New Strategies in the Treatment of Ovarian Cancer: Current Clinical Perspectives and Future Potential
Susana Banerjee,Stanley B. Kaye +1 more
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TLDR
Progress in targeting the VEGF pathway and the potential for targeting other pathways and receptors that may be activated in ovarian cancer are reviewed, including the RAS/RAF/MEK and PI3K/AKT/mToR pathways, the ErbB and IGF family of receptors, mitotic check points, and also the folate receptor.Abstract:
The treatment of ovarian cancer is set to undergo rapid changes, as strategies incorporating molecular targeted therapies begin to take shape. These are based on a better appreciation of approaches targeting the tumor microenvironment as well as specific subtypes of the disease, with distinct molecular aberrations. Targeting the VEGF pathway through bevacizumab is clearly effective, with positive randomized trials at all disease stages; targeting defective homologous recombination repair pathways with PARP inhibitors is also proving successful in a substantial proportion of patients with high-grade serous ovarian cancer. In this article, we will review progress in these two leading areas and also discuss the potential for targeting other pathways and receptors that may be activated in ovarian cancer, including the RAS/RAF/MEK and PI3K/AKT/mToR pathways, the ErbB and IGF family of receptors, mitotic check points, and also the folate receptor. Here, single-agent therapy may play a role in selected cases but essential components of future strategies should include combination treatments aimed at dealing with the key problem of drug resistance, together with rational approaches to patient selection.read more
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References
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Journal ArticleDOI
Integrated genomic analyses of ovarian carcinoma
Debra A. Bell,Andrew Berchuck,Michael J. Birrer,Jeremy Chien,Daniel W. Cramer,Fanny Dao,Rajiv Dhir,Philip J. DiSaia,Hani Gabra,Pat Glenn,Andrew K. Godwin,John D. Gross,Lynn C. Hartmann,M. Huang,David G. Huntsman,Mary Iacocca,Marcin Imielinski,Steve E. Kalloger,Beth Y. Karlan,Beth Y. Karlan,Douglas A. Levine,Douglas A. Levine,Douglas A. Levine,Gordon B. Mills,Gordon B. Mills,Carl Morrison,David G. Mutch,Narciso Olvera,Sandra Orsulic,Kay J. Park,Nicholas J. Petrelli,Brenda Rabeno,Janet S. Rader,Branimir I. Sikic,Karen Smith-McCune,Anil K. Sood,David D.L. Bowtell,Robert Penny,Joseph R. Testa,Kyle Chang,Huyen Dinh,J. A. Drummond,G. Fowler,Preethi H. Gunaratne,A. C. Hawes,C. L. Kovar,L. R. Lewis,M. B. Morgan,I. F. Newsham,J. Santibanez,Jeffrey G. Reid,L. R. Trevino,Yue Wu,M. Wang,Donna M. Muzny,D. A. Wheeler,Richard A. Gibbs,Gad Getz,Gad Getz,Michael S. Lawrence,Michael S. Lawrence,Kristian Cibulskis,Kristian Cibulskis,Andrey Sivachenko,C. Sougnez,Douglas Voet,Douglas Voet,Jane Wilkinson,Toby Bloom,Kristin G. Ardlie,Kristin G. Ardlie,T. Fennell,Jennifer Baldwin,S. Gabriel,Eric S. Lander,Li Ding,Robert S. Fulton,Daniel C. Koboldt,Michael D. McLellan,Todd Wylie,Jason Walker,M. O'Laughlin,D. J. Dooling,Linnea Fulton,R. Abbott,N. D. Dees,Qizhou Zhang,Cyriac Kandoth,Michael C. Wendl,William Schierding,D. Shen,Chris Harris,Hayden R. Schmidt,Joelle Kalicki,K. D. Delehaunty,Catrina Fronick,Ryan Demeter,L. Cook,J. W. Wallis,L. Lin,Vincent Magrini,J. S. Hodges,James M. Eldred,S. M. Smith,Craig Pohl,Fabio Vandin,Benjamin J. Raphael,George M. Weinstock,Elaine R. Mardis,Richard K. Wilson,Matthew Meyerson,Wendy Winckler,R. G.W. Verhaak,Suzie Carter,Craig H. Mermel,G. Saksena,G. Saksena,H. Nguyen,R. C. Onofrio,D. Hubbard,S. Gupta,A. Crenshaw,A. H. Ramos,Lynda