Molecular Approaches to Controlling Cancer

Symposium Participants v Dedication xxiii Foreword xxv

Cancer Genetics and Genomes

Oncogenes Come of Age H. Varmus, W. Pao, K. Politi, K. Podsypanina, and Y.-C.N. Du 1 Common and Contrasting Genomic Profiles among the Major Human Lung Cancer Subtypes G. Tonon, C. Brennan, A. Protopopov, G. Maulik, B. Feng, Y. Zhang, D.B. Khatry, M.J. You, A.J. Aguirre, E.S. Martin, Z. Yang, H. Ji, L. Chin, K.-K. Wong, and R.A. DePinho 11 “Lineage Addiction” in Human Cancer: Lessons from Integrated Genomics L.A. Garraway, B.A. Weir, X. Zhao, H. Widlund, R. Beroukhim, A. Berger, D. Rimm, M.A. Rubin, D.E. Fisher, M.L. Meyerson, and W.R. Sellers 25 Polygenic Inherited Predisposition to Breast Cancer B.A.J. Ponder, A. Antoniou, A. Dunning, D.F. Easton, and P.D.P. Pharoah 35 Somatic Mutations in Human Cancer: Insights from Resequencing the Protein Kinase Gene Family P.A. Futreal, R. Wooster, and M.R. Stratton 43 High-Resolution ROMA CGH and FISH Analysis of Aneuploid and Diploid Breast Tumors J. Hicks, L. Muthuswamy, A. Krasnitz, N. Navin, M. Riggs, V. Grubor, D. Esposito, J. Alexander, J. Troge, M. Wigler, S. Maner, P. Lundin, and A. Zetterberg 51 Ductal Pancreatic Cancer in Humans and Mice D.A. Tuveson and S.R. Hingorani 65 Detection of Oncogenic Mutations in the EGFR Gene in Lung Adenocarcinoma with Differential Sensitivity to EGFR Tyrosine Kinase Inhibitors R.K. Thomas, H. Greulich, Y. Yuza, J.C. Lee, T. Tengs, W. Feng, T.-H. Chen, E. Nickerson, J. Simons, M. Egholm, J.M. Rothberg, W.R. Sellers, and M.L. Meyerson 73 Two Decades of Cancer Genetics: From Specificity to Pleiotropic Networks S. Grisendi and P.P. Pandolfi 83

DNA Damage Response

Abnormalities of the Inactive X Chromosome Are a Common Feature of BRCA1 Mutant and Sporadic Basal-like Breast Cancer S. Ganesan, A.L. Richardson, Z.C. Wang, J.D. Iglehart,A. Miron, J. Feunteun, D. Silver, and D.M. Livingston 93 The ATM-dependent DNA Damage Signaling Pathway R. Kitagawa and M.B. Kastan 99 Single-Nucleotide Polymorphisms in the p53 Pathway S.L. Harris, G. Gil, W. Hu, H. Robins, E. Bond, K. Hirshfield, Z. Feng, X. Yu, A.K. Teresky, G. Bond, and A.J. Levine 111 Transcriptional Regulation by p53 and p73 M. Lokshin, T. Tanaka, and C. Prives 121 p53-Dependent and -Independent Functions of the Arf Tumor Suppressor C.J. Sherr, D. Bertwistle, W. den Besten, M.-L. Kuo, M. Sugimoto, K. Tago, R.T. Williams, F. Zindy, and M.F. Roussel 129 Exploiting the DNA Repair Defect in BRCA Mutant Cells in the Design of New Therapeutic Strategies for Cancer A.N.J. Tutt, C.J. Lord, N. McCabe, H. Farmer, N. Turner, N.M. Martin, S.P. Jackson, G.C.M. Smith, and A. Ashworth 139

