Index

Page numbers in italics denote fi gures, those in bold denote tables.

A1 cyclin 140, 280 alanine transaminase 512 angiogenesis 158, 207, 209, 403, 429–37 A2 cyclin 140 alcohol 96–7 clinical outcomes 436–7 Abelson mouse leukemia 193 aldehyde dehydrogenase see ALDH future directions 436–7 abiraterone 483, 540 ALDH 304, 305, 454 general principles 430, 431 ABL 98, 195, 196 ALDH2 87 pathological 430–1, 432 abraxane 453, 533–4 alemtuzumab 63, 480, 484, 538 angiogenesis inhibitors 436, 450, 450, 485, 493, Abraxas 333 ALK growth factor receptor 168, 169, 170, 197 536–7, 537 ABT-510 485 molecular targeting 486 angiogenic switch 158, 432 ABT-737 484, 541 ALK oncogene 196 stimulation of 432–6 ABT-888 542 alkaline phosphatase 512 angiography 520 ACTH 44 alkyl sulphonates 532 angiopoietin 435 ectopic production 46 alkylating agents 52, 441–2, 442, 531–2 angiostatin 18, 429, 436, 485 α-actinin 230 see also individual drugs aniline dyes 94 actinomycin D 534 all-trans-retinoic acid (ATRA) 157, 419 animal models see cancer models; mouse models of activation-induced cell death (AICD) 424 alleles 71 tumorigenesis; and specifi c animal models active pharmaceutical ingredients (APIs) 456 allodynia 547 annexin A1 566 acute lymphoblastic leukemia 62 ALN-APC 496 anoikis 25, 27, 222, 271, 404–5 chromosomal analysis 513 ALN-PCS02 496 control of acute lymphoblastic lymphoma 263 ALN-RSV01 496 cell adhesion and growth factor receptors acute myeloid leukemia (AML) 62, 170, 305 ALN-TTR02 496 405–6 chromosomal analysis 513 ALN-VSP 496 integrins 406 acute promyelocytic leukemia (APL) 157, 378 5-α reductase inhibitors 57, 483 anorexia 549, 549 adamantine 452 α-fetoprotein 502, 512, 513 ANRIL 369 adaptive immunity 411 alternative lengthening of telomeres (ALT) 296, 310 antagomirs 373, 495 adenocarcinoma 11 alternative reading frame see ARF antagonistic pleiotropy 301 adenoma 11 Alvocidib see fl avopiridol anthracyclines 52, 448, 534 adenoma-carcinoma sequence 80, 106, 107 am11 197 anti-androgens 57 adenoviruses 99 amentofl avone 483 anti-CD20 antibodies 443 adherens junctions 230 Ames test 98 anti-CTLA-4 antibodies 425 adhesomes 387, 389, 389 amethopterin see methotrexate anti-Delta-like 4 ligand (DLL4) antibodies 305 adjustment disorders 550 AMG102 541 anti-MiRNAs 262 adjuvant chemotherapy 531 aminoglutethimide 539 anti-PD-1 antibodies 425 adoptive therapy 422–3 aminopeptidase-P 566 anti-STAT3 drugs 477 adriamycin 61 aminopterin 441, 441 antibody therapy 423, 423 adult T-cell leukemia (ATL) 100 AML1-ETO fusion protein 364 see also specifi c antibodies afatinib 536 AMN107 499 antibody-dependent cell-mediated cytotoxicity Afi nitor see everolimus COPYRIGHTEDAMP-activated protein kinase (AMPK) MATERIAL 177, 303 (ADCC) 413, 443, 488 afl ibercept 537 analgesic ladder 545, 546 anticancer drugs see chemotherapy; and specifi c drugs age, and cancer development 10 anaphase 116, 133 antidiuretic hormone (ADH) 44 agitation 550 anaphase-promoting complex/cyclosome see APC/C antiepileptics 547 AGO14699 542 anaplastic lymphoma kinase (ALK) 169 antigen presentation 413–15, 414, 415 agrin 385 anastrazole 483, 539 antigen-presenting cells (APC) 337, 411, 415 AGTRL1 89 anchorage 148 antigen-specifi c T-cell therapy 422–3 air pollution 96 androgens 172 antigen-specifi c therapy 416, 416, 420–2 Airn 369 deprivation 540 antimetabolites 305, 441, 441, 532–3, 533 AKT 24, 141, 153, 154, 155, 160, 161, 169, 173, receptor antagonists 540 see also individual drugs 226, 378 anesthetic techniques in pain control 547 antipurines 533 see also PI3K–AKT pathway aneuploidy 22, 70, 82, 319, 320, 336 see also individual drugs AKT substrates 176 Angelman’s syndrome 564 antipyrimidines 533, 533 AKT2 174 angioblasts 121, 430, 431, 433 see also individual drugs

The Molecular Biology of Cancer: A Bridge From Bench to Bedside, Second Edition. Edited by Stella Pelengaris and Michael Khan. © 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

603 Index antisense oligo(deoxy)nucleotides (ASOs) 451 asymmetrical cell division 156 BAX family 273–4, 280, 283, 285, 318, 342, 343, antisense therapy 451 AT islands 344 406 antithrombin III 496 AT9283 541 BAY 43–9006 537 anxiety 550 ataxia telangiectasia 85, 141, 252, 336, 345 4-1BB 415 AP endonuclease 1 (APE1) 327 ATF4 282 Bbc3 252 AP23451 488 Atg7 287 BCA2 128 AP23464 488 Atg8 378 BCG vaccine 452 APAF-1 130, 273, 274, 275, 283, 285 Atg12 378 BCL-1 195 Apak 338 athymic nude mice 412, 417 BCL-2 inhibitors 450, 450 APC gene 22, 53, 80, 83, 84, 87, 88, 105, 106, 116, ATM gene 85, 86, 88, 130, 141, 241, 561 BCL-2 oncogene 259, 271 124, 228, 241, 364, 514 ATM protein 252, 318, 322, 333 BCL-2 protein family 82, 98, 197, 199, 209, 235, APC protein 179, 224, 225, 227, 259, 260, 305 inhibitors 142 279–81, 279, 280, 470 APC specifi city factors 124 ATM-CHK2 pathway 318, 320, 322–3, 330, 346 MYC signaling through 284–6 APC/C 123, 126, 128, 129, 130, 132, 133, 135, 138, ATM-CHK2-p53 pathway 322, 325 proapoptotic members 280 320, 337 ATM/ATR 124, 136 prosurvival (antiapoptotic) members 280 APC/CCDC20 337 ATR 318, 322, 333, 346 regulation of apoptosis 280–1, 281 apoptosis 7, 24, 26–7, 135, 148, 154, 201, 207, 239, ATR-CHK1 pathway 318, 320, 325, 330, 334 BCL-w 280 267 ATRIP complex 118, 136, 318, 325, 330, 336 BCL-xL 226, 280 as barrier to cancer formation 271 Atu027 496 BclxL 338 BCL-2 protein family 82, 98, 197, 199, 209, 235, AURKA 134, 138, 140–2, 337 BCNU see carmustine 279–81, 279, 280 aurora mitotic kinases 134–5 BCR ligase 129 caspases see caspases and cancer 140–1 BCR–ABL oncogene 368, 474, 504 context 267–71, 268–70 inhibitors 142 BCR-ABL protein 32, 82, 171, 196, 198, 232–5, in diabetes 287 Aurora-A see AURKA 233, 234, 470, 475, 564 IAPs 274, 276–9, 277 autoimmune lymphoproliferative syndrome (ALPS) inhibition of 480 mitochondrial pathway 342 272 molecular targeting 486, 488 MOMP 235, 272, 273, 274, 279–82, 285 autologous tumor cell-based vaccines 421 BCR–JAK2 178 MYC 209, 283–7, 284–5 autophagy 27, 287–90, 289 Beckwith-Weidemann syndrome 23, 85, 363, 366, p53 protein 282–3, 283 and cancer 288–9 564 pathways 272–4, 273, 274 mechanism 288 beclins 27, 288 extrinsic pathway 26, 272–3, 273 signal pathways 288 benign prostatic hypertrophy (BPH) 514 intrinsic pathway 26, 272, 273–4, 273, 274 AUY922 542 benign tumors 384 RAS superfamily 222–3, 223 Avastin see bevacizumab benzodiazepines 547 type I cells 272 avian myelocytomatosis 193 Benzvix 451 type II cells 272 avian sarcoma 17 193 bevacizumab 49, 52–3, 57, 480, 485, 488, 493, see also cell death; necrosis avodart 483 537 apoptosis inducers 425, 541 axitinib 478, 482, 485, 537 Bexaar see tositumomab apoptosis regulators 197, 198–9, 484 AZ703 484 BH3-only family 280, 280, 283 apoptosis-inducing factor 26 5-azacytidine 368 see also BAD; BID; BIK; BIM; BMF; HRK; NOXA; apoptosome 274, 275 AZD1152 484, 541 PUMA apoptotic bodies 270, 272 AZD1840 483 BI 2536 142, 484 apoptotic protease-activating factor 1 see APAF1 AZD2281 542 bi-orientation 133 AR 364 AZD6244 483, 541 BID 272, 280, 342 Arabidopsis thaliana 559 AZD7762 484, 541 BIIB021 542 arabinosides 532–3 aziridines 532 BIK 279, 280, 282, 492 see also individual drugs bilirubin, raised 512 ARF gene 130, 245 B-cell leukemia 82, 470 BIM 130, 233, 280, 282, 285, 378, 475 ARF protein 254, 338 B-cell lymphoma 23, 181, 185, 196, 197, 206, 222, biochemical tests 511–12, 512 functions 254–6, 256 235, 243, 279, 287, 355, 372, 423, 470, 484, biological therapies 410–28, 466 in oncogenic stress 339, 340–1, 340 493, 538, 564 biomarkers 2, 13, 15, 102–3, 368, 501–5, 502, 503, ARF-BP1 342 B-RAF 198 512–13, 513 ARF-HDM2-p53 pathway 133 B7 family 415 cancer stem cells 304 ARF-Mdm2-p53 pathway 256 B12536 541 colorectal cancer 504–5 ARF-p53 tumor suppressor pathways 286 B16727 541 screening 104 arginase 425 bacteria 101 and treatment selection 104–5 ARID1A 351, 353 BAD 169, 173, 174, 175, 176, 222, 223, 233, 234, see also specifi c biomarkers Arimidex see anastrazole 280, 285, 325 biopsy 518–19 aromatase inhibitors 483, 539 BAF180 338 fi ne needle aspiration 518 aromatic amines 95 BAI3 89 incision and excision 518–19 Arpp19 133 BAK 222, 223, 235, 273–4, 279, 280, 281, 282, 286, needle 518 ARQ197 541 288, 342 biotherapy 497 ARRY-142886 477, 541 Bannayan-Zonana syndrome 259 BIR domains 277, 277 arsenic compounds 45 BARD7 357 BIRC2 278 arylamines/amides 95 Barker hypothesis 301 BIRC3 278 Arzerra see ofatumumab Barrett’s esophagus 12, 29 bisphosphonates 57 asbestos 45, 95 basal cell carcinoma 59 bizelesin 344 ASCL1 304 base excision repair (BER) 135, 325, 326–7, 327, BKM120 541 ASF1a 379 335, 475 bladder cancer, susceptibility 88–9 Asn-Gly-Arg tripeptide 485 basement membrane bladder tumor-associated antigen 502 asparaginase 534 adhesive interactions 384–5 blast crisis 486 aspartate transaminase 512 growth and survival signals 386, 386 blenoxane 448 aspirin 90 and polarity 385–6, 386 bleomycin 61, 447–8, 534 ASPP1 342 BAT-25 106 BLM 85 ASXL1 355 BAT-26 106 blood oxygen level (BOLD) 522

