Future Therapies in Medical Oncology

Chapter

Abstract

Antibodies to EGFR (cetuximab and panitumumab) and VEGF-A (bevacizumab) that are routinely used for treating metastatic colorectal cancer have failed to find a role in the management of localized rectal cancer. Other molecular targets worth considering include Her2/neu, BRAF, the PI3 kinase pathway, HSP90, and most recently the hypermutated phenotype of MSI tumors. Here we review selected trials using targeted agents in localized rectal cancer and propose other targeted strategies that have not yet been tested. In this era of molecular profiling, rectal cancer is an ideal opportunity to test the biological effects and clinical outcomes of preoperative molecularly targeted therapy.

Keywords

Rectal Neoadjuvant Targeted therapy Immunotherapy Defective DNA repair 

References

  1. 1.
    Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011–9. doi: 10.1200/JCO.2010.33.5091.CrossRefPubMedGoogle Scholar
  2. 2.
    Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–78. doi: 10.1056/NEJMoa053422.CrossRefPubMedGoogle Scholar
  3. 3.
    Dewdney A, Cunningham D, Tabernero J, Capdevila J, Glimelius B, Cervantes A, et al. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C). J Clin Oncol. 2012;30(14):1620–7. doi: 10.1200/JCO.2011.39.6036.CrossRefPubMedGoogle Scholar
  4. 4.
    Kripp M, Horisberger K, Mai S, Kienle P, Gaiser T, Post S, et al. Does the addition of Cetuximab to Radiochemotherapy improve outcome of patients with locally advanced rectal cancer? Long-term results from phase II trials. Gastroenterol Res Pract. 2015;2015:273489. doi: 10.1155/2015/273489.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Helbling D, Bodoky G, Gautschi O, Sun H, Bosman F, Gloor B, et al. Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07. Ann Oncol. 2013;24(3):718–25. doi: 10.1093/annonc/mds519.CrossRefPubMedGoogle Scholar
  6. 6.
    Mardjuadi FI, Carrasco J, Coche JC, Sempoux C, Jouret-Mourin A, Scalliet P, et al. Panitumumab as a radiosensitizing agent in KRAS wild-type locally advanced rectal cancer. Target Oncol. 2015;10(3):375–83. doi: 10.1007/s11523-014-0342-9.CrossRefPubMedGoogle Scholar
  7. 7.
    Jin T, Zhu Y, Luo JL, Zhou N, Li DC, Ju HX, et al. Prospective phase II trial of nimotuzumab in combination with radiotherapy and concurrent capecitabine in locally advanced rectal cancer. Int J Color Dis. 2015;30(3):337–45. doi: 10.1007/s00384-014-2097-2.CrossRefGoogle Scholar
  8. 8.
    Sorscher SM. Marked response to single agent trastuzumab in a patient with metastatic HER-2 gene amplified rectal cancer. Cancer Investig. 2011;29(7):456–9. doi: 10.3109/07357907.2011.590569.CrossRefGoogle Scholar
  9. 9.
    Disel U, Germain A, Yilmazel B, Abali H, Bolat FA, Yelensky R, et al. Durable clinical benefit to trastuzumab and chemotherapy in a patient with metastatic colon adenocarcinoma harboring ERBB2 amplification. Oncoscience. 2015;2(6):581–4.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Siena S, Sartore-Bianchi A, Lonardi S, Trusolino L, Martino C, Bencardino K, et al. Trastuzumab and lapatinib in HER2-amplified metastatic colorectal cancer patients (mCRC): The HERACLES trial. ASCO Meeting Abstracts. 2015;33(15 Suppl):3508.Google Scholar
  11. 11.
    Kopetz S, Desai J, Chan E, Hecht JR, O'Dwyer PJ, Maru D, et al. Phase II pilot study of Vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol. 2015;33(34):4032–8. doi: 10.1200/JCO.2015.63.2497.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379(9829):1893–901. doi: 10.1016/S0140-6736(12)60398-5.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al. Vemurafenib in multiple Nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373(8):726–36. doi: 10.1056/NEJMoa1502309.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hong DS, Morris VK, El Osta BE, Fu S, Overman MJ, Piha-Paul SA, et al. Phase Ib study of vemurafenib in combination with irinotecan and cetuximab in patients with BRAF-mutated metastatic colorectal cancer and advanced cancers. ASCO Meeting Abstracts. 2015;33(15 Suppl):3511.Google Scholar
  15. 15.
