne
`
`Review
`to Alkylaling Agents In Malignant Glioma.
`Medlanlsms of Chemoresistance
`Gaspar
`I. Kitange, C. David James, Ruth Plummer, Hilary Calvert. Michael Weller,
`and Wolfgang Wick
`.
`.
`
`'ann N. Sarkaria,
`
`2895
`
`29t1t1
`
`Human Cancer Biology
`
`H.lioob..aer pylori Augments Growth of Gastrio Cancers via the Upopolysaccharlde- Toil-like
`Receptor 4 Pathway whereas Its Upopolysaccharlde Attenuates Antitumor Activities of
`Human Mononudear
`Cells. Kentaro Chochi, Takashi lchikura, Manabu Kinoshita, Takashi Majima,
`Nariyoshi Shinomiya, Hironori Tsujirnoto, Toshinobu Kawabata, Hidekazu Sugasawa. SatoshiOno,
`Shuhji Seki, and Hidetaka Mochizuki....................................................
`
`Epigenetic Silendng of the Tetraspanln CD9 during Disease Progression in Multiple
`Myeloma Cells and Correlation with Survival. Elke De Bruyne, Tomas
`Ian Bos, Kewal Asosingh,
`Isabelle Vande Broek, Eline Menu, Els Van Valckenborgh,
`Peter Atadja, Valerie Coiteux, Xavier Leleu,
`Kris Thielernans,
`Ben Van Camp, Karin Vanderkerken,
`and Ivan Van Riet...........................
`.
`
`...2909
`
`2918
`
`Detection of Copy Number Alterations In Metastatic Melanoma by a DNA fluorescence
`In situ Hybridization Probe Panel and Array Comparative Genontic Hybridization:
`A Southwest Oncology Group Study (S9431). Stephen R. Moore, Diane L. Persons,
`Jeffrey A. Sosman, Dolores Bobadilla, Victoria Bedell, David D. Smith, Sandra R. Wolman,
`lim Moon, Vernon K. Sondak,
`and Marilyn L. Slovak
`Ralph J. Tuthill,
`
`.
`
`2927
`
`Divergent Effects of Castration on Prostate Cancer In TRAMPMice: Possible Implications
`for Therapy. Yao Tang, Linbo Wang, Olga Goloubeva, Mohammad Afnan Khan, Bin Zhang,
`and Arif Hussain
`.
`
`Gene Expression Promes Assodated with the Presence of a fibrotic focus and the Growth
`Pattern In Lymph Node-Negative Breast Cancer. Gen G. Van den Eynden, Marcel Srnid.
`lise Van der Auwera, Trinh Xuan Bieh, Peter van Dam,
`Steven I. Van Laere, Cecile G. Colpaert,
`Michael A. den Bakker, Luc Y. Dirix, Eric A. Van Marek, Peter B. Vermeulen,
`and John A. Foekens
`
`Loss of Heterozygosity at the BRCAl Locus Detected by Multiplex Ugation-Dependent
`Probe Ampllllcation Is Common in Prostate Cancers from Men with a Gerntilne BRCAl
`Mutation. Amber J. Willems, Sarah- Jane Dawson, Hema Sarnaratunga, Alessandro De Luca,
`Yoland C. Antill, John L. Hopper,
`and Heather
`J. Thorne
`and kConFab Investigators
`
`Critical Role of Notch Signaling In Osteosarcoma Invasion and Metastasis. Pingyu Zhang,
`Yanwen Yang, Patrick A. Zweidler-McKay,
`and Dennis P.M. Hughes
`
`Imaging, Diagnosis, Prognosis
`
`Imaging Bone and Soft Tissue Tumors with the Proliferation Marker
`[18f)f1uorodeoxythymldlne.