Cancer Biology and Stem Cells

Identifying Site-specific Metastasis Genes and Functions G.P. Gupta, A.J. Minn, Y. Kang, P.M. Siegel, I. Serganova, C. Cordón-Cardo, A.B. Olshen, W.L. Gerald, and J. Massagué 149 The von Hippel-Lindau Tumor Suppressor Protein: Roles in Cancer and Oxygen Sensing W.G. Kaelin, Jr. 159 The Src Substrate Tks5, Podosomes (Invadopodia), and Cancer Cell Invasion S.A. Courtneidge, E.F. Azucena, Jr., I. Pass, D.F. Seals, and L. Tesfay 167 Modeling Neurofibromatosis Type 1 Tumors in the Mouse for Therapeutic Intervention L.F. Parada, C.-H. Kwon, and Y. Zhu 173 Stem Cell Self-Renewal and Cancer Cell Proliferation Are Regulated by Common Networks That Balance the Activation of Proto-oncogenes and Tumor Suppressors R. Pardal, A.V. Molofsky, S. He, and S.J. Morrison 177 Prostate Stem Cells and Prostate Cancer D.A. Lawson, L. Xin, R. Lukacs, Q. Xu, D. Cheng, and O.N. Witte 187

Telomeres, Senescence, and Aging

Telomere-related Genome Instability in Cancer T. de Lange 197 Telomerase and Cancer Stem Cells M. Armanios and C.W. Greider 205 Regulation of Telomerase by Human Papillomaviruses D.A. Galloway, L.C. Gewin, H. Myers, W. Luo, C. Grandori, R.A. Katzenellenbogen, and J.K. McDougall 209

Animal Models for Cancer

Genomic Progression in Mouse Models for Liver Tumors A.D. Tward, K.D. Jones, S. Yant, M.A. Kay, R. Wang, and J.M. Bishop 217 Genotype–Phenotype Relationships in a Mouse Model for Human Small-Cell Lung Cancer J. Calbó, R. Meuwissen, E. van Montfort, O. van Tellingen, and A. Berns 225 Cell Cycle and Cancer: Genetic Analysis of the Role of Cyclin-dependent Kinases M. Barbacid, S. Ortega, R. Sotillo, J. Odajima, A. Martín, D. Santamaría, P. Dubus, and M. Malumbres 233 Mouse Models of Human Non-Small-Cell Lung Cancer: Raising the Bar C.F.B. Kim, E.L. Jackson, D.G. Kirsch, J. Grimm, A.T. Shaw, K. Lane, J. Kissil, K.P. Olive, A. Sweet-Cordero, R. Weissleder, and T. Jacks 241 Generation and Analysis of Genetically Defined Liver Carcinomas Derived from Bipotential Liver Progenitors L. Zender, W. Xue, C. Cordón-Cardo, G.J. Hannon, R. Lucito, S. Powers, P. Flemming, M.S. Spector, and S.W. Lowe 251 Oncogene-dependent Tumor Suppression: Using the Dark Side of the Force for Cancer Therapy G.I. Evan, M. Christophorou, E.A. Lawlor, I. Ringshausen, J. Prescott, T. Dansen, A. Finch, C. Martins, and D. Murphy 263 Chromosomal Translocation Engineering to Recapitulate Primary Events of Human Cancer A. Forster, R. Pannell, L. Drynan, F. Cano, N. Chan, R. Codrington, A. Daser, N. Lobato, M. Metzler, C.-H. Nam, S. Rodriguez, T. Tanaka, and T. Rabbitts 275 Deciphering Cancer Complexities in Genetically Engineered Mice K. Simin, R. Hill, Y. Song, Q. Zhang, R. Bash, R.D. Cardiff, C. Yin, A. Xiao, K. McCarthy, and T. Van Dyke 283

Gene Expression and Cancer

The Evolving Portrait of Cancer Metastasis P.B. Gupta, S. Mani, J. Yang, K. Hartwell, and R.A. Weinberg 291 Genomic Binding and Transcriptional Regulation by the Drosophila Myc and Mnt Transcription Factors A. Orian, S.S. Grewal, P.S. Knoepfler, B.A. Edgar, S.M. Parkhurst, and R.N. Eisenman 299 Regulation of the Arf/p53 Tumor Surveillance Network by E2F P.J. Iaquinta, A. Aslanian, and J.A. Lees 309 Genetic and Epigenetic Changes in Mammary Epithelial Cells Identify a Subpopulation of Cells Involved in Early Carcinogenesis H. Berman, J. Zhang, Y.G. Crawford, M.L. Gauthier, C.A. Fordyce, K. McDermott, M. Sigaroudinia, K. Kozakiewicz, and T.D. Tlsty 317 Epigenetic Changes in Cancer and Preneoplasia J.G. Herman 329 A Genetic Approach to Cancer Epigenetics A.P. Feinberg 335