    Tabernero J, van Geel R, Bendell JC, Spreafico A, Schuler M, Yoshino T, et al. 11LBA Phase I study of the selective BRAFV600 inhibitor encorafenib (LGX818) combined with cetuximab and with or without the α-specific PI3K inhibitor alpelisib (BYL719) in patients with advanced BRAF mutant colorectal cancer. European Journal of Cancer. 2014;50:199. doi: 10.1016/S0959-8049(14)70732-4.CrossRefGoogle Scholar
  16. 16.
    Buijsen J, Lammering G, Jansen RL, Beets GL, Wals J, Sosef M, et al. Phase I trial of the combination of the Akt inhibitor nelfinavir and chemoradiation for locally advanced rectal cancer. Radiother Oncol. 2013;107(2):184–8. doi: 10.1016/j.radonc.2013.03.023.CrossRefPubMedGoogle Scholar
  17. 17.
    Hill EJ, Enescu M, West N, Franklin JM, Chu K-Y, Li J, et al. Oral nelfinavir before and during radiation therapy for rectal cancer: Changes in tumor perfusion and correlation between tissue and radiological markers of response. ASCO Meeting Abstracts. 2014;32(3 Suppl):491.Google Scholar
  18. 18.
    Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367(17):1596–606. doi: 10.1056/NEJMoa1207756.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    El-Rayes BF, Staley CA, Diaz R, Sullivan PS, Shaib WL, Landry JC. Phase I study of ganetespib (G), capecitabine (C), and radiation (RT) in rectal cancer. ASCO Meeting Abstracts. 2015;33(15 Suppl):3596.Google Scholar
  20. 20.
    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20. doi: 10.1056/NEJMoa1500596.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42. doi: 10.1056/NEJMoa032691.CrossRefPubMedGoogle Scholar
  22. 22.
    Willett CG, Duda DG, di Tomaso E, Boucher Y, Czito BG, Vujaskovic Z, et al. Complete pathological response to bevacizumab and chemoradiation in advanced rectal cancer. Nat Clin Pract Oncol. 2007;4(5):316–21. doi: 10.1038/ncponc0813.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Marechal R, Vos B, Polus M, Delaunoit T, Peeters M, Demetter P, et al. Short course chemotherapy followed by concomitant chemoradiotherapy and surgery in locally advanced rectal cancer: a randomized multicentric phase II study. Ann Oncol. 2012;23(6):1525–30. doi: 10.1093/annonc/mdr473.CrossRefPubMedGoogle Scholar
  24. 24.
    Salazar R, Capdevila J, Laquente B, Manzano JL, Pericay C, Villacampa MM, et al. A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer: clinical and biological features. BMC Cancer. 2015;15:60. doi: 10.1186/s12885-015-1053-z.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Network CGA. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7. doi: 10.1038/nature11252.CrossRefGoogle Scholar
  26. 26.
    Park DI, Kang MS, Oh SJ, Kim HJ, Cho YK, Sohn CI, et al. HER-2/neu overexpression is an independent prognostic factor in colorectal cancer. Int J Color Dis. 2007;22(5):491–7. doi: 10.1007/s00384-006-0192-8.CrossRefGoogle Scholar
  27. 27.
    Kavanagh DO, Chambers G, O'Grady L, Barry KM, Waldron RP, Bennani F, et al. Is overexpression of HER-2 a predictor of prognosis in colorectal cancer? BMC Cancer. 2009;9:1. doi: 10.1186/1471-2407-9-1.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7. doi: 10.1038/nature11252.CrossRefGoogle Scholar
  29. 29.
    Ramanathan RK, Hwang JJ, Zamboni WC, Sinicrope FA, Safran H, Wong MK, et al. Low overexpression of HER-2/neu in advanced colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy. A phase II trial. Cancer Investig. 2004;22(6):858–65.CrossRefGoogle Scholar
  30. 30.
    Liming S, Yuan Z, Qinghua D, Lei W, Qifeng J, Haojie L. Human epidermal growth factor receptor-2 and topoisomerase II alpha expressions in rectal cancer. Hepato-Gastroenterology. 2011;58(106):359–63.PubMedGoogle Scholar
  31. 31.