Chin,Lynda Chin,Alexei Protopopov,Jinghui Zhang,Jinghui Zhang,Jinghui Zhang,T. M. Kim,Ilana Perna,Y. Xiao,Hailei Zhang,Gang Ren,N. Sathiamoorthy,R. W. Park,R. W. Park,Eunjung Lee,Peter J. Park,Peter J. Park,Raju Kucherlapati,D. M. Absher,L. Waite,Gavin Sherlock,James D. Brooks,Jun Li,Jian Xu,Richard M. Myers,Peter W. Laird,L. Cope,James G. Herman,H. Shen,Daniel J. Weisenberger,Houtan Noushmehr,F. Pan,Timothy J. Triche,Benjamin P. Berman,D. J. Van Den Berg,J. Buckley,Stephen B. Baylin,Paul T. Spellman,Paul T. Spellman,Elizabeth Purdom,Pierre Neuvial,Pierre Neuvial,Henrik Bengtsson,Henrik Bengtsson,L. R. Jakkula,S. Durinck,S. Durinck,Junhong Han,Junhong Han,S. Dorton,H. Marr,Y. G. Choi,V. Wang,N. J. Wang,J. Ngai,J. G. Conboy,Bahram Parvin,H. S. Feiler,Terence P. Speed,Joe W. Gray,Joe W. Gray,N. D. Socci,Yanke Liang,Barry S. Taylor,Nikolaus Schultz,Nikolaus Schultz,L. Borsu,Alex E. Lash,Cameron Brennan,A. Viale,Chris Sander,M. Ladanyi,M. Ladanyi,Katherine A. Hoadley,Katherine A. Hoadley,S. Meng,Y. Du,Y. Du,Yigong Shi,Lulin Li,Y. J. Turman,D. Zang,E. B. Helms,S. Balu,Xiang Zhou,Jane Y. Wu,M. D. Topal,D. N. Hayes,D. N. Hayes,Charles M. Perou,Chaowei Wu,S. Shukla,A. Sivachenko,R. Jing,Yingkai Liu,M. Noble,Hannah Carter,D. Kim,Rachel Karchin,James E. Korkola,Laura M. Heiser,Raymond J. Cho,Zhi Hu,Ethan Cerami,A. Olshen,B. Reva,Yevgeniy Antipin,R. Shen,P. Mankoo,Robert L. Sheridan,Giovanni Ciriello,William K. Chang,J. A. Bernanke,David Haussler,Christopher C. Benz,Joshua M. Stuart,Stephen C. Benz,J. Z. Sanborn,Charles J. Vaske,Jieqing Zhu,Christopher Szeto,G. K. Scott,Christina Yau,Matthew D. Wilkerson,N. Zhang,Rehan Akbani,Keith A. Baggerly,W. K. Yung,John N. Weinstein,T. Shelton,Dirk Grimm,Martha Hatfield,Scott Morris,P. Yena,P. Rhodes,Mark E. Sherman,J. Paulauskis,S. Millis,A. Kahn,John M. Greene,R. Sfeir,M. A. Jensen,John W. Chen,J. Whitmore,S. Alonso,J. Jordan,A. Chu,A. Barker,Carolyn C. Compton,Greg Eley,Martin L. Ferguson,Peter Fielding,Daniela S. Gerhard,R. Myles,Carl F. Schaefer,K. R. Mills Shaw,Jim Vaught,J. B. Vockley,Peter J. Good,Mark S. Guyer,Bradley A. Ozenberger,Jane Peterson,Elizabeth J. Thomson +285 more
TL;DR: It is reported that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1,BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes.
Journal ArticleDOI
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Hannah Farmer,Nuala McCabe,Christopher J. Lord,Andrew Tutt,Andrew Tutt,Damian A. Johnson,Tobias B. Richardson,Manuela Santarosa,Krystyna J. Dillon,Ian Hickson,Charlotte Knights,Niall M. B. Martin,Stephen P. Jackson,Graeme C. M. Smith,Alan Ashworth +14 more
TL;DR: BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis, illustrating how different pathways cooperate to repair damage.
Integrated genomic analyses of ovarian carcinoma
Daphne W. Bell,Andrew Berchuck,Michael J. Birrer,Jeremy Chien,Daniel W. Cramer,Fanny Dao,Rajiv Dhir,Philip J. DiSaia,Hani Gabra,Pat Glenn,Andrew K. Godwin,John D. Gross,Lynn C. Hartmann,Mei Huang,David G. Huntsman,Mary Iacocca,Marcin Imielinski,Steve E. Kalloger,Beth Y. Karlan,Douglas A. Levine,Gordon B. Mills,Carolyn A. Morrison,David G. Mutch,Narciso Olvera,Sandra Orsulic,Kay J. Park,Nicholas J. Petrelli,Brenda Rabeno,Janet S. Rader,Branimir I. Sikic,Karen Smith-McCune,Anil K. Sood,David D.L. Bowtell,Robert Penny,Joseph R. Testa,Kyle Chang,Huyen Dinh,Jennifer Drummond,Gerald R. Fowler,Preethi H. Gunaratne,Alicia Hawes,Christie Kovar,Lora Lewis,Margaret B. Morgan,Irene Newsham,Jireh Santibanez,Jeffrey G. Reid,Lisa R. Trevino,Yuan Qing Wu,Min Wang,Donna Muzny,D Wheeler,Richard A. Gibbs,Gad Getz,Michael