`Andreas K. Buck, Ken Herrmann, Christian Meyer zum Btlschenfelde,
`Malik E. luweid, Mark Bischoff, Gerhard Glatting, Gregor Weirich, Peter Moller, Hans-Iurgen Wester,
`Klemens Scheid bauer, Tobias Dechow, Christian
`Peschel, Markus Schwaiger, and Sven N. Reske
`
`Novel Glioblastoma Markers with Diagnostic and Prognostic Value Identi6ed through
`Transcriptome Analysis. Sreekanth
`P. Reddy, Ramona Britto, Katyayni Vinnakota, Hebbar Aparna,
`Hari Kishore Sreepathi, Balaram Theta, Arpana Kumari, B.M. Shilpa, M. Vrinda, Srikantha Umesh,
`Cini Samuel, Mitesh Shetty, Ashwani Tandon, Paritosh Pandey, Sridevi Hegde, A.S. Hegde,
`Anandh Balasubramaniam, B.A. Chandramouli, Vani Santosh, Paturu Kondaiah,
`Kumaravel Somasundararn,
`and M.R. Satyanarayana Rao
`
`2936
`
`2944
`
`2953
`
`2962
`
`2970
`
`2978
`
`

`

`Analysis of the ~ammaPrin~Breast ~ancer Assay in a Predominantly PosbDeDopausal
`Cohort. Ben S. Winner, Dennis C. Sgroi, Paula D. Ryan, Tako J. Bruinsma, Annuska M. Clas.
`Anitha Male, Sonika Dahiya. Karleen Habin, Rene Bernards, Daniel A. Haber, Laura J. Van't Veer,
`and Sridhar Ramaswamy
`-..
`
`.
`
`2988
`
`and
`Protein and Signal Transducers
`between Raf Kinase inhibitory
`Inverse Assodation
`Patients:
`Implications
`Activators of Transcription
`3 Expression In Gastric Adenocarcinoma
`for Clinical Outcome. Devasis Chatterjee, Edmond Sabo, Rosemarie Tavares, and Murray B. Resnick
`
`2994
`
`Heavy Chain Gene Locus Predict Better
`Involving tbe Immunoglobulin
`Translocations
`Survival
`In Gastric Diffuse Large B-CeU Lymphoma. Shotaro Nakamura, Hongtao Ye,
`Chris M. Bacon, Alison Goatly, Hongxiang Liu, Lucy Kerr, Alison H. Banham, Berthold Streubel,
`Takashi Yao, Masazumi
`Tsuneyoshi, Antonella
`Savio, Morishige Takeshita,
`Peggy Danigues,
`Agnes Ruskone-Fourmestraux,
`Takayuki Matsumoto, Mitsuo
`lida, and Ming-Qing Du
`
`.
`
`3002
`
`and Nonepltbelial Mallgnandes. Maryla Krajewska,
`In Human Epltbellal
`Bd-B Expression
`Jane N. Winter, Daina Variakojis, Alan Lichtenstein, Dayong Zhai, Michael Cuddy,
`Shinichi Kitada,
`Xianshu Huang, Frederic Luciano, Cheryl H. Baker, Hoguen Kim, Eunah Shin, Susan Kennedy,
`Allen H. Olson, Andrzej Badzio, Iacek lassem, Ivo Meinhold-Heerlein, Michael I. Duffy,
`Aaron D. Schimmer, Ming Tsao, Ewan Brown, Anne Sawyers, Michael Andreeff Dan Mercola,
`Stan Krajewski, and John C. Reed
`
`Impact of InsuUn-Like Growth Factor Type 1 Receptor, Epidermal Growth Factor R2ceptor,
`on Outcomes of Patin1ts with Gasbic Cancer. Junichi Matsubara,
`and HERl Expressions
`Yasuhide Yamada, Yoshinori Htrashtma. Daisuke Takahari. Natsuko T. Okita, Ken Kato,
`Tetsuya Hamaguchi,
`Kuniaki Shirao. Yasuhiro Shimada,
`and Tadakazu Shimoda
`
`for Targeted
`In Ovarian Cancer: A Model
`Vascular Endotbellal Growth Factor Expression
`Use of Novel Theraplesr
`Timothy J. Duncan, Ahmad AI-Attar, Phil Rolland, Ian V.Scott, Suha Deen,
`David TY Liu. Ian Spendlove, and Lindy G. Durrant..