    Conradi LC, Styczen H, Sprenger T, Wolff HA, Rödel C, Nietert M, et al. Frequency of HER-2 positivity in rectal cancer and prognosis. Am J Surg Pathol. 2013;37(4):522–31. doi: 10.1097/PAS.0b013e318272ff4d.CrossRefPubMedGoogle Scholar
  32. 32.
    Meng X, Wang R, Huang Z, Zhang J, Feng R, Xu X, et al. Human epidermal growth factor receptor-2 expression in locally advanced rectal cancer: association with response to neoadjuvant therapy and prognosis. Cancer Sci. 2014;105(7):818–24. doi: 10.1111/cas.12421.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Yao YF, Du CZ, Chen N, Chen P, Gu J. Expression of HER-2 in rectal cancers treated with preoperative radiotherapy: a potential biomarker predictive of metastasis. Dis Colon Rectum. 2014;57(5):602–7. doi: 10.1097/DCR.0000000000000107.CrossRefPubMedGoogle Scholar
  34. 34.
    Seo AN, Kwak Y, Kim DW, Kang SB, Choe G, Kim WH, et al. HER2 status in colorectal cancer: its clinical significance and the relationship between HER2 gene amplification and expression. PLoS One. 2014;9(5):e98528. doi: 10.1371/journal.pone.0098528.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Sclafani F, Roy A, Cunningham D, Wotherspoon A, Peckitt C. Gonzalez de Castro D et al. HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab. Ann Oncol. 2013;24(12):3123–8. doi: 10.1093/annonc/mdt408.CrossRefPubMedGoogle Scholar
  36. 36.
    Park DI, Yun JW, Park JH, Oh SJ, Kim HJ, Cho YK, et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci. 2006;51(8):1371–9. doi: 10.1007/s10620-005-9057-1.CrossRefPubMedGoogle Scholar
  37. 37.
    Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007;369(9555):29–36. doi: 10.1016/S0140-6736(07)60028-2.CrossRefPubMedGoogle Scholar
  38. 38.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–92. doi: 10.1056/NEJM200103153441101.CrossRefPubMedGoogle Scholar
  39. 39.
    Petrelli F, Borgonovo K, Cabiddu M, Ghilardi M, Barni S. Neoadjuvant chemotherapy and concomitant trastuzumab in breast cancer: a pooled analysis of two randomized trials. Anti-Cancer Drugs. 2011;22(2):128–35.CrossRefPubMedGoogle Scholar
  40. 40.
    Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X, et al. AVEREL: a randomized phase III trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol. 2013;31(14):1719–25. doi: 10.1200/JCO.2012.44.7912.CrossRefPubMedGoogle Scholar
  41. 41.
    Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25–32. doi: 10.1016/S1470-2045(11)70336-9.CrossRefPubMedGoogle Scholar
  42. 42.
    Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97. doi: 10.1016/S0140-6736(10)61121-X.CrossRefPubMedGoogle Scholar
  43. 43.
    Chen J, Guo F, Shi X, Zhang L, Zhang A, Jin H, et al. BRAF V600E mutation and KRAS codon 13 mutations predict poor survival in Chinese colorectal cancer patients. BMC Cancer. 2014;14:802. doi: 10.1186/1471-2407-14-802.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Saridaki Z, Tzardi M, Sfakianaki M, Papadaki C, Voutsina A, Kalykaki A, et al. BRAFV600E mutation analysis in patients with metastatic colorectal cancer (mCRC) in daily clinical practice: correlations with clinical characteristics, and its impact on patients' outcome. PLoS One. 2013;8(12):e84604. doi: 10.1371/journal.pone.0084604.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    He Y, Van't Veer LJ, Mikolajewska-Hanclich I, van Velthuysen ML, Zeestraten EC, Nagtegaal ID, et al. PIK3CA mutations predict local recurrences in rectal cancer patients. Clin Cancer Res. 2009;15(22):6956–62. doi: 10.1158/1078-0432.CCR-09-1165.CrossRefPubMedGoogle Scholar
  46. 46.
    Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA, et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res. 2005;65(14):6063–9. doi: 10.1158/0008-5472.CAN-05-0404.CrossRefPubMedGoogle Scholar
  47. 47.
    Clancy C, Burke JP, Kalady MF, Coffey JC. BRAF mutation is associated with distinct clinicopathological characteristics in colorectal cancer: a systematic review and meta-analysis. Color Dis. 2013;15(12):e711–8. doi: 10.1111/codi.12427.CrossRefGoogle Scholar
  48. 48.
    Falchook GS, Lewis KD, Infante JR, Gordon MS, Vogelzang NJ, DeMarini DJ, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13(8):782–9. doi: 10.1016/S1470-2045(12)70269-3.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, et al. Combined BRAF and MEK inhibition with Dabrafenib and Trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol. 2015;33(34):4023–31. doi: 10.1200/JCO.2015.63.2471.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483(7387):100–3. doi: 10.1038/nature10868.CrossRefPubMedGoogle Scholar
  51. 51.
    S1406 Phase II Study of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer. 2014. https://clinicaltrials.gov/ct2/show/study/NCT02164916.
  52. 52.
    Study of LGX818 and Cetuximab or LGX818, BYL719, and Cetuximab in BRAF Mutant Metastatic Colorectal Cancer. 2012. https://clinicaltrials.gov/ct2/show/NCT01719380/.
  53. 53.
    Johnson SM, Gulhati P, Rampy BA, Han Y, Rychahou PG, Doan HQ, et al. Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer. J Am Coll Surg. 2010;210(5):767–76, 76–8. doi: 10.1016/j.jamcollsurg.2009.12.008.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Danielsen SA, Eide PW, Nesbakken A, Guren T, Leithe E, Lothe RA. Portrait of the PI3K/AKT pathway in colorectal cancer. Biochim Biophys Acta. 2015;1855(1):104–21. doi: 10.1016/j.bbcan.2014.09.008.PubMedGoogle Scholar
  55. 55.
    Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 1998;391(6663):184–7. doi: 10.1038/34432.CrossRefPubMedGoogle Scholar
  56. 56.
    Bussink J, van der Kogel AJ, Kaanders JH. Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol. 2008;9(3):288–96. doi: 10.1016/S1470-2045(08)70073-1.CrossRefPubMedGoogle Scholar
  57. 57.
    Schuurbiers OC, Kaanders JH, van der Heijden HF, Dekhuijzen RP, Oyen WJ, Bussink J. The PI3-K/AKT-pathway and radiation resistance mechanisms in non-small cell lung cancer. J Thorac Oncol. 2009;4(6):761–7. doi: 10.1097/JTO.0b013e3181a1084f.CrossRefPubMedGoogle Scholar
  58. 58.
    Bendell JC, Nemunaitis J, Vukelja SJ, Hagenstad C, Campos LT, Hermann RC, et al. Randomized placebo-controlled phase II trial of perifosine plus capecitabine as second- or third-line therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2011;29(33):4394–400. doi: 10.1200/JCO.2011.36.1980.CrossRefPubMedGoogle Scholar
  59. 59.
    Bendell JC, Ervin TJ, Senzer NN, Richards DA, Firdaus I, Lockhart AC, et al. Results of the X-PECT study: A phase III randomized double-blind, placebo-controlled study of perifosine plus capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC). ASCO Meeting Abstracts. 2012;30(18 Suppl):LBA3501.Google Scholar
  60. 60.
    Gupta AK, Cerniglia GJ, Mick R, McKenna WG, Muschel RJ. HIV protease inhibitors block Akt signaling and radiosensitize tumor cells both in vitro and in vivo. Cancer Res. 2005;65(18):8256–65. doi: 10.1158/0008-5472.CAN-05-1220.CrossRefPubMedGoogle Scholar
  61. 61.
    Domingo E, Church DN, Sieber O, Ramamoorthy R, Yanagisawa Y, Johnstone E, et al. Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J Clin Oncol. 2013;31(34):4297–305. doi: 10.1200/JCO.2013.50.0322.CrossRefPubMedGoogle Scholar
  62. 62.