604 Index

blood vessels 429, 430 brivanib 537, 541 capecitabine 52, 56, 441, 442, 455 cancer spread through 31 BRM 353, 356 capillaries, cancer spread through 396–7, 397 see also angiogenesis bronchoscopy 519, 519 carboplatin 49, 449, 532 Bloom syndrome 85, 345 BSI-201 542 carcinoembryonic antigen (CEA) 55, 418, 502, 512, BMF 280 Btg proteins 252 513 BMI 304 BUB proteins 123, 138, 337 carcinogenesis, multistage 16–18, 17, 79, 80 BMI-1 gene 367 BUB1 gene 319 carcinogens 91–2, 92, 93 BMI-1 protein 21, 154, 302, 336, 341 BUB1 protein 118, 123, 127, 134, 137, 337, 346 activation 94–5 BMP 178, 182, 184, 241 BUB1–3 137 chemical 94, 95 BMS214662 483 BUBR1 gene 130, 138 lung cancer 45 BMS354825 see dasatinib BUBR1 protein 346 skin cancer 58 BMS536924 483 buprenorphine 546 testing for 98 BMS540215 541 burden of cancer 43–66 see also environmental causes of cancer BMS554417 486 Burkitt’s lymphoma 61, 82, 255 carcinoma 11 BNC2 89 MYC overexpression in 363 carcinoma in situ 11 Bnip3 130 busulfan 63, 532 caretaker genes 24–5, 24, 317, 324 body fl uids, cytological examination 518 carmustine (BCNU) 368, 440, 449, 532 BOK 130, 280 c-ABL 82, 195, 232, 310, 406 Gliadel Wafers 456 bone metastases 494 c-ErbB2 402 CAS 230 bone pain 546 c-ErbB3 402 CASP-3 130 bone-localizing α-emitting agents 497 c-FOS gene 362 CASP-7 130 BOPP 451 c-FOS protein 173, 184, 218, 234, 235 CASP-8 418 borealin 134 c-kit 168, 170, 232, 304, 478, 479, 502 caspases 26, 252, 272, 274–6, 276, 276 BORIS 360, 366 inhibition of 480, 482, 485, 537 effector (executioner) 274–5, 276 bortezomib 376–7, 484, 493, 493, 538, 541 c-MET 149, 168, 401, 402 inhibition 277–8, 277 bosutinib 479, 488 antibodies 478, 484, 485 initiator 274–5, 276 bowel obstruction 548–9, 549 c-MYC see MYC molecular targeting 496 bowel pain 546 c-MYCER system 469 procaspases 275, 276 53BP1 318, 336 C-reactive protein 512 Castleman disease 99 brachytherapy 527 c-sis 164 catching cancer 31–2 prostate cancer 57 c-SRC see SRC β-catenin 376, 393, 418 Bradford Hill, Austin 73–6, 78 C/EBP homologous protein (CHOP) 282 molecular targeting 496 BRAF 32, 58, 90, 106, 194, 198, 220, 366 C20orf126 570 β-catenin-WNT 394 mutations 224 CA-15–3 502, 513 cause and effect 70–1 brain tumors 511 CA-19–9 502, 512, 513 causes of cancer 16–21 BRCA1 2, 14, 15, 22, 52, 71, 77, 84, 91, 104, 105, CA-27–9 502 cells of origin 18–20, 19 241, 318, 333, 334–5, 363, 364, 504, 514, 556, CA-125 104, 502, 512, 513 clonal evolution theory 16 561 CAAX motif 215 multistage carcinogenesis 16–18, 17 synthetic lethality 476 cabozantinib 541 CAV-1 489 BRCA1-A complex 333 cachexia 44, 549, 549 Cbl 128 BRCA1-BARD1 333 cadherins 393–4 Cbx7 367 BRCA2 2, 14, 15, 22, 52, 71, 77, 84, 91, 104, 105, see also specifi c cadherins CCCTC-binding factor (CTCF) 366 241, 333, 334–5, 363, 364, 504, 514, 556, Caenorhabditis elegans 267, 268–9, 370, 556, 557 CCL21 397 561 CAGE 363 CCND1 87, 140 BRD2 357 CALAA-01 452, 496 CCND2 204, 205, 207 BRD4 357, 365 calcitonin 44, 502, 512, 513 CCNE1 88 BRD4-NUT oncoprotein 365 calpains 208 CCNU see lomustine BRD7 338 Campath see alemtuzumab CCR2 414 breast cancer 49–53, 334–5 camptothecin 448, 448, 534 CCR6 414 BRCA mutation see BRCA1; BRCA2 cancer biology 3–42, 5 CCR7 397, 413, 414 clinical features 50, 50, 511 cancer cells 1 CD4 411, 411, 413, 415, 416 diagnosis and investigations 50–1 heterogeneity 466–7 CD8 411, 411, 413, 415, 416–17 familial 84, 91, 514 life history 9 CD13 485, 576 genetic testing 513 cancer environment 28–9 CD14 421 HER2 mutation 14, 467 cancer genes 559–62 CD20 418, 423 incidence 8, 49 see also specifi c genes antibodies 443, 484 molecular classifi cation 467 cancer models 557–9 CD22 423 mortality 43, 49 mouse see mouse models of tumorigenesis CD24 304 pathology 50 cancer pain syndromes 546–7, 547 CD25 417 RB pathway 248 cancer pathways 18 CD28 415, 424 risk factors 49–50 cancer profi ling 367–8 CD33, antibodies 484 staging 51 cancer road-map 189, 474 CD34 304, 421 susceptibility 83, 86 cancer stem cells (CSCs) 1, 6, 18, 19, 20, 106, CD36 413 treatment 51–3 178–9, 298, 303–6, 464 CD40 413, 414, 421 chemotherapy 52–3 markers for 304 CD44 21, 304, 373 hormone therapy 53, 539 targeting of 20–1 CD52, antibodies 484 PARP inhibitors 2 cancer susceptibility syndromes 345–6 CD80 413, 414, 415 radiotherapy 51–2, 52 see also specifi c syndromes CD83 413, 414 surgery 51, 463–4 cancer therapy see chemotherapy; radiotherapy; CD86 413, 414, 415 triple-negative 467, 486, 488 surgery; and specifi c cancer types CD90 304 breathlessness 547 cancer-initiating cells (CICs) 106 CD95 see FAS ligand Breslow staging of malignant melanoma 58 cancer-testis antigens 420 CD105 304 BRG1 353 canertinib 478 CD117 see c-kit BRIP1 86, 345 canine transmissible venereal tumor (CTVT) 31 CD133 21, 304

605 Index

CD166 21, 304 cell-cell signaling junctions 394–5 chromatin 131, 203, 324, 353, 354, 378–9, 556 CDC5C 330 cells of origin 18–20, 19 molecular targeting 484 CDC6 130 cellular differentiation 157–8 remodeling 364–5 CDC7 see DDK terminal differentiation 158 chromatin immunoprecipitation see ChIP CDC7/Dbf4 kinase 132 cellular information fl ow 35 chromatin remodeling factors 356 CDC20 129, 133, 337 cellular networks 569–70, 571, 572 chromatolysis 267 CDC25 133, 336 cellular senescence see senescence chromium 45 CDC25A 330, 336 CENP-A 137 chromosomal instability (CIN) 106, 319 CDC25B 330, 336, 337 centromere proteins 337, 489 chromosomal passenger complex (CPC) 137 CDC25C 336 centromeres 137–8 chromosomal translocations 81, 82 CDC42 30, 226, 402 centrosomal cycle 118 chromosomes 114, 115 CDH1 364 centrosomes 133–4 segregation in mitosis 133 CDH13 364 CEQ508 496 chronic lymphocytic leukemia (CLL) 23, 62 CDK1 133 cervical cancer 60 chromosomal analysis 513 CDK2 300 screening 103–4, 514 chronic myeloid (myelogenous) leukemia (CML) CDK4 195, 246 cetuximab 56, 478, 480, 488, 535, 536 82, 170, 195 CDK4 kinase 420, 418 Ch14.18 484 BCR-ABL signaling 234 CDK6 246 CH401 monoclonal antibody 484 chromosomal analysis 513 CDK7 328 chaperones 344 CI1033 478 CDKN1B 140, 241 checkpoints 117, 118, 119–20, 126, 135, 136, CI1040 477 CDKN1C 469 336–43 cilengitide 494–5, 495 CDKN2 368 in cancer 141 CIMP 106, 363, 365–6, 365 CDKN2A 85, 87, 132, 241, 363, 365 G1/S 120, 121, 131–3, 136–7 CIP/KIP family 125, 126, 126, 246 CDKN2B 363, 469 G2/M 120, 122, 136 circadian rhythms 31 CDKN2C 241 inhibitors 142 circulating tumor cells (CTCs) 52, 405, 488, 523–4 cDNA 562 organ-size 154–5 cisplatin 49, 60, 305, 444–5, 445, 446, 532 CDR3 420 spindle 120, 123, 137–8 CKS 204 Cdt1 115, 129, 132, 320 see also specifi c checkpoint genes/proteins Claspin 318, 330 cediranib 489, 537 checkpoint effectors 316 classifi cation of cancer 11 celecoxib 90 checkpoint mediators 316 clinical features of cancer 510–11 cell adhesion 139, 179–80, 179, 383–409, 384 checkpoint sensors 124, 318 breast cancer 50, 50, 511 control of anoikis 405–6 checkpoint transducers 316, 318 colorectal cancer 55, 511 extracellular matrix 384–93 CHEK2 86, 105, 336 lung cancer 511 cell adhesion molecules (CAMs) 394 chemical carcinogens 94, 95 lymphoma and leukemia 510 cell cycle 111–45, 113, 127, 207, 244 Chemistry, Manufacturing, and Control (CMC) neurological tumors 511 and cancer 139–41 program 456 prostate cancer 56–7 cancer therapy effects 141–2 chemokines 211, 387, 397, 411, 413, 494 clinical trials 506 checkpoints 117, 118, 119–20 chemokine receptors 414 fi rst-in-man studies 506 DNA replication 6, 115, 131–5 chemoprevention 90 immunotherapy 425 entry 138–9 chemoradiation 530 vaccines 422–3, 423 global gene expression 139 chemoresistant niche 20 clofarabine 441, 442 inhibitors 484, 490, 490, 541 chemosaturation 497 clonal evolution theory 7, 16, 20 mitosis 22, 116, 133 chemotherapy 15–16, 438–60 clusterin 451 phases of 120–3 breast cancer 52–3 coanalgesia 547, 547 proteins 124 and cell cycle 141–2 cobalt gamma ray machines 527 regulation 117, 150–1, 151 and cell death 290, 290 Cockayne syndrome 329 translational control 184–5 cervical cancer 60 Cockayne syndrome proteins 328 see also specifi c elements colorectal cancer 56 Coco 182 cell cycle engine 123–4, 150 combination chemotherapy 530 cohesin 124, 134 inhibitors of 125–6 cytotoxic drugs 531–5 Coley, William 410 cell death 266–94 drug delivery 452 collagen 385 apoptosis see apoptosis drug development 442–57 fi brillar 387 autophagy 27, 287–90, 289 indications 530–1 collective cell migration 403–4, 405 and cancer control 290–2, 291 individualization of 33–4 colon cancer see colorectal cancer endoplasmic reticulum stress 220, 222, 282 leukemia 63 colonoscopy 515, 515 historical perspective 267 lung cancer 49 colorectal cancer 53–6 mitotic catastrophe 290 neoadjuvant 531 biomarkers 504–5 necrosis 26–7, 267, 270, 271–2 new agents 541–2 clinical features 55, 511 oncogenic stress 26, 126, 209, 283–7, 284–5, 323–4 non-Hodgkin lymphoma 62 diagnosis 54, 54, 55 programmed 267, 269 rationale 530 epigenetics 370 response to cancer therapy 290, 290 resistance to see drug resistance familial 91 cell differentiation 208–9 targeted see targeted therapy and genomic instability 346 cell division, asymmetrical 112, 156 see also specifi c drugs incidence 8, 53 cell plasticity 158 chick chorioallantoic membrane (CAM) 432, 433 mortality 43 cell proliferation see entries beginning with growth chicken erythroleukemia 193 multistage carcinogenesis 80 cell senescence 295–313 chimeric proteins 584 risk factors 53 cell size regulation 155 ChIP 203 screening 54 cell stress 126 ChIP on Chip 559, 560, 564 staging 54–5, 54 cell suicide see apoptosis CHK1 330 susceptibility 82, 84 cell surface toponome 575–6, 575 CHK2 130, 330, 333, 338, 561 treatment 55–6 cell-cell interactions 393–5, 393 chlorambucil 63, 440, 449, 532 chemotherapy 56 cadherins 393–4 cholangiocarcinoma (CCA) 101 radiotherapy 55 β-catenin-WNT 394 CHOP see C/EBP homologous protein targeted therapy 488 desmosomes 394 CHOP regimen 62, 538 combination chemotherapy 530