S. Lawrence,Kristian Cibulskis,Andrey Sivachenko,Carrie Sougnez,Douglas Voet,Jane Wilkinson,Toby Bloom,Kristin G. Ardlie,T. J. Fennell,Jennifer Baldwin,S. Gabriel,Eric S. Lander,Li Ding,Robert S. Fulton,Daniel C. Koboldt,Michael D. McLellan,Todd Wylie,Jason Walker,Michelle D O'Laughlin,David J. Dooling,Linnea Fulton,Rachel Abbott,Nathan D. Dees,Qizhou Zhang,Cyriac Kandoth,Michael C. Wendl,William Schierding,D. Shen,Chris Harris,Heather K. Schmidt,Joelle Kalicki,Kimberly D. Delehaunty,Catrina Fronick,Ryan Demeter,Linda S. Cook,John W. Wallis,Ling Lin,Vincent Magrini,Jennifer S. Hodges,James M. Eldred,Shaleigh Smith,Craig Pohl,Fabio Vandin,Benjamin J. Raphael,George M. Weinstock,Elaine R. Mardis,Richard K. Wilson,Matthew Meyerson,Wendy Winckler,Roeland Verhaak,Suzie Carter,Craig H. Mermel,Gordon Saksena,Huy V. Nguyen,Robert C. Onofrio,Diana D. Hubbard,Sonal Gupta,Andrew Crenshaw,Alex H. Ramos,Lynda Chin,Alexei Protopopov,Juinhua Zhang,T. M. Kim,Ilana Perna,Yonghong Xiao,Hailei Zhang,Gang Ren,Narayanan Sathiamoorthy,Richard W. Park,Eunjung Lee,Peter J. Park,Raju Kucherlapati,Devin Absher,Lindsay L. Waite,Gavin Sherlock,James D. Brooks,Jun Li,Jian Xu,Richard M. Myers,Peter W. Laird,Leslie Cope,James G. Herman,Hui Shen,Daniel J. Weisenberger,Houtan Noushmehr,Fei Pan,Timothy J. Triche,Benjamin P. Berman,D. J. Van Den Berg,Jonathan D. Buckley,Stephen B. Baylin,P. Spellman,Elizabeth Purdom,Pierre Neuvial,Henrik Bengtsson,Lakshmi Jakkula,Steffen Durinck,Junhong Han,Shannon Dorton,Henry Marr,Y. G. Choi,V. Wang,N. J. Wang,J. Ngai,John G. Conboy,Bahram Parvin,Heidi S. Feiler,Terence P. Speed,Joe W. Gray,Nicholas D. Socci,Yanke Liang,Barry S. Taylor,Nikolaus Schultz,Laetitia Borsu,Alex E. Lash,Cameron Brennan,Agnes Viale,Chris Sander,M. Ladanyi,Katherine A. Hoadley,Shaowu Meng,Ying Du,Yan Shi,Lulin Li,Yidi J. Turman,D. Zang,E. B. Helms,Saianand Balu,Xiang Zhou,Jane Y. Wu,Michael D. Topal,David N. Hayes,Charles M. Perou,Junihua Zhang,Chaowei Wu,Sachet A. Shukla,Andrey Sivachenko,Rui Jing,Yingkai Liu,Michael S. Noble,Hannah Carter,D. Kim,Rachel Karchin,James E. Korkola,Laura M. Heiser,Raymond J. Cho,Zhi Hu,Ethan Cerami,Adam B. Olshen,Boris Reva,Yevgeniy Antipin,Ronglai Shen,Parminder K. Mankoo,Rachael Sheridan,Giovanni Ciriello,William K. Chang,J. A. Bernanke,David Haussler,Christopher C. Benz,Joshua M. Stuart,Stephen C. Benz,John Zachary Sanborn,Charles J. Vaske,Jingchun Zhu,Christopher Szeto,Gary K. Scott,Christina Yau,Matthew D. Wilkerson,Nianxiang Zhang,Rehan Akbani,Keith A. Baggerly,W. K. Yung,John N. Weinstein,Troy Shelton,Dirk Grimm,Martha Hatfield,Shannon R. Morris,Peggy Yena,P. Rhodes,Mark E. Sherman,Joseph Paulauskis,S. Millis,Ari B. Kahn,John M. Greene,Robert Sfeir,Mark A. Jensen,John W. Chen,Jon Whitmore,Shelley Alonso,Justin T. Jordan,Anna L. Chu,Jinghui Zhang,Anna D. Barker,Carolyn C. Compton,Greg Eley,Martin L. Ferguson,Peter Fielding,Daniela S. Gerhard,R. Myles,Carl F. Schaefer,K. R. Mills Shaw,Jim Vaught,J. B. Vockley,Peter J. Good,Mark S. Guyer,Bradley A. Ozenberger,Jessica L. Peterson,E. Thomson +261 more
TL;DR: The Cancer Genome Atlas project has analyzed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours as mentioned in this paper.
Journal ArticleDOI
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Helen E. Bryant,Nilklas Schultz,Huw D. Thomas,Kayan M. Parker,Dan Flower,Elena Lopez,Suzanne Kyle,Mark Meuth,Nicola J. Curtin,Thomas Helleday,Thomas Helleday +10 more
TL;DR: It is proposed that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair and exploited in order to kill BRCA2-deficient tumours by PARP inhibition alone.
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