`r ISF]DCFBC:
`Fluorobenzyl-L-Cystelne,
`N-IN-( (SJ-l,3- Dicarboxypropyl]Carbamoylj-4-[ISFI
`A New lmaging Probe for Prostate Cancer. Ronnie C. Mease, Crystal L Dusich, Catherine A. Foss,
`Hayden T. Raven, Roben
`F. Dannels,
`Iurgen Seidel, Andrew Prideaux,
`James J. Fox, George Sgouros,
`Alan P. Kozikowski, and Martin G. Pomper.....
`.
`..
`
`.3011
`
`.3022
`
`3030
`
`3036
`
`Cancer Therapy: Clinical
`
`Study of CT-Oll, a Humanized Antibody Interact1ng
`Phase I Safety and Pharmacoklnetic
`wltb PD-l,
`in Patients wltb Advanced Hematologic Mallgnandes. Raanan Berger,
`Rinat Rotern-Yehudar, Gideon
`Slama, Shimon Landes, Abraham Kneller, Merav Leiba,
`Maya Koren-Michowitz, Avichai Shimoni, and Arnon Nagler ..
`
`..
`
`3044
`
`In Patients
`Sargramostim and Thalidomide
`Clinical and Biological Effects of Neoadjuvant
`with LoeaUy Advanced Prostate Carcinoma. Jorge A. Garcia, Eric A. Klein, Cristina Magi-Galluzzi,
`Paul Elson, Pierre Triozzi, and Robert Dreicer
`
`...3052
`
`Pilot Study of Vacd nation wltb Recombinant CEA-MUC-I-TRICOM Poxviral-Based Vacdnes
`In Patients wltb Metastatic Cardnoma.
`lames L. Gulley, Philip M. Arlen, Kwong-YokTsang,
`lunko vokokawa. Claudia
`Palena, Diane J. Poole, Cinzia Rernondo, Vittore Cereda,
`Jacquin L Jones,
`Mary P. Pazdur, Jack P. Higgins, James w. Hodge, Seth M. Steinberg, Herbert Kotz, William L. Dahut,
`and leffrey Schlom...
`
`...3060
`
`Inhibitors Differentially Affect Vascular Endotbellal Growth
`Tamoxlfen and Aromatase
`Factor and Endostadn Levels in Women with Breast Cancer. Chris E. Holmes,
`Joe C. Huang,
`Thomas R. Pace, Alan B. Howard,
`and Hyman B. Muss...............
`.
`.
`
`........3070
`
`as Maintenance Therapy In First Complete Remission In Ad.dts
`Phase II Trial of Tlplfarnlb
`wltb Acute Myelogenous Leukemia and Poor-Risk Features.
`ludlth E.Karp, B. Dou&las Smith,
`Jacqueline Creer, Maureen KlelO, La.rry Morns, Mark J. leviS,
`Ivana Gojo,
`Jeffrey E. Lancet,
`Steven D. Gore, John J. Wright, and Elizabeth Garrett-Mayer
`..
`
`.
`
`..3077
`
`

`

`In Patients with Noo-Small Cell Lung Cancer According to
`Efficacy of Gemdtablne
`of the Ribonucleotide Reductase Ml Gene. Soo-Ok Kim,
`Promoter
`Polymorphlsms
`Iu-Yeon Jeong, Mi-Ran Kim, Hyun-lu Cho, lin-Yung Iu, Yong-Soo Kwon, ln-lae Oh, Kyu-Sik Kim,
`Yu·1IKim, Sung-Chul Lim, and Young-Chul Kim
`
`of the Novel Innate Immune Modulator
`Pharmacology
`Phase I Study and Preliminary
`rBBX-Ol In Gynecologic Cancers,
`Janet S. Rader, Charles F. Aylsworth, David A. Juckett,
`David G. Mutch, Matthew A. Powell, Lynne Lippmann, and Nikolay V. Dimitrov
`.