606 Index

combinatorial molecular phenotypes (CMPs) 572, CYP171A 540 desmoplastic small round cell tumor (DSRCT) 573, 576 cystic fi brosis transmembrane conductance regulator 367 combretastatin A 485 (CFTR) gene 556 desmosomes 394 communication with patients 544–5 cytarabine 441, 442 detection of cancer 13–4 blocking strategies 545 cytochrome c 235, 266, 272, 273–4, 273, 275, 279, see also biomarkers; diagnosis; screening comparative genome hybridization 22 280, 281, 282–3, 283, 284, 288, 342 Developmental Therapeutics Program (DTP) 441, comparative genomic hybridization arrays 559, 560, cytochrome P450-dependent monooxygenases 446, 493 564 (CYPs) 94 dexamethasone 549 COMPARE algorithm 444 see also specifi c CYPs diabetes 287 complement-mediated cytotoxicity (CMC) 443 cytokeratins 502 DIABLO/Smac 274 complementary DNA see cDNA cytokines 162 diacylglycerol (DAG) 170 Compton scatter 526 immune response 411 diagnosis 44, 509–25 computerized tomography (CT) 497, 516–17, 517 signal pathways 177–8 angiography 520 conformal radiation therapy (CRT) 497 cytokine therapy 423–4 clinical symptoms 510–11 connective tissue growth factor 496 IL-2 423–2 fl ow cytometry 522–3 constipation 549 IL-7 and IL-15 424 fl uorescent in situ hybridization 523 contact inhibition 148, 395 IL-12 424 interventional radiology 520 continuous hyperfractionated accelerated IL-21 424 investigations 511–15 radiotherapy (CHART), lung cancer 49 interferons 424 molecular pathology 522 COP9 128 cytokinesis 116 radionuclide imaging 520–1, 521, 522 cost-benefi t ratio 36 cytomegalovirus 99 see also staging; and specifi c cancer types Cowden syndrome 83, 85, 174, 177, 259 cytoplasmic polyadenylation element-binding diamorphine 546 COX-2 364 protein (CPEB) 373 dibenzanthracene (DBA) 94, 95 COX-2 inhibitors 89, 491–2 cytoplasmic regulators 196 diet 75, 76, 96–7 CpG islands 242, 352, 353, 360, 362–3, 368, 380, cytosine, methylation of 352 diethylstilbestrol 540 556 cytostatic signals 150 differential methylated regions (DMR) 366 CpG island methylator phenotype see CIMP cytotoxic (CD8) T cells 416–17 differentiation therapy 157 CpG island microarrays 559, 560, 564 cytotoxic drugs 531–5 diffusion weighted MRI 522 creatinine, raised 512 alkylating agents 52, 441–2, 442, 531–2 difl uoromethylornithine (DFMO) 90 CREB-binding protein (CBP) 220 antimetabolites 305, 441, 441, 532–3, 533 dihydrofolate reductase (DHFR) 130, 441, CREBBP 356 enzymes 534 532 Cripto-1 182 mitotic inhibitors 533–4 dihydrotestosterone 540 crizotinib 169, 478, 541 platinum compounds 448–9, 449, 532 dioxins 95 crk 196 topoisomerase inhibitors 534 disability-adjusted life years see DALYs crossing over 22 see also chemotherapy; and individual drugs DISC see death-inducing signaling complex cryosurgery cytotoxic T lymphocyte-associated antigen 4 see diurnal rhythms 31 prostate cancer 57 CTLA-4 DKK4 505 squamous cell carcinoma 59 DLC1 (deleted in liver cancer 1) 227–6 CTGF 30 dacarbazine 59, 61, 489, 532 DLL4 436 CTLA-4 415 dacomitinib 478 DMP1 241 antibodies 484 DALYs 36 DNA 77, 556 CTNNB1 106 damage-regulated autophagy modulators (DRAM) complementary (cDNA) 562 CUL1/CUL1 128, 204 27 endoreplication 115 cullin-RING E3 ubiquitin ligases (CRLs) 128 DAPK 364, 368 junk 316, 352 CXCL12 397 darinaparsin 453 methylation 243, 359–60, 359, 360, 361, CXCR4 305, 397 dasatinib 63, 478, 479, 482, 488, 489, 499, 541 362 CYC202 541 molecular target 477 noncoding (ncDNA) 23, 352 cyclic reversible termination 565 resistance 501 repair 2, 135 cyclin B-CDK1 complex 336 daunorubicin 448, 534 replication 6, 115, 131–5, 244 cyclin D1 179, 198, 226 DAXX 364 synthesis 126 cyclin-dependent activating kinase (CAK) 205, 246 Dbl 196 DNA damage 24, 141, 316 cyclin-dependent kinase inhibitors (CKIs) 119, 123, DCC 84 checkpoints see checkpoints 124, 125, 127, 142, 246, 248, 362 DCGR8 261 life-death decisions 337–8, 338 and cancer 125, 141 DDB1 328 radiotherapy 346 CIP/KIP 125, 126, 126, 246 DDK 124, 132 response to see DNA repair INK4 125, 126, 126, 204 death ligands 291 signaling of 325 cyclin-dependent kinases (CDKs) 117, 120, 123, death receptor pathway 26, 272–3, 273 DNA damage sensors 316, 324–5 124, 125, 125, 127, 132, 150, 203, 204 death-inducing signaling complex (DISC) 272, 9-1-1 complex 325 and cancer 125, 140 284 ATRIP 118, 136, 318, 325, 330, 336 cyclins 117, 120, 123, 125, 127 dedifferentiation 20 KU80 141, 318, 322, 324, 331, 325, 333 and cancer 125, 140 defi nition of cancer 8, 10–1 DNA methyltransferases (DNMTs) 23, 205–6, 352, cyclizine 548 degradation of proteins 126, 128–9 355, 556 cyclodextrin 452 degrons 128 inhibitors of 477 cyclophosphamide 62, 305, 440, 449, 454–5, 454 delayed gastric emptying 547–8 DNA microarrays see microarrays CYP1A1 87, 95 deletions 17, 80, 82 DNA mismatch repair 22, 23, 106, 135, 318, 325, CYP1B1 87 Deltex 180 329–30, 329, 343 CYP2A6 87 dendritic cells 411, 411, 413, 414 DNA polymerases 130, 336 CYP2B6 455 dendritic cell vaccines 421 DNA repair 136, 260, 286, 299, 317, 321–4, 322–4, CYP2C9 455 5'-deoxy-azacytidine (decitabine) 368 325–36, 326, 527 CYP2C19 455 depression 550 double-strand breaks 330–3, 331–2 CYP2E 87 Dermo 255 fragile sites 325–6 CYP3A4 455 Desert Hedgehog pathway 489 molecular targeting 490–2 CYP17 87 desmocollins 394 PARP 35, 333, 335–6 CYP19 87 desmogleins 394 short telomeres 310

607 Index

single-strand breaks 326–30 E1 140 epigenetic factors 6, 23, 105–6 base excision repair 135, 325, 326–7, 327, 335, E2 140 drugs targeting 368 475 E2F oncogene 190 epigenetics 157, 242, 353–9 mismatch repair 22, 23, 135, 325, 329–30, E2F transcription factors (E2F1–5) 129–8, 244 and cancer 362–5, 364 329, 343 E2F-associated phospho-protein (EAPP) 130 chromatin 131, 203, 324, 353, 354 nucleotide excision repair 135, 325, 327–9, E2F1 oncogene 255 clinical uses 367–8 328, 345 E2F3a 244 cancer profi ling 367–8 stalled replication forks 330, 331 E2F3b 244, 245 drug therapy 368 translesional synthesis 326, 330 E2F6 245 historical perspective 358 stem cells 336 E2F7 245 regulator genes 355–7 transcription-coupled repair 325, 328 E6 oncoprotein 344 molecular targeting 492–3, 493, 537–9 DNA segments with chromatin alterations E7 oncoprotein 344 epigenome 352 reinforcing senescence (DNA-SCARS) 299 early-response genes 204 epigenomics 559 DNA synthesis 204 4EBP-eIF4E 475 epimutagens 366 DNA viruses 25, 98–100 effector cells 413–17 epimutations 1, 2, 6, 8, 21 see also specifi c viruses dendritic cells 411, 411, 413, 414 critical 24 DNA-dependent protein kinase (DNA-PK) 333 natural killer (NK) cells 291, 411, 417 drug resistance 500 DNMT1 gene 363 T cells see T cells epirubicin 534 DNMT1 protein 355, 359 Tregs 29, 417 epithelial cell transforming sequence 2 (ECT2) 227 DNMT3a protein 352, 355, 359 effector kinases 124 epithelial-mesenchymal transition (EMT) 1, 178–9, DNMT3b gene 363 EGF 148, 149, 160 296, 305–6, 399, 401–2, 401, 467 DNMT3b protein 355, 359 EGFR gene 90, 168, 193, 194, 195, 196, 214, 224, epothilones 534 docetaxel 49, 57, 447, 533 368, 475, 502 epoxyeicosatrienoic acids (EETs) 492 DOCK180 402 EGFR 21, 32, 45, 101, 105, 106, 147, 149, 167, Epstein-Barr virus 99, 413, 418 dominant 71, 189–90 168–71, 184, 195, 196, 197, 227, 229, 377, Hodgkin disease 60 domperidone 547 477, 569 latent membrane proteins (LMPs) 420 donor lymphocyte infusions (DLI) 422 EGFR inhibitors 89, 535–6, 536, 537 ER 364 dormant cancer cells 464 EGFR-RAS-MAPK system 181 ErbA1 197 double strand breaks (DSBs) 283, 316, 318, 527 EHMT2 355 ErbA2 197 repair 330–3, 331–2 Ehrlich, Paul 443, 465 ErbB gene 98 double-minute chromosomes 81 eIF3E 175 ErbB family 32–3, 168, 535 dovitinib lactate 537 EKB-569 478 anti-ErbB monoclonal antibodies 477–8, 478, doxorubicin 62, 305, 448, 448, 534 elastin 387 488 doxycycline 468 electrons 527 ErbB1 see EGFR DPC4 84, 241 Elk-1 378 ErbB2 see HER2 Drosha 261 Eloxatin see oxaliplatin ErbB4 88 Drosophila melanogaster 556, 557 embryonal rest theory 19 Erbitux see cetuximab Hippo signaling pathway 183–4, 184 embryonic stem cells (ESCs) 113, 302–3 ERCC1 328 Notch signaling pathway 180 Emi1 130 Erks 393 drozitumab 541 EML4-ALK fusion gene 486 erlotinib 32, 49, 478, 481, 499, 535–6, 536 drug delivery 452 EMT see epithelial-mesenchymal transition molecular target 477 drug design 438–42 end-replication problem 296 resistance 498, 499 historical perspective 439–42, 440–2 endogenous inhibitors of angiogenesis 436 ERTAM 210, 211, 468, 584 drug development 442–57 endometrial cancer 172 erythrocyte sedimentation rate (ESR) 511 lead compounds 443–53 endonuclease G 26 erythropoietin 44, 149 lead optimization 453–6 endoplasmic reticulum stress 220, 222, 282 estrogen receptors 467, 502 target selection 443, 468 endoplasmic reticulum stress elements (ERSEs) estrogens 171–2 timeline 442 282 and cancer 97 see also individual drugs endoreplication 115 etoposide 534 drug resistance 2, 34–5, 473 endoscopic retrograde cholangiopancreatography ETS family 170, 172, 197, 198, 216, 217, 218, 234, chemoresistant niche 20 (ERCP) 519 261 downstream mutations 499 endoscopic ultrasound 516 euchromatin 353, 354 epimutations 500 endoscopy 519 European Medicines Agency (EMEA) 457 mutations or changes in drug target protein endostatin 18, 429, 436 European Randomized Study of Screening for 498–9 endothelial cell progenitors (EPCs) 430 Prostate Cancer 103 switching of oncogene dependence 499 endothelial cell proliferation inhibitors 485 everolimus 483, 541 target defi nition in 501 entosis 321 Ewing, James 439 targeted therapy 487, 497–501, 498 environmental causes of cancer 93–101 exemestane 483 drug targeting see targeted therapy individual risk factors 93–4 exercise 76 DSBs see double-strand breaks see also specifi c causes expression analysis 559 DTIC see dacarbazine enzastaurin 483 EXT1 364 Dukes’ staging 101–2 enzyme inhibitors 483, 541 extracellular matrix (ECM) 139, 162 colorectal cancer 54 EP300 356 adhesive interactions 384–93, 385 duplications 82 EpCAM 304 basement membrane 384–6 dyads 115 EPH receptor family 395, 435 fi brillar collagen 387 dying patients 550 EPH-ephrin signaling pathway 394, 435 GAGs 387 dynamic contrast enhanced CT (DCE-CT) 518, 522 EPHA3 88 integrins and adhesomes 387, 389, 389 dynamic contrast enhanced MRI (DCE-MRI) 518 ephrins 394, 395, 435 stromal-epithelial interactions 387 dynein 134 EPIC (European Prospective Investigation into degradation 403 DYRK2 338 Cancer and Nutrition) study 75, 95–6 elasticity 389, 391, 391, 392–3 Dyskeryn 310 epidemiology 8, 73–6 p53-ATM responsiveness 406 epidermal growth factor see EGF transmembrane proteoglycan receptors 389 E-cadherin 30, 179, 229, 363, 394, 399–401 epidermal growth factor receptor see EGFR extrinsic pathway of apoptosis 26, 272–3, 273 E-twenty six family see ETS family epidural catheters 547 EZH2 355, 367, 563

608 Index

F-box proteins 128 fl utamide 57 gene expression signature 33, 398, 563 FADD 272, 275 FM165 449 gene gun 421, 422 FAK 230, 278, 391, 406 FM190 449 gene knockouts 558, 582–4 false-negative diagnosis 103 fms 196 gene rearrangements 80 false-positive diagnosis 103 FMS-like tyrosine kinase 3 receptor (FLT3) 170 gene silencing 359, 359, 368 familial adenomatous polyposis coli (FAP) 53, 83, focal adhesion kinase see FAK hypermethylation 362–3, 364 84, 259–60, 514 focal adhesions 230 gene therapy 495–7, 538–9 screening 105 folate antagonists 532 gene-environment interactions 89, 91 familial cancer syndromes 514 folic acid 441 genetic locus 70 see also specifi c syndromes Food and Drug Administration (FDA) 457 genetic testing 14, 15, 513, 513, 514 familial hypercholesterolemia (FH) 72 forkhead transcription factors 131, 176 genetics of cancer 21, 70, 78–89 FANCA 345 FOS 98, 197, 198 mutations see mutations FANCB 345 Foscan 451 see also oncogenesis FANCA-FANCH 85 14-3-3 proteins 325 genome-wide association studies (GWAS) 72, 74, FANCD1 gene see BRCA2 14-3-3δ 363 88–9 FANCD2 gene 345 FOXC 178 genomic instability 260, 314–49 FANCD2 protein 118, 136, 137, 318 FOXO 24, 153, 167, 173, 174, 176, 216, 221, 233, cancer susceptibility syndromes 345–6 FANCE 318 234 chaperones 344 FANCF 318 FoxO3a 133, 340, 378 colorectal cancer 346 FANCG 318 Fra 179 radiation-induced 229 FANCI 318 fragile sites 325–6 telomere attrition 27, 154, 306, 321–4 FANCJ 318 frameshift mutations 80 types of 319–20, 320 FANCL 318 Frizzled 394 see also DNA repair; mutations Fanconi anemia 83, 85, 318, 345–6 FUB1 378 genomic mutations 105 Fanconi anemia proteins 345 fulvestrant 483, 539 genomics 87–9, 559 Farber, Sidney 441 functional MRI 522 genotoxic stress 25, 126 farnesyl transferase (FTase) 215, 489 FWT1 367 genotype 14, 71 farnesyl transferase inhibitors (FTIs) 215, 477, 489 FWT2 367 genotype-dependent lethality 464 FAS ligand 29, 291, 342 geranylgeranyl transferase (GGT) 489 FAS receptor 272 G-protein coupled receptors 89, 161, 170–1, 194, geranylgeranyl transferase type I (GGTase-I) FAS-associated death domain see FADD 196 215 Fas-like inhibitor protein see FLIP molecular targeting 489 germline mutations 242 Faslodex see fulvestrant G-proteins, membrane-associated 161 gip 196 FAT 364 G0/G1 transition 132 Gleason system 56 FAT10 378 G1 cyclin 124 Gleevec see imatinib fatigue 549 G1/S checkpoint 120, 121, 131–3, 136–7 GLI 198 Fbw7 128–9, 376 G2/M checkpoint 120, 122, 136 GLI1 182, 259, 305 Fbxw7 128 GADD45 136 GLI2 182, 298, 470 FdUMP 533, 533 GADD45A 130 GLI3 182 fecal occult blood 502, 515 GAGE 418 Gliadel Wafers 456 fentanyl 546 GAGs 387 glial cell line-derived neurotrophic factor (GDNF) fes 196 galactosyltransferase 389 169 FGF 149, 160, 306, 434–5 galectin-1 29, 425 glial-derived neurotropic factor (GDNF) 85, 149, FGFR 170 gantetespib 542 169, 196 antibodies 484 gap junctions 394 glioblastoma 164 FGFR1 194 GAPs see GTPase-activating proteins RB pathway 248 FGFR3 194 Gardner’s syndrome 53 glioma 367 fgr 196 gastric cancer, mortality 43 global genome repair (GGR) 328–9 fi brillar collagen 387 gastrin 171 glucuronosyltransferases 94 fi brillin 387 gastrointestinal stromal tumor (GIST) 32, 170 glutathione S-transferases (GST) 94 fi brin 502 GATA-4 364 glycogen synthase kinase 3 (GSK-3) 176 fi broblast growth factor see FGF GATA3 467 glycogen synthase-3β (GSK-β) 394 fi bronectin 387, 391 GATA5 364 glycolysis 159 fi bulin 385 GD2 antibodies 484 glycosylation 557, 569 fi eld cancerization 497 gefi tinib 32, 49, 90, 478, 480–1, 485, 499, 535, 536 GM-CSF 421 fi eld effect 29–30 resistance 498, 501 Goldie–Coldman hypothesis 530 fi gitumumab 486 GEFs see guanine nucleotide exchange factors gonadotrophin-releasing hormone agonists/ fi nasteride 483 geldanamycin 448 antagonists 539 fi ne needle aspiration (FNA) 518 gemcitabine 49, 52, 305, 441, 442, 532 Good Laboratory Practice (GLP) 456 Finsen, Niels 450 gemtuzumab 480, 484 Good Manufacturing Practice (GMP) 456 fi rst-in-man studies 506 gender and cancer incidence 8 Gorlin syndrome 85, 182, 259 fl avopiridol 484, 490, 490, 541 genes 77 goserelin 53, 57, 483 Flemming, Walther 267 cancer-causing see oncogenes gp100 418 FLICE inhibitory protein (FLIP) 284 cancer-relevant 161 graft-versus-host disease (GVHD) 422 FLIP 376, 425 caretaker 24–5, 24, 317, 324 granzymes 417 fl ow cytometry 522–3 see also specifi c genes granzyme B 291 Flt3 170 gene amplifi cation 81, 193 green fl uorescent protein (GFP) 570 fl udarabine 441, 442, 532–3 gene chips see microarrays GRM8 89 fl uorescence microscopy 573 gene expression growth fl uorescence-activated cell sorting (FACS) 579 epigenetic regulation 361–2 arrest 299 fl uorescent in situ hybridization (FISH) 523 profi ling 419 homeostasis 151–5, 152–4, 258–60, 258–60 5-fl uoro-2 deoxyuridine monophosphate see FdUMP regulatable systems 583–4 MYC 204–6, 205 5-fl uorouracil 56, 441, 442, 533 signatures 33 RAS superfamily 217 mechanism of action 533 “tet” system 210, 211, 468, 584 regulated/deregulated 155–7, 156