Tumor Responses to Microenvironment

Microenvironmental Regulators of Tissue Structure and Function Also Regulate Tumor Induction and Progression: The Role of Extracellular Matrix and Its Degrading Enzymes M.J. Bissell, P.A. Kenny, and D.C. Radisky 343 How Do Cancer Cells Acquire the Fuel Needed to Support Cell Growth? C.B. Thompson, D.E. Bauer, J.J. Lum, G. Hatzivassiliou, W.-X. Zong, D. Ditsworth, F. Zhao, M. Buzzai, and T. Lindsten 357 Mitochondria and Cancer: Warburg Addressed D.C. Wallace 363 Inductions of Complete Regressions of Oncogene-induced Breast Tumors in Mice R. Benezra, E. Henke, A. Ciarrocchi, M. Ruzinova, D. Solit, N. Rosen, D. Nolan, V. Mittal, and P. de Candia 375 The Fibroblastic Coconspirator in Cancer Progression M. Egeblad, L.E. Littlepage, and Z. Werb 383

Angiogenesis

Is Oncogene Addiction Angiogenesis-dependent? J. Folkman and S. Ryeom 389 Structural Basis for the Functions of Endogenous Angiogenesis Inhibitors M.A. Grant and R. Kalluri 399 VEGF Trap as a Novel Antiangiogenic Treatment Currently in Clinical Trials for Cancer and Eye Diseases, and VelociGene-based Discovery of the Next Generation of Angiogenesis Targets J.S. Rudge, G. Thurston, S. Davis, N. Papadopoulos, N. Gale, S.J. Wiegand, and G.D. Yancopoulos 411

Discovering Cancer Targets

Molecular Targeted Therapy of Lung Cancer: EGFR Mutations and Response to EGFR Inhibitors D.A. Haber, D.W. Bell, R. Sordella, E.L. Kwak, N. Godin-Heymann, S.V. Sharma, T.J. Lynch, and J. Settleman 419 Aberrant Gene Silencing in Tumor Progression: Implications for Control of Cancer S.B. Baylin and W.Y. Chen 427 Dissecting Cancer Pathways and Vulnerabilities with RNAi T.F. Westbrook, F. Stegmeier, and S.J. Elledge 435 Emerging Approaches in Molecular Profiling Affecting Oncology Drug Discovery S.H. Friend 445 Screens Using RNAi and cDNA Expression as Surrogates for Genetics in Mammalian Tissue Culture Cells J. Pearlberg, S. Degot, W. Endege, J. Park, J. Davies, E. Gelfand, J. Sawyer, A. Conery, J. Doench, W. Li, L. Gonzalez, F.M. Boyce, L. Brizuela, J. LaBaer, D. Grueneberg, and E. Harlow 449 Cancer Targets in the Ras Pathway P. Rodriguez-Viciana, O. Tetsu, K. Oda, J. Okada, K. Rauen, and F. McCormick 461

Therapeutic Approaches

Subversion of the Bcl-2 Life/Death Switch in Cancer Development and Therapy J.M. Adams, D.C.S. Huang, A. Strasser, S. Willis, L. Chen, A. Wei, M. Van Delft, J.I. Fletcher, H. Puthalakath, J. Kuroda, E.M. Michalak, P.N. Kelly, P. Bouillet, A. Villunger, L. O’Reilly, M.L. Bath, D.P. Smith, A. Egle, A.W. Harris, M. Hinds, P. Colman, and S. Cory Making Progress through Molecular Attacks on Cancer C.L. Sawyers 479 Predicting Clinical Benefit in Non-Small-Cell Lung Cancer Patients Treated with Epidermal Growth Factor Tyrosine Kinase Inhibitors L.C. Amler, A.D. Goddard, and K.J. Hillan 483 Exploiting the p53 Pathway for the Diagnosis and Therapy of Human Cancer D.P. Lane 489 Drugging the Cancer Kinome: Progress and Challenges in Developing Personalized Molecular Cancer Therapeutics P. Workman 499 Modeling of Protein Signaling Networks in Clinical Proteomics D.H. Geho, E.F. Petricoin, L.A. Liotta, and R.P. Araujo 517 Summary: The Beginning of the End of Frustration T. Jacks 525

Author Index 529

Subject Index 531