`
`In Patients with Relapsed
`Postoperative Adjuvant Dendritic Ce\I-Based Immunotherapy
`Glioblastoma Multlforme, Steven De Vleeschouwer, Steffen Fieuws, Stefan Rutkowski,
`Frank Van Calenbergh, Johannes Van Loon, Jan Goffin, Raf Sciot, Guido Wilms, Philippe Demaerel,
`Monika warmuth-Metz, Niels Soerensen, Johannes E.A.Wolff, Sabine Wagner, Eckhart Kaempgen,
`and Stefaan W. Van GooL............................................................
`.
`
`as a I·Hour Weekly Intravenous
`Study of Plltldepsln
`Phase I Clinical and Pharmacoklnetlc
`Infusion in Patients with Advanced Solid Tumors, Miguel A. Izquierdo, Angela Bowman,
`Margarita Carda, Duncan Iodrell. Marlsa Martinez, Beatriz Pardo, Javier Gomez, Jose A. Lopez-Martin,
`Jose lirneno, Jose R. Cerma, and John F. Smyth
`
`Cancer Therapy: Preclinical
`
`Evaluation of the In vitro and In vivo Antitumor ActivIty of Histone Deacetylase
`for the Therapy of Retinoblastoma,
`Clifton Lee Dalgard, Kurtis R. Van Quill,
`and Joan M. O'Brien
`
`Inhibitors
`
`of Vascular Endothelial Growth Factor-A Signaling Induces Hypertension:
`Inhibition
`in Rat
`Examining the Effect of Cedlranib
`(Recentln: AZD2171) Treatment on Blood Pressure
`and the Use of Concomitant Antihypertensive
`Therapy.
`Ion O. Curwen, Helen 1. Musgrove,
`lane Kendrew, Graham H.P. Richmond, Donald J. Ogilvie, and Stephen R.Wedge........................
`
`and Blockade of the Glycolytic Pathway Synergistically
`Inhibition
`Histone Deacetylase
`Induce Glioblastoma Cell Death. Vivian Egler, Serdar Korur, Mike Failly, Jean-Louis Boulay,
`Roland Imber, Maria M. l.ino, and Adrian Merlo
`.
`
`4
`
`3083
`
`.....3089
`
`3098
`
`3105
`
`3113
`
`...3U4
`
`.3132
`
`of lmatlnlb with Human Organic Ion Carriers. Shuiying Hu, Ryan M. Franke,
`Interaction
`Kelly K. Filipski, Chaoxin Hu, Shelley I. Orwick, Ernst A. de Bruijn, Herman Burger, Sharyn D. Baker,
`and Alex Sparreboom
`.
`
`3141
`
`A In1J/POZ Gene, NAC-l, a Tumor Recurrence-Assodated
`Gene, as a Potential Target
`for Tuol Resistance in Ovarian Cancer. Masako Ishibashi, Kentaro Nakayama,
`Shamima Yeasmin, Atsuko Katagiri, Kouji lida, Naomi Nakayama, Manabu Fukumoto,
`and Kohji Miyazaki
`.
`
`.
`
`.3149
`
`Plus Regulatory T-Cell Depletion Promotes Potent Rejection of
`Proliferation
`Homeostatic
`B16 Melannma.
`Justin Kline, Ian E. Brown, Yuan-Yuan Zha, Christian Blank, Iohn Strickler,
`Harald Wouters, Long Zhang, and Thomas F. Gajewski......................................................................
`
`Aspirin Sensitizes Cancer Cells to TRAIL-Induced Apoptosls by Redudng Survlvln Levels.
`Meiling Lu, Anne Strohecker, Feng Chen, Toni Kwan, Joshua Bosman, V. Craig Jordan,
`.
`and Vincent 1. Cryns..........................................