609 Index growth factors 139, 147, 148, 149, 160–4, 162, 163, hemoglobin, low 512 HPC1 85 164, 194, 196 hepadnaviruses 98–9 hPMS1 53 activation 175 hepatocyte growth factor (HGF) 304 hPMS2 53 and cancer 163–4 EMT activation 401–2 HPP1 365 cell cycle regulation 150–1, 151 HER 368 HRAS gene 87, 95, 194, 201, 214, 474 mechanism of action 162 Her-2-neu 418 HRAS protein 222, 470, 472, 489 oncogenes 164 HER1 see EGFR HRAS1 193, 195 signaling pathways 32, 160 HER2 14, 51, 168, 194, 195, 196, 467, 475, 488, HRK 280 see also signal transduction pathways 502 Hrk/DP5 130 stromal 387 HER2 tyrosine kinase receptor 423 HSPs see heat shock proteins targeted therapy 482–5, 483–5 HER2-Neu receptor tyrosine kinase 476 HST 196 vascular 432–6 HER3 196 HSTF1 195 see also specifi c growth factors HERC2 335 HtrA2/Omi 273, 278 growth factor receptor tyrosine kinases 165, 167, Herceptin see trastuzumab human chorionic gonadotrophin β(β-HCG) 502, 167 hereditary cancer syndromes 78, 82–6, 83, 512, 513 growth factor receptors 163, 194, 196, 197 84–5 human double minutes (HDMs) 338 control of anoikis 405–6 hereditary nonpolyposis colorectal cancer see Lynch Human Genome Project 164, 564–5 GSK461364 142, 484, 541 syndrome human immunodefi ciency virus (HIV) 100 GSK1070916 541 hereditary papillary renal cancer (HPRC) 85 human nonmetastatic gene 23 (Nm23-H1) 494 gsp 196 herpesviruses 99 human papillomavirus (HPV) 8, 15, 99, 344, 413, GSTM1 87 heterochromatin 353, 354, 360 418 GSTP1 87, 364, 368 heterogeneity of cancer cells 466–7 cervical cancer 60 GTPase exchange factors 196 effect on therapy 467 human T-cell leukemia viruses (HTLVs) 100 GTPase-activating proteins (GAPs) 165, 215 single cells 467 hyaluronan 387 GTPases heterozygosity 70 hydromorphone 546 NF-1 260 loss of 22, 22, 240 5-hydroxyindoleacetic acid (5-HIAA) 513 RAS superfamily 213, 214–5, 217 Hexvix 451 hydroxyurea 63, 534 RHO family 225–8, 226 HGF 149, 226 hyperalgesia 547 guanine 445 HGF inhibitors 541 hypercalcemia 512, 548, 548 guanine nucleotide exchange factors (GEFs) 165, HGS1029 541 hypermethylation 362–3, 368 215 HIC1 363 gene silencing 362–3, 364 HIFI 226 hyperparathyroidism, tertiary 155 H-RAS 98, 198 high-intensity focused ultrasound (HIFU) 497 hyperpathia 547 H2AFX 563 high-penetrance mutations 71 hyperplasia 395–6, 396 H2AFZ 563 high-throughput screening (HTS) 443 hypoalbuminemia 512 H2AX 141, 318, 325, 332–3, 336 highly conserved genes 70 hypokalemia 512 H3K9triMe 301 HIPK2 338 hypomethylation 363 H19 369 Hippo proteins 183–4, 183, 184, 271 hyponatremia 512 HA14-1 450, 450 HIRA 379 hypoxia 305 Haddow’s paradox 439 Hirschsprung’s disease 169 hypoxia-inducible transcription factor (HIF) Hakai 399 histology 101–2, 403 375 halichondrin B 448 breast cancer 399 hallmarks of cancer 37, 37 Hodgkin disease 60 IAPs see inhibitor of apoptosis proteins haloperidol 548 NSCLC 466–7 90Y-ibritumomab tiuxetan 443, 538 haploinsuffi ciency 22, 71, 190, 240, 242 histone acetyl transferases (HATs) 352, 356, 360–2, IC486241 484 haplotypes 561, 561 559 ICAM-1 415 HapMap 560–1, 579 histone code 352, 361, 364 ICAT 566, 567, 568 Harvey rat sarcoma 193 histone deacetylases see HDACs ICOS 415 haspin 134 histone lysine deacetylases see sirtuins idarubicin 534 HATs see histone acetyl transferases histones 203, 324, 354 ifosfamide 49, 454–5, 454 HAUSP 376 acetylation 360–2, 361, 365 IGFs 44, 149, 160, 366, 387 Hayfl ick limit 27, 296, 300 demethylation 355 and cancer 163 hCDC4 337 methylation 355, 361 IGF-1 receptor 169 HDACs 208, 245, 252, 263, 352, 356, 360 hit-and-run models 584 IGF-binding proteins (IGFBPs) 162, 164 HDAC inhibitors 477, 542 hit-to-lead phase 443 IGF2 360 HDM2 128 HIV-1 Rev-binding protein (Hrb) 100 IGFBP2 489 HDM2 ligase 375 HJURP 137 IGFBP3 164, 364 heat shock proteins (HSPs) 475, 570 HLA-DR 414 IKK-NFκB 330 and cancer 379 HMGA2 23, 372 IL-1β 210 inhibitors of 493, 542 hMLH1 53, 364 IL-2 415, 423–4 stress-inducible 282 HMN-214 142 IL-6 20, 178 HECT 128 hMSH2 53 IL-7 424 Hedgehog signaling pathway 21, 59, 157, 178, 182, HNPCC 91 IL-8 29 298, 489 Hockenbery, David 259 IL-12 424 HeLa cells 27, 70 Hodgkin disease 60–1, 60, 61 IL-15 424 Helicobacter pylori 25, 93, 101 homologous recombination 324, 331–2, 333 IL-21 424 helper (CD4) T cells 416 homozygosity 70 image-guided radiotherapy (IGRT) 529 hematological malignancies 60–3 hormone therapy imaging 516–8 Hodgkin disease 60–1, 60, 61 breast cancer 53, 539 computerized tomography 497, 516–7, 517 leukemia 8, 11, 23, 62–3 prostate cancer 57, 539–40 future uses 521–2 non-Hodgkin lymphomas 61–2 Horvitz, H. Robert 267, 268–9 magnetic resonance imaging 517–8, 518 hematological tests 511–2, 512 HOTAIR 369 plain fi lm X-ray 516 hematopoietic stem cells (HSCs) 303, 304 HOXA9 364 radionuclide imaging 13, 520–1, 521, 522 hemi-desmosomes 389 HOXD1 89 ultrasound 516, 522

610 Index

imatinib 32, 34, 63, 90, 170, 232, 475, 478, 480, interferon-γ 412–3 Kaposi’s sarcoma herpesvirus (KSHV) 99 485, 486, 535 interleukins see IL karyotype 70, 115 discovery of 479 International Agency for Research on Cancer KAT2B 356 molecular target 477 (IARC) 8 KAT5 356 resistance 498, 501 interphase 116 KDM2B 355 IMC-18F1 537 interventional radiology 520 KDM4 355 IMC-1121b 537 intra-S-phase checkpoint 120 KDM4C 355 immortalization 258, 299–301 intrathecal catheters 547 KDM5A 355 immune evasion 419, 424–5 intrinsic pathway of apoptosis 26, 272, 273–4, 273, KDM5B 355 immune privilege 29, 164 274 KDM5C 355 immune response 278, 411–3 intusseption 430 KDM6A 355 adaptive immunity 411, 411 invasion 395–6, 397–9 KDR see kinase insert domain receptor cancer immunosurveillance 412–3 integrins in 402–4, 403, 404 ketamine 547 danger signal 411 MMPs in 402–4, 403, 404 killer activating receptors (KARs) 417 immunosuppression 413 molecular targeting 493–4 killer inhibitory receptors (KIRs) 417 innate immunity 411, 411 see also metastasis kinase insert domain receptor (KDR) 88, 170 molecular targeting 495 inversions 81–2 kinesin 134 immunocytes 29 investigations 511–5 kinesin spindle protein 496 immunodefi ciency, and non-Hodgkin lymphoma 61 angiography 520 kinetochores 115, 116, 133, 134, 137–8, immunologic ignorance 425 biomarkers 2, 13, 15, 102–3, 368, 501–5, 502, 337 immunosuppression 413 503, 512–3, 513 King, Frank 443 immunosurveillance 412–3 cancer stem cells 304 kinome 537 immunotherapy 410–28, 538 colorectal cancer 504–5 KIP1 241 antigen-specifi c 416, 416 screening 104 KIP2 85 clinical trials 425 and treatment selection 105 KISS1 30 imprinting 366–7 biopsy 518–9 KIT 32, 170, 194, 196 imprinting control region (ICR) 366 bronchoscopy 519, 519 KITLG 87, 89 INCENP 134, 138 colonoscopy 515, 515 Klf4 87, 131, 209, 304 INCEP 134 endoscopy 519 knockout (KO) mice 558, 582–4 incidence of cancer 5, 8, 10 fecal occult blood 502, 515 Knudson, Alfred G. 240 incident pain 546 genetic tests 513, 513, 514 Korsmeyer, Stanley 259 incision/excision biopsy 518–9 hematological and biochemical tests 511–2, 512 KP1019 453 Indian Hedgehog pathway 489 imaging 516–8 KRAS 14, 23, 45, 95, 106, 194, 196, 366, 470, 474, individualized medicine see personalized medicine interventional radiology 520 502 infl ammation 27, 28–9 mammography 50, 50, 103, 514 KRAS2 195 ING proteins 356, 366–7 radionuclide imaging 520–1, 521, 522 Kruppel-like factor 4 (KLF4) 182 inheritance 21–2, 77 screening 12, 102–3, 513–4 KS3 196 inhibitor of apoptosis proteins (IAPs) 274, 276–9, cervical cancer 103–4, 514 KU-55933 142 277, 376, 492 colorectal cancer 54 KU-60019 142, 484 caspase inhibition 277–8, 277 genomic mutations 105 KU70 136, 141, 318, 330, 331, 332, 333, cell survival 278 MEN 105 334 inhibition of 278–9 opportunistic 12 KU80 141, 318, 322, 324, 331, 325, 333 and metastasis 278 population 12 KU86 297, 308 inhibitory protein of cyclin-dependent kinase 4 see prostate cancer 514–5 INK4 ionizing radiation 96 L-BLP25 483 iniparib 483, 542 IPI-504 542 lactate dehydrogenase 502, 513 initiation 20, 94 ipilumumab 484 Lamarck, Jean-Baptiste 23, 358 INK4 proteins 125, 126, 126, 246 Iressa see gefi tinib lamellipodia 402 INK4a gene 241 irinotecan 56, 448, 448, 449, 488, 506, 534 laminin 385, 389 INK4a protein 254 ISG15 378 lapatinib 52, 478, 481–2, 535, 536 functions 254–5 isotopecoded affi nity tagging see ICAT laser capture microdissection (LCMD) 579 INK4a/ARF 29, 141, 254–7 ixabepilone 534 late S-phase cyclin 124 in cancer 256, 257 latency-associated peptide (LAP) 387 locus 254, 255 Jagged1 306 latent niche 21 mouse models 256–7, 257 JAK-STAT pathway 160, 177–8 LATS/WARTS protein kinase 271 INK4b 254 inhibitors 490 LATS1 271 INK4c 241 JAK2 194 LATS2 271 innate immunity 411, 411 JAK–STAT–SOCS pathways 177 LBH589 542 insertions 80 Janus kinases (JAKs) 177 LDE225 489 insulin receptor 169 JARID-1 361 lead compounds 442, 443–53 insulin-like growth factors see IGFs JARID-1A 305 selection of INT1 195 JARID-1B 304 antisense therapy 451 INT2 164, 195, 196 jelly belly ligand 169 natural products 445–8 integrated stress response (ISR) 282 Jesionek, Albert 450 pharmacological tools 449–50 integrins 148, 386, 387, 389, 389, 391 JUN gene 98, 197, 198 photodynamic therapeutics 450–1 cell invasion 402–4, 403, 404 JUN protein 128, 179, 184 RNA interference 451–2 control of anoikis 406 JUN kinase 172 serendipity 444–5 in signal transduction 389, 390 JUN N-terminal kinase interacting protein (JIP1) 1, vaccines 452 in tumor formation 391 172 see also individual drugs integrin antagonists 494–5, 495 JUN N-terminal kinase (JNK) 230 lead optimization 442, 453–6 intensity-modulated radiotherapy (IMRT) 497, 529, junk DNA 316, 352 lenolidamide 538 529 leptin 139, 482 interferons 424 K-RAS 198, 213–4, 216, 223, 224 lestaurtinib 483 interferon-α 59, 63 KAI1 30 Let7 495

611 Index letrozole 483, 539 Lynch syndrome 22, 53, 71, 83, 84, 106, 321, 330, melphalan 440, 449, 532 leukapheresis 416 365, 514 membrane-associated G-proteins 161 leukemia 11, 62–3 screening 105 membrane-associated nonreceptor tyrosine kinases chromosomal analysis 513 lysosomes 352 161 clinical features 510 memory T cells 411, 412, 412 incidence 8 M-CSF 149 MEN see multiple endocrine neoplasia see also specifi c types M-phase cyclin 124 MEN 241 levomepromazine 548 M-phase-promoting factor 133 MEN1 15, 85, 105, 170, 356, 364, 376, 514 levorphanol 546 MabThera see rituximab MEN2 85, 170, 514 Levulan 451 McDonough feline sarcoma 193 Mendel, Gregor 77 LFA-1 415 MAD see MXD family menin 333, 364 Lhermitte-Duclos disease 259 mad1–3 137 66-mercaptopurine 441–2, 442, 533 Li-Fraumeni syndrome 22, 78, 83, 84, 91, 253, 254, MAD2 130, 137 Merkel cell carcinoma (MCC) 100 336, 514 MAGE 363 mesothelioma 45, 96 genetic testing 513 MAGE-1 417, 418 messenger RNA see mRNA screening 105 MAGE-3 418 MET inhibitors 541 lifestyle factors 96–7 MAGE-A3 422 MET oncogene 85, 195, 196, 501 see also diet; smoking magnetic resonance imaging (MRI) 517–8, 518 MET tyrosine kinase 168–9 lifestyle interventions 14–5, 75 diffusion weighted 522 metabolic switch 159–60, 159 LIN28 23, 373 functional 522 metabolism 207 LIN28B 23, 372 major histocompatibility complex (MHC) 31, 413, metabolizer phenotype 505 linear accelerators 527 415 metaphase 116 linkage (association) studies 560 malignant tumors 384 metaphase plate 116, 134 lipid kinases 161 hallmarks of 396 metastasis 1–2, 9, 10, 30–1, 44, 384, 395–9 liquid chromatography 567 Maml1 306 hyperplasia 395–6, 396 liquid-based cytology (LBC) 103 Maml2 306 IAPs 278 lithocholic acid 172 mammalial target of rapamycin see mTOR invasion and dissemination 395–6, 397–9 liver cancer, mortality 43 mammography 50, 50, 103, 514 micrometastasis 398, 400 liver capsule pain 546 mantle cell lymphomas, RB pathway 248 molecular targeting 493–4 liver kinase B1 (LKB1) 158 MAP2K4 89 metastasis suppressor genes (MSGs) 30, 398–9 LKB1 177 MAPK pathway 161, 172, 216 metastasis-associated protein 1 (MTA1) 306 LKB1–STK11 364 MAPKAP kinases 130, 318 metformin 90, 97, 162, 482 LMO1 87, 89 mapsin 372 methadone 546 LMYC 197 Marek’s disease virus 99 methotrexate 305, 441, 441, 449 lncRNA 369 MARK2 570 mechanism of action 533 lomustine (CCNU) 532 MART1 420 methylation 557 lonafarnib 483 MART1/MelanA 418 methylation mark 361 long noncoding RNA see lncRNA mas 196 metoclopramide 547, 549 long terminal repeats (LTRs) 100 maspin 363 Metvix 451 loss of heterozygosity (LOH) 22, 22, 240 mass spectrometry 567 MGMT 363, 364, 368 loss of imprinting (LOI) 23, 366–7 mast cell growth factor 170 MICA 411, 417 loss-of-function mutations 17, 300 Mastermind-like (MAML) family 181 MICB 417 low- to moderate-penetrance mutations 71 Matrigel 228, 433, 490 microarrays 523, 559 LPHN3 89 matrix metalloproteinases see MMPs data analysis 562 LRP1B 88 matrix-assisted laser desorption ionization (MALDI) microenvironment 28–9 LRRC19 489 567 micrometastasis 398, 400 LTA 87 matuzumab 536 microorganisms and cancer 98–9, 98, 99–101 lung cancer 45–9 MAX 202, 202, 362 microRNAs 23, 131, 203, 260–3, 296, 352, 369–71 clinical features 46–7, 46, 511 maximum tolerated dose (MTD) 453 biology 260–2, 261 diagnosis and staging 47, 48 MBD1 355 molecular targeting 495, 497 incidence 8, 45 MBD2 355 and MYC 206, 207 mortality 43 MBD3 355 and p53 262, 262 non-small-cell see non-small-cell lung cancer MC1R 87 and RB 262, 263 pathology 45–6 MCL-1 226, 280 treatments based on 373 small-cell 46, 47, 248 MCM2–7 helicase 132 microsatellite instability (MSI) 83, 106, 319, 344, treatment 47, 49 MDC1 318, 333 346, 365–6, 365 chemotherapy 49 MDM2 26, 251, 251, 255, 338, 406, 491 microsatellites 343–4 radiotherapy 47, 49 MDM4 250, 251, 338 midkine 169 surgery 47 Mdmx 250 minichromosome maintenance proteins (MCMs) luteinizing hormone-releasing hormone (LHRH) MDR 81 129 antagonists 53 MEDI-577 484 minimal quantitative trait loci 560 Lutex 451 mediator of DMA damage checkpoint protein-1 see minisatellites 343–4 LXCXE motif 245, 248 MDC1 mir-2 372 LY294002 477, 483 medical treatments and cancer 97 mir-10b 373 LY2181308 451 Medicines and Healthcare Products Regulatory mir-31 373 LY2603618 541 Agency (MHRA) 457 mir-34 372, 495 LY2606368 484 medulloblastoma 259 mir-121 373 LY21813081 541 Meier–Gorlin syndrome 132 mir-146a 372 lymphadenopathy 44 meiosis 22, 112, 561 mir-146b-5p 372 lymphatics, cancer spread through 31, 397 MEK-ERK pathway 475 mir-155 372 lymphokine-activated killer cells (LAKs) MEK5b 570 mir-205 372 422 melanoma, malignant 58–9, 58, 257 mir-372 372 lymphoma 11 familial 85 mir-373 372 clinical features 510 MELC/TIS toponomics 571, 573 mir-449 263

612 Index

miRNAs see microRNAs MRE11–RAD50–NBS1 (MRN) complex 332 NAT1 87 mismatch repair (MMR) 22, 23, 135, 325, 329–30, MRI see magnetic resonance imaging natural killer (NK) cells 291, 411, 417 329 MRN 332 natural products 444, 445–8 missense mutations 80 mRNA 556 see also individual drugs mitochondrial outer membrane permeabilization see mRNA expression analysis 562–4 natural selection 21, 70 MOMP MSH2 84, 105, 241, 260, 321, 514 nausea and vomiting 547–8 mitogens 147, 246 mSin3A corepressor 362 chemically induced 548 mitogen-activated protein kinase see MAPK Msm2 195, 197 intractable 548 mitosis 22, 116, 133, 244 MTA1–3 356 NBR1 288 mitotic catastrophe 290 MTHFR 87 NBS1 130, 333, 345 mitotic cell cycle see cell cycle mTOR 27, 154, 158, 167, 176–7, 217 ncDNA 23, 352 mitotic centromere-associated kinesin (MCAK) 134 mTOR inhibitors 57 NCoR1 357 mitotic inhibitors 533–4 multiple endocrine neoplasia (MEN) 85, 169–70, ncRNA 2, 351, 369 see also individual drugs 514 NCT00464113 486 mitotic kinases 133–5 screening 105 NCT00526838 486 and cancer 140–1 see also MEN; MEN1; MEN2 NCT01013506 486 inhibitors 142 multiple susceptibility loci 88–9 necrosis 26–7, 267, 270, 271–2 mitotic spindle 133 multistage tumorigenesis 16–8, 17, 79, 80, 105–6, Nedd4 proteins 180, 377 MIZ-1 204, 205, 286–7, 300, 362 213 Nedd8 proteins 128, 378 MK1775 541 MUM-3 418 needle biopsy 518 MK2206 541 Münchausen Trilemma 6 negative feedback loops 500–1 MK4827 542 mustard gas 439 neoadjuvant chemotherapy 531 MLH1 23, 84, 105, 241, 260, 321, 363, 365, 514 mutagens 94 neovascularization 430–1, 431 MLL 133, 355 mutation rate 25 see also angiogenesis MLN8237 142 mutations 6, 7, 21, 78–82, 79, 89–90, 92, 319 neratinib 536 MMPs 29, 30, 162, 230, 301, 398 frameshift 80 nerve blocks 547 cell invasion 402–4, 403, 404 high-penetrance 71 NESPAS 369 ECM degradation 403 loss-of-function 17, 300 NEU gene 81, 196, 436 growth factor activation 175 low- to moderate-penetrance 71 NEU protein 224, 229, 470 molecular targeting 494 missense 80 neuroblastoma 367 release of tumor-promoting factors 404 nonsense 80 neurofi bromatosis 215 Mms22 330 point 80, 81 type 1 84, 514 MMSET 333 silent 80 type 2 84 MNT-MAX 208 somatic 72, 105–6 neurofi bromin 215 model organisms 557–9 splice-site 80–1 neuropathic pain 546, 547 molecular adaptation 497 mutator phenotype 320–1, 321, 365–6, 365 neuropilin 1 434 molecular classifi cation 88, 367–8, 466–7 MutSβ complex 330 neutrophils 29 breast cancer 467 MUTYH 86, 326 nevaxar 537 future directions 467 MXD family 130, 137, 208–9 new chemical entities 453 molecular pathology 522 MXD-MAX 205, 208 Nexavar see sorafenib molecular signatures 33 MYB oncogene 195, 197, 198 nexin 403 molecular targeted therapies see targeted therapy MYC oncogene 18, 19, 20, 23, 24, 25, 28, 81, 128, next-generation sequencing (NGS) 559, 564–6 MOMP 235, 272, 273, 274, 279–82, 285, 342 158, 179, 190, 195, 197, 198, 199–213, 255, cyclic reversible termination 565 see also BCL-2 protein family 474, 579 454 pyrosequencing 565 MONO-27 106 expression in human tumours 200–2, 201, 363 sequencing by ligation 565 monoclonal antibodies 466, 484 MYC protein 89, 98, 202–13, 202, 226–7, 340, 346 NF-κB 31, 178, 198, 226–7, 299 anti-EGFR 536 apoptosis 209, 283–7, 284–5 activation 278 anti-ERBB 478 cell differentiation 208–9 NF-κBIL2–TONSL 330 anti-VEGF 537 cell growth/proliferation 204–6, 205 NF1 84, 88, 215, 241, 260, 261, 514 tyrosine kinase inhibitors 480, 485–6, 488 and diabetes 287 NF2 84, 241 see also specifi c antibodies and microRNAs 206, 207, 263 NFkBIA 168 morphine 546 regulation of 206, 208 NFY 131 mortality rates 6, 10, 43 signaling through BCL-2 family 284–6 NGF 149 see also specifi c cancer types translation 203–4 nibrin 345 mos 196 tumorigenesis 209–12, 211, 212 Nicd 393 MOSAIC trial 56 levels for 212–3 nickel 45 motesanib 537 mouse models 209–12, 211, 212, 468–73, 470, nidogen 385 mouse embryonic fi broblasts (MEF) 308–9 471 Nijmegen breakage syndrome (NBS) 260, 333, 345 mouse mammary tumor virus (MMTV) 164 MYC-MAX 205, 208 nilotinib 63, 449, 478, 479, 481, 482, 541 mouse models of tumorigenesis 557–9 MYC-RAS cooperation 221 resistance 501 athymic nude mice 412, 417 MYCERTAM 210, 211, 212, 286, 584 nimotuzumab 536 INK4a/ARF 256–7, 257 MYCLK1 195 9-1-1 complex 325, 330 knockout (KO) mice 558, 582–4 MYCN 195 nitrogen mustards 439–40, 440, 532 MYC 209–12, 211, 212, 468–73, 470, 471 Mycobacterium bovis 452 see also individual drugs MYCERTAM 210, 211, 212, 286, 584 Myelotarg see gemtuzumab nitrosoureas 532 osteosarcoma 193 mypomagnesemia 512 NM23 30, 31 p53 protein family 253–4, 254 MYST3 356 Nm23-H1 494 P388 (leukemia) model 443 MYT1 336 NMp22 502 RAS superfamily 224–5, 225 NMYC 197 RB protein family 248–50, 249 N-acetyltransferases (NAT) 94 Nodal signaling pathway 182 resistance and recurrence 473 N-CoR–SMRT 362 Nolvadex-D see tamoxifen MPS1 337 N-RAS 198 nomenclature 11 MR spectroscopy 522 NAMI-A 453 non-Hodgkin lymphomas 61–2 MRE11 333, 336 Nanog 209, 304, 305 non-oncogene addiction 474, 475