`
`....3156
`
`3168
`
`against Prostate Tumor Growth and
`Efficacy of Inositol Heupbosphate
`Chemopreventive
`Progression
`In TRAMP MIce. Komal Raina, Subapriya Rajamanickam, Rana P. Singh,
`and Rajesh Agarwal......................................................................................................................................
`
`......3177
`
`Pretreatment with Cisplatin Enbances E7-Spedflc CD8· T-Ce\l-Medlated Antitumor
`Immunity Induced by DNA Vacdnatlon. Chih-Wen Tseng, Chien-Fu Hung, Ronald D. Alvarez,
`Cornelia Trimble, Warner K. Huh, Daejin Kim, Chi-Mu Chuang, Cheng-Tao Lin, Ya-Chea Tsai,
`Liangmei He, Archana Mortie, and T-e. Wu........................................................................................
`
`.....3185
`
`www.aacrjoumals.org
`
`

`

`In Ovarian Adenocardnoma
`by Enhandng
`of Drug Resistance
`Modulation
`Ceramlde Using Tamoxlfen-Loaded
`Biodegradable
`Polymeric Nanopartides.
`Harikrishna Devalapally, Zhenfeng Duan, Michael V. Seiden, and Mansoor M. Amiji
`
`Intracellular
`
`Stromal Tumors.
`of Pediatric Gastrointestinal
`Molecular Characterization
`Narasimhan P. Agaram, Michael P. Laquaglia, Bertin Ustun, Tianhua CUD, Grace C. Wong,
`Nicholas D. Socci, Raben G. Maki, Ronald P. DeMatteo, Peter Besmer; and Cristina R. Antonescu
`
`3193
`
`....3204
`
`Cancer Prevention and Susceptibility
`
`EGF Serum Levels, aod
`(EGF) Polymorphism,
`A Functional Epidermal Growth Factor
`Esopbageal Adenocarcinoma
`Risk and Outcome. Michael Lanuti, Geoffrey Liu,
`Jonathan M. Goodwin, Rihong Zhai, Bryan C. Fuchs, Kofi Asomaning, Li Su, Norman S. Nishioka,
`Kenneth K. Tanabe, and David C. Christiani
`
`.
`
`3216
`
`in Both
`to Increase Risk for Prostate Cancer
`Combine
`VDR and SRD5A2 Polymorphlsms
`Non-Hispanic White and Hispanic White Men. Kathleen C. Torkkc, Adrie van Bokhoven,
`Phoung MaL Joke Beuren. Ivana Balk, Tim E. Byers, John E. Hokanson, Jill M. Norris, Anna E. Baron,
`and Robin [. Leach.,
`.
`M. Scott Lucia, Ian M. Thompson,
`
`In Cell Death Pathway Genes and Risk of Pancreatic Cancer. Ming Yang,
`functional Variants
`Tong Sun, Li Wang. Dianke Yu. Xuemei Zhang. Xiaoping Miao, Junniao Liu, Dan Zhao, Hui Li,
`Wen Tan, and Dongxin Lin
`.. .
`.
`
`.3223
`
`.3230
`
`About the Cover
`
`identified by 11.JNEL staining in
`APOPlOlic cancer cells (bright
`red)
`orthotopic MDA-MB·435 xenograft
`tumors. Female nude mice with
`xenograft tumors were treated with vehicle (upper left panel), TRAIL
`(upper right panel), aspirin (lower left panel), or the combination
`of
`aspirin and TRAIL (lower right panel). Aspirin cooperated with
`TRAILto induce apoptosis and reduce tumor burden in this model,
`supporting the potential
`therapeutic utility of this combination.
`For further details, please see Lu and colleagues on page 3168 in
`this issue.