613 Index non-small-cell lung cancer (NSCLC) 27, 29, 32, 45 senenescence induced by 27–8, 219–20, 221 functions of 252 histological and molecular classifi cation 466–7 signal transducers see signal transduction and microRNAs 262, 262 RB pathway 248 pathways molecular targeting 491, 491, 496 staging 47, 48 targeting of 473–5, 473 mouse models 253–4, 254 surgery 47 as tumor suppressors 28 senescence and immortalization 258, 298 non-steroidal anti-infl ammatory drugs see NSAIDs types of 193–4 see also TP53 noncoding DNA see ncDNA viral 98, 193 p57 85 noncoding RNA see ncRNA see also specifi c oncogenes p57KIP2 246 nonhereditary mutations 72 oncogene addiction 2, 32, 169, 235, 468, 473, 473, p62 288 nonhistone proteins 354 474–5 p63 250, 252 nonhomologous end joining (NHEJ) 308, 324, oncogene-induced senescence (OIS) 27–8 p73 gene 130 331–2, 333, 334, 335 oncogenesis 67–110 p73 protein 250, 252 nonmelanoma skin cancer (NMSC), incidence 8 cancer prevention 14–5, 76–8 p107 130, 135, 243 nonpharmacological treatments 497 cause and effect 70–1 p110 198 see also radiotherapy environmental causes 93–101 p130 130, 243 nonreceptor tyrosine kinases 172, 194–5, 196 gene-environment interactions 89, 91 p130Cas 391 molecular targeting 485–8 genetics 21, 70, 78–89 P276–00 484 nonsense mutations 80 genomics 87–9 paclitaxel 49, 52, 446, 447, 533–4 NORE1 223 mutations see mutations pain control 545–7, 546, 547 Notch pathway 21, 100, 128, 178, 180–2, 181, 304, polymorphisms 22–3, 70, 86–7, 87 analgesic ladder 545, 546 306, 395, 435–6 risk factors 73–6, 90–93, 91, 92 anesthetic techniques 547 Notch-Delta signaling pathway 394, 395 oncogenic stress 26, 126, 209, 283–7, 284–5, 323–4, coanalgesia 547, 547 NOXA 130, 280, 283, 286, 318, 342, 406 338–43, 339–43 PAK1 123 NR-21 106 double-strand breaks 330–3, 331–2 palliative care 544–53 NR-24 106 oncomirs 23, 372, 495 assessment 545 NRAS 194, 195, 196 Oncotype DX Breast Cancer Assay 14, 504 case history 551 Nrf2 transcription factor 500 oncoviruses 100–101 communication with patients 544–5 NSAIDs 90, 491–2, 547 Onocovin see vincristine indications 545 NSB1 260 opioids 546, 546 key concepts 544, 545 NSCLC see non-small-cell lung cancer opportunistic screening 12 supportive care 550–1 NSD1 355 Orf63 protein 99 symptom control NU7026 484 organ-level checkpoints 154–5 bowel obstruction 548–9, 549 nuclear factor see NF origin recognition complex (ORC) 115 cachexia and anorexia 549, 549 nuclear proto-oncogenes 184 orthologues 570 constipation 549 nuclear receptors 161, 171–2 OSI-906 486 dying patients 550 nuclear respiratory factor-1 (NRF-1) 285 ovarian cancer fatigue 549 nucleolar stress 342 biomarkers 105 nausea and vomiting 547–8 nucleophosmin (NPM) 340–1 familial 514 pain 545–7, 546, 547 nucleosomes 353, 354 genetic testing 513 psychological problems 549–50 nucleotide excision repair (NER) 135, 325, 327–9, susceptibility 89 respiratory symptoms 547 328, 345 overdiagnosis 103 pan-deactylase inhibitors (pan-DACi) 492 nucleotide–oligmerization domain family (NOD) overtreatment 103 Pancoast tumor 511 receptors 411 OX40 415 pancreas plasticity 287 NUMB 180, 181 oxaliplatin 56, 449, 488, 532 pancreatic β-cells 158 Nurse, Paul 556 oxidative phosphorylation 159 pancreatic cancer Nutlins 250, 484, 491, 491 oxidative stress 97–8, 476 RB pathway 248 nutrients 139, 148 oxycodone 546 susceptibility 89 and cancer 158 oxygen supply 139, 148 pancreatic ductal adenocarcinoma (PDA) 224 NY-ESO-1 418 oxymorphone 546 panitumumab 478, 488, 535, 536 panobinostat 492, 542 obatoclax 484 p arm 115 Pap smear 502, 514 obesity 15, 27, 36, 57, 73, 75, 86, 90, 92, 93, 96, p14ARF 245, 364 papillomavirus see human papillomavirus 97, 169, 287, 301, 358, 465, 482 p15INK4b 130, 133, 135, 246, 364 Paracelsus 93–4, 93 oblimersen 451 p16 58 paracetamol 547 occupational cancers 94 p16INK4a 25, 130, 132, 135, 246, 254, 255, 286, 363, paraneoplastic syndromes 510 Oct4 209, 305 364 parathyroid hormone (PTH) 44 octreotide 466 cellular senescence 298–9 PARP 35, 333, 335–6 ofatumumab 484 p18INK4c 135, 240, 246 PARP inhibitors 2, 51, 142, 335–6, 476, 538, 542 off-target toxicity 500 p19ARF 29, 254, 255, 255, 286 PARP1 475, 476 OGX-011 451 p19INK4d 135, 246 parthanatos 335 Okazaki fragments 132, 330 p21-activated kinases (PAKs) 225 passenger genes 88 olaparib 483, 538, 542 p21CIP1 26, 130, 135, 136, 252, 298 Patched pathway 179–80, 179, 305, 367, 489 Omi/HtrA2 26, 274 p21Cip1/Waf1 240, 246 pattern recognition receptors 411 Omnitarg see pertuzumab p27KIP1 89, 204, 240, 246, 255 paxillin 230 ON01910 142, 541 p38MAPK-MK2 stress response pathway 330 pazopanib 478, 485, 537 oncogenes 17, 23–4, 71, 188–238, 351 p53 gene 17, 21, 22, 23, 24, 25, 30, 84, 91, 105, PBRM1 357 cellular 193 129, 133, 135, 174, 240, 241, 282–3, 283, 366, Pc2 367 classifi cation 194–9, 195–8 467, 561, 579 Pc4 451 collaboration 199, 200 mutations 253, 514 PCSK9 496 discovery 191 see also p53 protein family PD-1 416 growth factors see growth factors p53 protein family 250–4, 250, 418 PD-L1 416 inactivation of 468, 469 activation 251–2, 251 PD-L2 416 nomenclature 201 and apoptosis 282–3, 283 PD98059 477, 483 products 190 in cancer 252–3, 253, 257–8 PD0325901 477

614 Index

PD332991 484, 541 platelet-derived growth factor receptor (PDGFR) promyelocytic leukemia protein (PML) 82, 157, PDCD4 372 170, 229, 478, 479, 481, 482, 485, 488, 493, 220, 299 PDGFR 170 537 prophase 116 PDGFRA 32, 194 antibodies 484 prostate cancer 29, 56–7 peau d’orange skin 50, 50 platinum compounds 448–9, 532 clinical features 56–7 PEBP1 30 photoactivable 449, 449 diagnosis and staging 57 pegaptanib 480 see also individual drugs hereditary 85 pegvisomant 482 pleiotrophin 169 hormone therapy 57, 539–40 peptide-based vaccines 421 plexopathy 546, 547 incidence 8 perforin 416, 417 PLK1 336, 337 mortality 56 pericytes 429, 430, 436 ploidy 115, 133 pathology 56 perifosine 483 pocket proteins 130, 243–4, 244 screening 514–15 peripheral blood mononuclear cells (PBMCs) 421 podoplanin 304 prostate-specifi c antigen (PSA) 14, 56, 104, 303, PERK 282 point mutations 80, 81 418, 502, 512, 513 permeability transition pore complex (PTCP) polo-like kinases (PLK1) 133, 135, 141, 323 prostatic acid phosphatase (PAP) 421 282 drug targeting 142 PROSTVAC-VF vaccine 495 peroxynitrite 425 polyacrylamide gel electrophoresis, 2D 566, 567, prosurvival proteins 280 personalized medicine 32, 33–4, 36, 102, 107, 474, 568 proteasome 352, 374, 374–5 535, 576 poly(ADP-ribose) polymerase see PARP and cancer 376 pertuzumab 478, 536 polycomb group proteins (PcG) 367 structure 378 Peutz-Jeghers syndrome 53, 83, 84, 177 polycyclic aromatic hydrocarbons (PAHs) 94, 95 therapeutic inhibition 376–7 PF-655 496 in tobacco smoke 95–6 ubiquitin-proteasome system 379 PF-02341066 541 polyethylene glycol 452 proteasome inhibitors 484, 492–3, 493 PF-03814735 484 polygenic diseases 86 proteins PFDN2 570 polymerase chain reaction (PCR) 562 cell cycle 124 phagocytosis 291, 414 polymorphisms 22–3, 70, 86–7, 87 degradation of 126, 128–9 pharmacogenetics 105, 505–6 single-nucleotide see single-nucleotide regulation of 373–6, 374, 375 pharmacogenomics 505–6 polymorphisms see also specifi c proteins Pharmacogenomics Knowledge Base 457 polynucleotide kinase–phosphatase (PNKP) 327 protein arginine methyltransferase 252 pharmacological tools 449–50 polyomaviruses 100 protein complexes 569–70, 571, 572 phenotype 34, 70 polyploidy 321 protein degradation 126, 128–9 mutator 320–1, 321 polyubiquitylation 128 protein expression profi les 34 2-phenylaminopyrimidines 499 population screening 12 protein kinase C 194 Philadelphia chromosome 82, 227, 232–5, 233, 234, positron emission tomography (PET) 520–1, protein phosphatase EYA 333 304 521 protein phosphatase PPA2 208 Phortress 455–6, 456 post-transplant lymphoproliferative disease (PTLD) protein poly(ADP-ribose) polymerase-1 (PARP-1) phosphatase and TENsin homolog on human 413 164 chromosome TEN see PTEN posttranslational modifi cation 215–6, 215, 567, 569, protein tyrosine phosphatases (PTPs) 171, 229 phosphatases 161 569 protein-protein interactions 570, 571 phosphatidylinositol phosphates see PIPs poxviruses 100 proteomics 523, 566–7 phosphatidylinositol 3,4,5-trisphosphate see PIP3 PPARs 172, 308, 492 clinical applications 570–1 phosphatidylinositol-3 kinase see PI3K PR 364 quantitative 566–7, 568 phosphatidylserine 266, 275 prad1 196 tools 567 phosphoenolpyruvate (PEP) 160 Prader-Willi syndrome 564 proto-cancer cells 8 phospholipase Cγ (PLCγ) 219 pRB 130, 135 proto-oncogenes 191, 193, 194, 271, 302 phosphoramide mustard 454–5, 454 pRB2/p130 135 proton radiotherapy 530 phosphorylation 557, 569 PRCA1 85 Provenge see sipuleucel-T photo-electric effect 526 PRDM1 355 psychological problems 549–50 photoactivable platinum compounds 449, 449 PRDM2 355 PTC see Patched pathway Photochlor 451 precancerous lesions 12 PTC1 259 photodynamic therapy 450–1, 497 prednisolone 62 PTCH 59, 85, 241 photofrin 450 preRC 124 PTEN gene 21, 23, 85, 174, 224, 241, 258–9, 258, PI3K 17, 172–4, 174, 176, 198, 216, 224, 233 prereplication complexes 132 261 autophagy 288 prevention 14–5, 76–8 germline mutations 259 PI3K inhibitors 541 chemoprevention 90 PTEN protein 332, 372 PI3K–AKT pathway 31, 150, 158, 160, 167, 215, PRIMA-1 491, 491 ptosis, lung cancer 46 224, 258, 282, 330, 345, 500 prion proteins 101 PTPN12 486 molecular targeting 489–90, 536 PRLR 364 PTPRD 88 RAS signaling 218–9 pro-drugs 453–4 puffer fi sh 557 PI3K–AKT–mTOR pathway 21, 184, 475, 485 proapoptotic proteins 280 pulse-chase techniques 18 PI9 425 procaspases 275, 276 PUMA 130, 252, 280, 283, 286, 318, 338, 342, 343, PIAS1 333 progastrin 171 406 PIAS4 333 progesterone 549 see also Bbc3 PIK3C 194 progesterone receptors 467, 502 Purlytin 451 PIK3CA 467 programmed cell death (PCD) 267, 269 454 pyrosequencing 565 pim1 196 see also cell death pyrrolobenzodiazepines 448, 455–6, 456 PIN1 208 programmed death-1 see PD-1 pyruvate kinase (PKM2) 160 PIPs 367 prolactinoma 171 PIP3 173, 288 prometaphase 116 q arm 115 pituitary adenoma 171 promoters, methylated 243 13q14 deletion 513 PKN3 496 promotion 20, 94 11q23 abnormalities 513 plasmid DNA-based vaccines 421–2 promyelocytic leukemia nuclear bodies (PML NBs) QALYs 36 platelet-derived growth factor (PDGF) 147–8, 149, 344, 377–9 QPI-1002 496 160, 170, 433 and senescence 378–9, 381 quality-adjusted life years see QALYs

615 Index quantitative proteomics 566–7, 568 cellular senescence vs. transformation 219–20 REL 195, 197 quantitative structure–activity relationship (QSAR) differentiation 222 renal carcinoma 57 444 endoplasmic reticulum stress 220, 222 susceptibility 88 quantitative trait loci 560 GTPase 213, 214–15, 217 replication licensing 132 quiescence 158, 220, 244, 246, 258, 298, 303, 432 PI3K–AKT pathway 218–19 replication origins 125 posttranslational modifi cation 215–16, 215 replication protein A (RPA) 330 R-RAS 230 signaling pathways 216–17, 216, 261 replicative senescence 306–7, 306, 307 R115777 483 therapeutic targeting 228 repopulation 527 Raab, Oscar 450 tumorigenesis 224–5, 225, 472–3 respiratory symptoms 547 RAC 30, 216, 402 RAS-like GTPases 219 response evaluation criteria in solid tumors see RAC1 225, 226 RAS-like guanine nucleotide dissociation stimulator RECIST race, and cancer incidence 8 see RALGDS restriction point 131 RAD1 346 RAS-MAPK pathway 167, 184 RET 15, 85, 105, 170, 194, 196, 514 RAD18 330 RAS-MYC cooperation 221 RET tyrosine kinase 169 RAD23A 328 RAS–PI3K–AKT pathway 208, 222 retaspimycin hydrochloride 542 RAD23B 328 RAS-RAF-ERK (MAPK) pathway 90, 150, 158, 160, retinoblastoma 21–2, 83, 84, 91, 118, 240, 514 RAD50 333 169, 171, 173, 176, 234–5, 500 mouse model 250 RAD51 22, 35, 71, 83, 141, 318, 344 molecular targeting 489–90, 536 screening 105 RAD52 344 RASs 372 therapy 250 radiation-induced genomic instability 229 RASSF family 223 see also RB gene; RB protein family radiobiology 527–8, 527 RASSF1A 363 retinoic acid receptor α (RARa) 157 radiofrequency ablation 497 RasV12 255 retinoid X receptor (RXR) 171 radionuclide imaging 520–1, 521, 522 RB gene 17, 21–2, 25, 71, 91, 105, 118, 119, 240, retroviral integration-induced transformation 100 whole-body scans 13, 522 364 retroviruses 25, 100 radiosensitivity 527 genomic locus 242–3 cis-activating 100 radiotherapy 16, 464 RB protein family 242–50, 362 trans-activating 100 advances in 529–30, 529 A-B pocket 243–4, 244 transducing 100 breast cancer 51–2, 52 in cancer 247–8, 248, 249, 257–8 retuximab 62, 63 cervical cancer 60 cell cycle and differentiation 244–6, 245, 246 RG3638 484 chemoradiation 530 hyperphosphorylation 131–2 RG7112 484 colorectal cancer 55 and microRNAs 262, 263 RG7414 483 DNA damage 346 mouse models 248–50, 249 RG7440 483 fractionation 527 senescence and immortalization 258, 298 RG7444 484 Hodgkin disease 61 signal pathways 246–7 RG7459 484 lung cancer 47, 49 see also specifi c proteins rhabdomyosarcoma 259 malignant melanoma 59 RB-binding protein 1 (RBP1) 245 RHEB 225 non-Hodgkin lymphoma 62 RB1 gene 84, 87, 241, 514 RHEBL1 225 physics 526–7 re-oxygenation 527 Rho proteins 30, 226, 227, 228, 402 prostate cancer 57 reactive oxygen species (ROS) 29, 97–8, 283, 425, inhibitors 490 resistance to 305 451, 476 Rho GAPs 227–8 side effects 528 reader proteins 365 Rho GEFs 227 treatment planning 528–9, 528 receptor activated solely by synthetic ligands Rho GTPases 225–8, 226, 391 radon gas 45, 96 (RASSLs) 171 and cancer 227 RAF gene 198 receptor activity modifying proteins (RAMPs) 171 transcription factor regulation 226–7 RAF1 gene 195 receptor degradation 377 Rho kinase 391 RAF kinase inhibitory protein (RKIP) 373 receptor tyrosine kinase (RTK) inhibitors 433, 493 inhibitors 490 RAF proteins 172, 216 receptor tyrosine kinases (RTKs) 161, 164–72, 175, Rho-associated coiled-coil domain kinases (ROCK) RAF-ERK pathway 222 194, 377, 477 225 RAF-MAP kinase pathway 217–18, 218 anaplastic lymphoma kinase 169 RHOGD12 30 RAF-MEK-ERK pathway 172, 215, 216, 475, 485 and cancer 167–8 ribonucleoside diphosphate reductase 534 RAF–MEK–MAPK pathway 31, 172 ERBBs 32–3, 168 rictor 176 RAG-2 412, 413 growth factor 165, 165–7, 167, 196 RING fi nger proteins 128, 333, 377 RALGDS 216, 219 HER2-Neu 476 risk factors 75–6 RALGDS-like gene 216 IGF-1 receptor 169 combined 90–3, 91, 92 raloxifene 172, 483 insulin receptor 169 environmental see environmental causes of cancer raltitrexed 532 MEN syndromes 169–70 see also specifi c cancer types ramucirumab 537 MET 168–9 Rituxan see rituximab RANK, antibodies 484 molecular targeting 485–8 rituximab 423, 443, 480, 484, 538 RANKL 494 RAS activation by 215 RNA Rap1 308 RET 169 double-stranded 556 Rap80 333 TIE2 435 long noncoding (lncRNA) 369 rapamycin, molecular target 477 receptors 164–70 messender (mRNA) 556 raptor 176 G-protein coupled see G-protein coupled receptors microRNAs see microRNAs RARβ2 364 nuclear 161, 171–2 noncoding (ncRNA) 2, 351, 369 RAS oncogene 2, 17, 19, 24, 25, 158, 190, 193, 196, tyrosine kinase see receptor tyrosine kinases small interfering (SiRNA) 302, 352, 369–71, 198, 213 see also specifi c receptor types 495–7, 496, 556 mutations 224 recessive 71, 190 transfer (tRNA) 203 RAS superfamily 208, 213–28 RECIST 473 RNA interference (RNAi) 371–3, 451–2, 458, 570 activation 214 RECK 30 and cancer 372–3 receptor tyrosine kinases 215 recombination-activating gene see RAG RNA polymerases 203, 324, 369 angiogenesis 225 RecQ helicases 345 RNF8 333 and cancer 224 redistribution 527 RNF169 333 cell growth/proliferation 217 Reed-Sternberg cells 60, 60, 99 robatumumab 486 cell survival/death 222–3, 223 regulatory T cells see Tregs rodent cornea pocket 432, 433

616 Index

romidepsin 368, 484, 542 SFRP1 364 smoking 75, 95–6 RON oncogene 501 SG2202 456 and lung cancer 45, 92 ros 196 SG2285 455–6, 456 Smoothened 59, 393, 489 roscovitine 484, 490 SGN-15 453 Smurfs 128 Rous sarcoma virus (RSV) 25, 98, 192 shepherdin 450 SMYD3 355 RPA 328 short telomeres 310 Snail proteins 178, 304, 306 rs6983267 88 SHP-1 178 SNF2H 357 RSF1 357 shugoshin 134 SnoN 302 RTP801 496 signal transducers and activators of transcription see SNPs 22, 74, 86–7, 88, 556, 559–62, 561 RXi-109 496 STAT proteins tagSNPs 561, 561 signal transduction pathways 160–84, 194–5, 196, see also specifi c SNPs S-phase cyclin 124 198 SNP chips 559 S6 kinases (S6Ks) 155 AKT 176 SOCS-1 gene 364 S100A4 363 cytokines 177–8 SOCS-1 protein 178 Saccharomyces cerevisiae 117, 124, 288 growth factors see growth factors SOCS-3 364 Safety Pharmacology Package 457 Hedgehog 21, 59, 157, 178, 182 somatic mutations 72, 105–6, 192, 242 SAGE 252, 419 Hippo 183–4, 183, 184 Sonic Hedgehog pathway 21, 179–80, 179, 367, 489 salirasib 483, 489 inhibitors of 483 sorafenib 57, 478, 481, 485, 493, 537 Salvador protein 271 integrins in 389, 390 molecular target 477 saracatinib 489 MAPK 161, 172 Sox2 209, 306 sarasar 483 mTOR 27, 154, 158, 167, 176–7 SP/KLF 131 sarcoma 11 nonreceptor tyrosine kinases 172 SP1 204, 205 scaffold proteins 475 Notch 21, 100, 128, 178, 180–2, 181 spectral karyotyping (SKY) 319–20, 320 SCF 124, 126, 128–9 phosphatidylinositol kinase 172–4, 176 spinal tumors 511 SCH66336 483 RAS superfamily 216–17, 216, 261 spindle checkpoint 120, 123, 137–8 Schizosaccharomyces pombe 117, 124 RB protein family 246–7 spindle fi bers 134 Schleiden, Jacob 267 receptor tyrosine kinases see receptor tyrosine splice-site mutations 80–1 Schwann, Theodore 267 kinases spliceosome 557 screening 12, 102–3, 513–14 see also individual pathways sporadic cancers 22 cervical cancer 103–4, 514 signalosome (CSN) 128F SPRY4 89 colorectal cancer 54 SILAC 566, 567, 568, 569 Sprycel see dasatinib fecal occult blood 502, 515 silatecan DB-67 453 squamous cell carcinoma genomic mutations 105 silent mutations 80 lung 45 mammography 50, 50, 103 simian sarcoma 193 skin 59 MEN 105 single gene defects 21–2 SRC gene 98, 196, 198, 228–32 opportunistic 12 single-nucleotide polymorphisms see SNPs and cancer 231 population 12 single-photon emission computed tomography mode of action 230, 231 prostate cancer 514–15 (SPECT) 520 molecular targeting 232, 488–9 secretions, retained 550 single-strand breaks (SSBs) 326–30, 527 phenotype 229–30 securin 124, 130 repair regulation and activation 228, 229 selective estrogen receptor downregulators (SERDs) base excision 135, 325, 326–7, 327, 335, 475 SRC family kinases (SFK) 228, 488, 489 539 mismatch repair 22, 23, 135, 325, 329–30, SRD5A2 87 selective estrogen receptor modulators (SERMs) 329, 343 STA-9090 542 172, 445, 483, 539 nucleotide excision 135, 325, 327–9, 328, stable isotope labeling by amino acids in cell culture see also tamoxifen 345 see SILAC self-antigens, over-expression 420 stalled replication forks 330, 331 staging 101–2, 523 self-renewal 18 translesional synthesis 326, 330 breast cancer 51 seliciclib 541 sipuleucel-T 452, 495 colorectal cancer 54–5, 54 selumetinib 483 SiRNA 302, 352, 369–71, 556 Dukes’ classifi cation 54, 101–2 senescence 7, 135, 148, 298–310, 378–9 molecular targeting 495–7, 496 Hodgkin disease 61 avoidance of 27 sirtuins 356, 361 lung cancer 48 and cancer 299–301 sis 98 non-Hodgkin lymphoma 62 and cancer behavior in other cells 301 sister chromatids 115, 133 prostate cancer 57 and cancer control 290–2, 291 SKAP1 89 TNM classifi cation 101–2, 523 drug-induced 292 ski 197 stalled replication forks 330, 331, 334 oncogene-induced 27–8 skin cancer 58–9, 58 STAT proteins 177, 198, 226, 230, 235 RAS 219–20, 221 Skp1 128 STAT1 412–13 premature 301–2 Skp2 296 stem cell factor 170 RB and p53 in 258 Slug 304, 338, 401 stem cells 156, 178–9, 395 replicative 306–7, 306 Smac mimetics 277, 278–9, 293, 492 cancer see cancer stem cells see also cell death Smac/DIABLO 273, 278, 280, 281 and cancer 302–3 senescence-associated heterochromatic foci (SAHFs) Smads 393 DNA repair 336 298, 300, 342 Smad receptors 164 embryonic 113, 302–3 separase 124 SMAD4 gene 89 hematopoietic 303, 304 sequencing by ligation 565 Smad4-DPC4 376 stereotactic radiosurgery 530 SEREX 418–19 small interfering RNA see SiRNA steroids 547 serial analysis of gene expression see SAGE small ubiquitin-like modifi er see SUMO stimuvax 483 serine, ECM degradation 403 SMARCA2 356 stress-inducible heat shock proteins 282 serine/threonine kinases 161, 177, 188, 196, 198 SMARCA4 356 stroma RAF-MAP kinase pathway 217–18, 218 SMARCB1 353, 356 in cancer 387, 388 serological recombinant expression cloning see SMARCC1 353, 357 epithelial interactions 387, 388 SEREX SMARCE1 357 growth factors in 387 Sezary’s syndrome 177 SMC proteins 344 molecular targeting 495 SFK see SRC family kinases SMC1 318, 333 structural maintenance of chromosome-1 see SMC1