`
`

`

`Cancer Therapy: Clinical
`
`Phase I Safety and Pharmacokinetic Study of CT-011. a Humanized
`Antibody Interacting with PD-1. in Patients with Advanced
`Hematologic Malignancies
`
`Gideon Slama,3 Shimon Landes,3 Abraham Kneller,'
`Raanan Berger,' Rinat Hotern-vebudat'
`Merav Leiba,' Maya Koren-Michowitz.f Avichai Shimoni,'
`and Arnon Nagler'
`
`Abstract
`
`the immune
`that modulates
`Purpose: CT-011 is a humanized IgG1 monoclonal antibody
`family present
`response through interaction with PD-1. a protein belonging to the 67 receptor
`on lymphocytes. The objectives of this phase I study were to assess the dose-limiting toxicities,
`to determine the maximum tolerated dose, and to study the pharmacokinetics of CT-011 admin-
`istered once to patients with advanced hematologic malignancies.
`Experimental
`Design: Seventeen patients were treated with escalating doses of CT-011
`ranging from 0.2 to 6 mg/kg. For pharmacokinetic analysis, blood samples were withdrawn from
`the patients before and immediately after treatment and at 24 hours, 48 hours, and on days 7, 14,
`and 21. CT-011 blood levels were assessed with a specific ELISA and derived concentrations were
`used to calculate pharmacokinetic parameters. Activation of the immune system was assessed
`by measuring peripheral blood CD4+, CD8+, and CD69+ lymphocytes.
`Results: The study showed the antibody to be safe and well tolerated in this patient population.
`No single maximum tolerated dose was defined in this study. Clinical benefit was observed in
`33% of the patients with one complete remission. Pharmacokinetic analyses show that serum
`em" and theAUC of CT-011 increased proportionally with dose. The median 111'of CT-011
`ranged from 217 to 410 hours. Sustained elevation in the percentage of peripheral blood CD4+
`lymphocytes was observed up to 21 days following CT-011treatment.
`Conclusions:
`A single administration of 0.2 to 6.0 mg/kg of CT-011 is safe and well tolerated in
`patients with advanced hematologic malignancies.
`
`The challenge in immunotherapy of cancer lies in the ability to
`establish a highly efficacious and safe immune response against
`the developing cancer. All clinically approved and most experi-
`mental antibody drugs aim directly at specific protein targets
`present on the surface of defined tumor cells. The interaction
`between the antibody and its target directs the immune system
`to the tumor,
`initiating a cascade of events culminating in the
`elimination of the cancer cells.
`T cells are the major cells that drive cellular immunity. The
`87 family of co-signaling molecules is expressed on the surface
`of T lymphocytes and is crucial for their optimal activation, as
`well as for the prevention of immunologic tolerance (1). These
`co-signaling molecules not only provide critical positive signals
`that stimulate T-cell growth, up-regulate cytokine production,
`and promote T-cell differentiation,
`but also contribute key
`
`'lnstituta of Oncology and Radiotherapy and 2Hematology
`Affiliation:
`Authors'
`Bone Marrow Transplantation,
`Chaim Sheba Medical Center. Tel
`Division,
`Israel; and 3Curetech Ltd., Yavne, Israel
`Hashomer,
`Received 8/30/07;
`revised 1/14/08; accepted 1/29/08.
`The costs of publication of this article were defrayed in part by the payment of page
`charges. This article must therefore be hereby marked advertisement
`in accordance
`with 18 U.S. C. Section 1734 solely to indicate this fact.
`Division, Bone Marrow
`Requests
`for
`reprints:
`Arnon Nagler, Hematology
`Israel. Phone: 972-
`Transplantation, Chaim Sheba Medical Center, Tel Hashomer,
`52-6667180; Fax: 972-3-5305377;
`E-mail: amon.nagler@sheba.health.gov.il.
`C2008 American Association for Cancer Research.
`doi: 10.1158/1 078- 0432. CCR-07-4079
`
`terminate, and/or attenuate T-cell
`limit,
`negative signals that
`responses (2-5). Anticancer
`immunotherapy
`based on anti-
`bodies directed against
`the 87 family of receptors, particularly
`the B7 homologue
`1 (B7-Hl)-programmed
`death 1 (PDI)
`system, suggests a promising novel approach for promoting
`immune responses against cancer as well as breaking up