617 Index

SU6656 488 t(11;14)(p13;q11) 513 “tet” system 210, 211, 468, 584 SU11248 537 t(15;17)(q22;q11) 513 tet-regulatable gene expression 584 subpolymorphism 70 TACE/ADAM17 171 TET1 353, 355 substrate recognition factors (SRFs) 128 TAF1 357 TET2 355 SUFU 182 tagSNPs 561, 561 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 95 sulfotransferases (SULT) 94 Talaporfi n 451 tetracycline see “tet” system sulindac 90 talin 230, 391 tetrazines 532 SUMO 344, 377–9 tamoxifen 53, 172, 290, 445, 446, 468, 483, 539 TFAP2E 505 SUMO E3 ligases 333, 344 metabolites 455 TGF-α 149 sumoylation 333 tandem affi nity purifi cation (TAP) 570, 571, 572 TGF-α-ErbB signaling pathway 394 sunitinib 57, 478, 481, 485, 537 tankyrase 305, 335 TGF-β 28, 29, 148, 149, 164, 305–6, 387 superior vena cava obstruction (SVCO) 46, 46 Tarceva see erlotinib and cancer 163 supportive care 550–1 target cyclins 124, 130 EMT activation 401 surgery 16, 530, 531 targeted therapy 20–1, 146–87, 228, 368, 461–508, TGFBR1 89 breast cancer 51 535–7, 536 thalidomide 485 cervical cancer 60 angiogenesis inhibitors 436, 450, 450, 485, 493, THBS-1 364, 365 lung cancer 47 536–7, 537 6-thioguanine 533 renal carcinoma 57 biomarkers see biomarkers thiopurine methyltransferase (TPMT) 505 survival factors 147, 161 clinical progress 476–9, 477, 478 thiotepa 532 survival pathways 232–3 DNA repair 490–2 thrombospondin-1 (TSP-1) 225, 436 molecular targeting 492 EGFR 535–6, 536, 537 thymidylate synthase 130, 532 survival time 5 epigenetic regulation 492–3, 493, 537–9 thymine DNA glycosylase (TDG) 327 survivin 134, 226, 278, 418, 425 PARP inhibitors 2, 51, 142, 335–6, 476, 538 thyroglobulin 502 susceptibility to cancer 78, 82–6, 83, 84–5 fi eld cancerization 497 TIE2 receptor tyrosine kinase 435 Sutent see sunitinib G-protein coupled receptors 489 tight junctions 394 SUV39H1 355 gene therapy 495–7 Timeless 318 SV40 T antigen 470 growth factors 482–5, 483–5 timing of cancer development 28 SW1-SNF complex 353, 363 integrin antagonists 494–5, 495 Timp-1 20 syndrome of inappropriate ADH secretion (SIADH) metastasis and invasion 493–4 TIMPs 230, 494 46 oncogenes 473–5, 473 tioguanine 441, 442 synthetic lethality 2, 35, 475–6, 476 PARP inhibitors 2, 51, 142, 335–6, 476, 538, 542 Tip60 332 systemic therapy 527 resistance to 487, 497–501, 498 TIPARP 89 systems biology 554–83 scheduling 497 tipifarnib 483 epigenomics 559 stromal and immune targeting 495 Tipin 318 genomics 87–9, 559 synthetic lethality 2, 35, 475–6, 476 tissue diagnosis see biopsy; histology information fl ow in cells 556–7, 557 target selection 443, 468 tissue mass homeostasis 11, 156 microarrays 523, 559 transcription factors 492 tissue remodeling 28–9 model organisms and cancer models 557–9 tyrosine kinase inhibitors see tyrosine kinase tissue repair/regeneration 151–5, 152–4 mRNA expression analysis 562–4 inhibitors tivozanib 537 next-generation sequencing (NGS) 559, 564–6 VEGF 496, 536–7 TLN-4601 489 posttranslational modifi cation 215–16, 215, 567, see also individual drugs TMS1 364 569, 569 Tasigna see nilotinib TNF 87 protein complexes and cellular networks 569–70, Taspase-1 475, 476 TNF-α-NF-κB pathway 570 571, 572 taxanes 52, 142, 533 TNM staging 101–2, 523 proteomics 523, 566–7, 570–1 taxol see docetaxel; paclitaxel breast cancer 51 toponomics 571–6 taxonomy 35–6 lung cancer 48 transcriptomics 559 taxotere see docetaxel Tob1 gene 241, 252 see also specifi c elements TBKBP1 570 Tob1 protein 252, 256 telomerase 27, 296, 418 tobacco smoke see smoking T cells 413–17 inhibition 310 Toll-like receptors (TLR) 411, 422 antigen presentation 413–15, 414, 415 telomerase reverse transcriptase (TERT) 296, 299 TopBP1 318, 330 antigen-specifi c therapy 422–3 telomeres 297, 303, 306–10, 306 topoisomerase inhibitors 534 costimulatory and inhibitory signals 415–16 and cancer 307 see also individual drugs cytotoxic (CD8) 416–17 critical loss 307–8 topoisomerases 130 differentiation 412, 412 dysfunction 308 topology, defi nition 573 helper (CD4) 416 heterochromatin 309 toponomics 571–6 memory 411, 412, 412 length 297, 308–9 cell surface toponome 575–6, 575 priming 411, 412, 412 protection from DNA repair process 333–4 protein location images 571–3, 573 regulatory see Tregs replicative senescence 306–7, 306, 307 structure, code and semantics 573–4, 574 repertoire 420 roles of 309–10 topological hierarchies 573 T-cell acute lymphoblastic lymphoma (T-ALL) 100, short 310 tumor cell mapping 575, 576, 576–8 128–9 telomere attrition 27, 154, 306, 321–4 topotecan 49, 448, 448, 449, 534 RB pathway 248 telomere-interacting proteins 307 TOR 155 T-cell leukemia 100 telomeric repeat-binding factors (TRFs) 297, 297 Torisel see temsirolimus T-cell lymphoma 62, 99, 196, 205, 216, 227, 260, telomestatin 448 tositumomab 443, 466, 538 286, 363, 368, 468, 469, 470, 484, 492, 538, telophase 116 totipotent cells 156 555 TEL–JAK2 178 TP53 see p53 gene T-cell lymphoma invasion and metastasis 1 (TIAM1) temozolomide 59, 368, 455, 455, 532 TPEF–HPP1 364 216, 227 temsirolimus 57, 483, 490, 541 TPM1 372 T-cell-defi ned tumor antigens 417–18, 418 tenascin 387, 395 Tpp1 308 t-loops 297, 297 terminal differentiation 158 TPX2 134 t(8;14)(q24;q11) 513 TERT/hTERT 154, 221, 296, 299, 355, 579 trabectedin 448, 534–5 t(8;21)(q22;q21) 513 testicular cancer, susceptibility 89 TRAF1 277 t(9;22)(q34.1;q11.2) 513 testosterone 172 TRAF7 570

618 Index

TRAIL 90, 233, 305 classifi cation 419–20 v-sis 193, 196 human recombinant 484 SEREX 418–9 v-Src 192 transarterial chemoembolization 520 T-cell repertoire 420 Vaccine European New Integrated Collaboration transcription 129–31 T-cell-defi ned 417–8, 418 Effort (VENICE) 99 transcription elongation factor b (P-TEFb) 362 tumor cell line-based vaccines 420 vaccines 416, 420–2, 452, 538–9 transcription factors 124, 184, 197, 198 tumor cell metabolism 159–60, 159 clinical trials 422–3, 423 molecular targeting 492 tumor cell-based vaccines 420–1 dendritic cell 421 transcription-coupled repair (TCR) 325, 328 tumor immunity 410–28 peptide-based 421 transcriptional regulators 357 effector cells 413–7 plasmid DNA-based 421–2 transcriptomics 559 dendritic cells 411, 411, 413, 414 tumor cell-based 420–1 transfer RNA see tRNA natural killer (NK) cells 291, 411, 417 vandetanib 478, 537 transferrin 452 T cells see T cells vascular endothelial growth factor see VEGF transformation/transcription domain-associated Tregs 29, 417 vascular growth factors 432–6 protein see TRRAP immune response see immmune response see also specifi c growth factors transforming growth factors see TGF-α; TGF-β tumor markers see biomarkers vascular permeability factor (VPF) 433 transgenesis 582, 583 tumor necrosis factor receptor-associated factor 1 see vascular targeted agents 436, 485 transition 80 TRAF1 vasculogenesis 430, 431 translation, regulation of 369 tumor necrosis factor-related apoptosis-inducing vatalanib 450, 450 translational control 184–5 ligand see TRAIL Vav 196 translesional synthesis (TLS) 326, 330 tumor profi ling 34 Vectibix see panitumumab transmembrane proteoglycan receptors 389 tumor protein (TP) p53 see p53 protein family VEGF 31, 164, 226, 405–6, 432–4, 434 transthyretin 496 tumor recurrence 473 molecular targeting 496, 536–7 transversion 80 tumor suppressor hypersensitivity 474 VEGF receptors 31, 432–4, 434 trastuzumab 51, 52, 168, 423, 478, 488, 535, 536 tumor suppressors 2, 17, 21–2, 24, 25–7, 71, 118, VEGF-Trap 485, 537 molecular target 477 239–65, 241, 484 Velban see vinblastine treatment 526–43 cell proliferation control 258–60, 258–60 Velcade see bortezomib chemotherapy 15–6, 438–60, 526, 530–42 defi nition 242 veliparib 542 and cell cycle 141–2 DNA damage response 260 vemurafenib 483 and cell death 290, 290 genomic stability 260 Verteporfi n 451 combination chemotherapy 530 see also specifi c tumor suppressors VHL 85, 241, 363, 364, 514 drug delivery 452 tumor-infi ltrating lymphocytes (TIL) 422 vimentin 372 drug development 442–57 tumor-initiating cells see cancer stem cells vinblastine 61, 447, 533 indications 530–1 tumor-promoting growth factors 404 vinca alkaloids 52, 142, 447, 533 individualization of 33–4 tumorigenesis 29 vincristine 62, 447, 533 new agents 541–2 mouse models see mouse models of tumorigenesis vinculin 230, 391 rationale 530 multistage 16–8, 17, 79, 80, 105–6, 213 vinorelbine 49, 533 resistance to see drug resistance MYC protein 209–12, 211, 212 viral oncogenes 98 targeted see targeted therapy RAS superfamily 224–5, 225, 472–3 and instability 344 see also specifi c drugs Turcot syndrome 83 viruses 25 hormone therapy Twist 31, 255, 256, 304, 306, 401 DNA viruses 25, 98–9 breast cancer 53, 539 two-hit hypothesis 22, 71, 240, 242, 334, 363 retroviruses 25, 100 prostate cancer 57, 539–40 Tykerb see lapatinib visfatin 482 radiotherapy 16, 464, 526–30 tyrosinase 418, 420 vismodegib 483 advances in 529–30, 529 tyrosine kinase inhibitors (TKIs) 32, 90, 477, 478, vitronectin 402, 403 chemoradiation 530 480–2, 485–8, 535, 537 Voegtlin, Carl 439 DNA damage 346 anti-EGFR 536 Vogt, Carl 267 fractionation 527 monoclonal antibodies 480, 488 volasertib 541 physics 526–7 nucleotide based 480 von Hippel-Lindau syndrome 57, 83, 85, 129, 375, resistance to 305 small-molecule drugs 480–2, 485 514 side effects 528 see also individual drugs genetic testing 513 treatment planning 528–9, 528 Von Tappeiner, Herman 450 response to 14 U0126 477, 483 vorinostat 368, 484, 492, 538, 542 surgery 16, 530, 531 UbcH10 E2 ligase 129 Votrient see pazopanib targeted therapy see targeted therapy ubiquitin ligases 126, 128, 180, 333, 342 VPS34 288 see also specifi c cancer types ubiquitin-proteasome system 379 Tregs 29, 417 ubiquitin-protein ligases 374–6 WAF-1 see p21CIP1 Trf1 134, 308 ubiquitin-specifi c protease 8 377 Warburg effect 16, 26, 159–60, 159, 558 tricyclic antidepressants 547 ubiquitination 333, 557 WARTS 123 TRIM24 365 UCNO1 484 WEE1 336 triple-helix-forming oligonucleotides (TFOs) 451 UFM1 378 Werner’s syndrome 83, 300, 346 Trisenox 453 UGT1A 89 Werner’s syndrome protein see WRN trisomy 12 513 ULF 342 wheel of death (apoptosome) 274, 275 Trithorax group proteins 367 ultrasound 516, 522 white cell count 512 TRK 196 unfolded protein response (UPR) 222, 282 whole-body scans 13, 522 tRNA 203 urea, raised 512 WHSC1 355 TRPC4AP–TRUSS 376 Urm1 378 Williams-Beuren syndrome 333 TRRAP 203, 332 urokinase receptor 494 Wilms’ tumor 23, 83, 84, 91, 366, 367, 514 ts1 197 Wip1 338 TSC1 84, 241 v-ABL 193, 255 Wnt pathway 21, 148, 178, 259–60, 260, 470 TSC2 84 v-erb-b 193 Wnt-β-catenin pathway 21, 179–80, 179 tuberin 177 v-fms 193 Wnt1 195 tuberous sclerosis 84, 176 v-fos 193, 198 Wolf-Hirschhorn syndrome 355 tuberous sclerosis complexes (TSC) 158 v-jun 193 Women’s Health Initiative Dietary Modifi cation Trial tumor angiogenesis see angiogenesis v-myc 193 97 tumor antigens 417–20, 418, 418 v-ras 193 Wortmanin 477

619 Index

WP-1034 483 XL147 541 ZEB1 178, 306, 372, 373 WRN 300, 337 XL184 541 ZEB2 306, 373 WSTF 333 XL228 486 zebra fi sh 557 WT1 gene 84, 91, 241, 367, 514 XL765 541 Zelboraf see vemurafenib WT1 protein 367, 418 XL844 541 Zevalin see 90Y-ibritumomab tiuxetan Wyllie, Andrew 267, 269 XPA-XPG 85, 345 ZIO-101 453 XRNF185 128 Zipf’s law 574, 574, 576 X-ray tubes 527 Zoladex see goserelin X-rays 516 YAP 391 zoledronic acid 483 Xalkon see crizotinib yes 196 Zolinza see vorinostat xenobiotic responsive elements (XREs) 95 Yes-associated protein 1 (Yap1) 342 ZONAB 219 xeroderma pigmentosum 58, 83, 85, 329, zonula adherens 393 345 Zactima see vandetanib zonula occludens 394 xeroderma pigmentosum proteins 328 zarnestra 483 ZW10–ROD–Zwilch complex 337 XIST 369 ZBRK1 130 zymogens 403

620