    Kothari N, Kim R, Jorissen RN, Desai J, Tie J, Wong HL, et al. Impact of regular aspirin use on overall and cancer-specific survival in patients with colorectal cancer harboring a PIK3CA mutation. Acta Oncol. 2015;54(4):487–92. doi: 10.3109/0284186X.2014.990158.CrossRefPubMedGoogle Scholar
  63. 63.
    Dimberg J, Samuelsson A, Hugander A, Söderkvist P. Differential expression of cyclooxygenase 2 in human colorectal cancer. Gut. 1999;45(5):730–2.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Dienstmann R, Patnaik A, Garcia-Carbonero R, Cervantes A, Benavent M, Roselló S, et al. Safety and activity of the first-in-class Sym004 anti-EGFR antibody mixture in patients with refractory colorectal cancer. Cancer Discov. 2015;5(6):598–609. doi: 10.1158/2159-8290.CD-14-1432.CrossRefPubMedGoogle Scholar
  65. 65.
    BRAF/MEK/EGFR Inhibitor Combination Study in Colorectal Cancer (CRC). 2012. https://clinicaltrials.gov/ct2/show/NCT01750918.
  66. 66.
    Do K, Speranza G, Bishop R, Khin S, Rubinstein L, Kinders RJ, et al. Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer. Investig New Drugs. 2015;33(3):720–8. doi: 10.1007/s10637-015-0212-z.CrossRefGoogle Scholar
  67. 67.
    Trepel J, Mollapour M, Giaccone G, Neckers L. Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer. 2010;10(8):537–49. doi: 10.1038/nrc2887.CrossRefPubMedGoogle Scholar
  68. 68.
    Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC, et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature. 2003;425(6956):407–10. doi: 10.1038/nature01913.CrossRefPubMedGoogle Scholar
  69. 69.
    Neckers L, Workman P. Hsp90 molecular chaperone inhibitors: are we there yet? Clin Cancer Res. 2012;18(1):64–76. doi: 10.1158/1078-0432.CCR-11-1000.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Russell JS, Burgan W, Oswald KA, Camphausen K, Tofilon PJ. Enhanced cell killing induced by the combination of radiation and the heat shock protein 90 inhibitor 17-allylamino-17- demethoxygeldanamycin: a multitarget approach to radiosensitization. Clin Cancer Res. 2003;9(10 Pt 1):3749–55.PubMedGoogle Scholar
  71. 71.
    Camphausen K, Tofilon PJ. Inhibition of Hsp90: a multitarget approach to radiosensitization. Clin Cancer Res. 2007;13(15 Pt 1):4326–30. doi: 10.1158/1078-0432.CCR-07-0632.CrossRefPubMedGoogle Scholar
  72. 72.
    Goldman JW, Raju RN, Gordon GA, El-Hariry I, Teofilivici F, Vukovic VM, et al. A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies. BMC Cancer. 2013;13:152. doi: 10.1186/1471-2407-13-152.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    He S, Smith DL, Sequeira M, Sang J, Bates RC, Proia DA. The HSP90 inhibitor ganetespib has chemosensitizer and radiosensitizer activity in colorectal cancer. Investig New Drugs. 2014;32(4):577–86. doi: 10.1007/s10637-014-0095-4.CrossRefGoogle Scholar
  74. 74.
    Nilbert M, Planck M, Fernebro E, Borg A, Johnson A. Microsatellite instability is rare in rectal carcinomas and signifies hereditary cancer. Eur J Cancer. 1999;35(6):942–5.CrossRefPubMedGoogle Scholar
  75. 75.
    Hong SP, Min BS, Kim TI, Cheon JH, Kim NK, Kim H, et al. The differential impact of microsatellite instability as a marker of prognosis and tumour response between colon cancer and rectal cancer. Eur J Cancer. 2012;48(8):1235–43. doi: 10.1016/j.ejca.2011.10.005.CrossRefPubMedGoogle Scholar
  76. 76.
    Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5(1):43–51. doi: 10.1158/2159-8290.CD-14-0863.CrossRefPubMedGoogle Scholar
  77. 77.
    Xiao Y, Freeman GJ. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov. 2015;5(1):16–8. doi: 10.1158/2159-8290.CD-14-1397.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Phase 2 Study of MK-3475 in Patients With Microsatellite Unstable (MSI) Tumors. 2013. https://clinicaltrials.gov/ct2/show/NCT01876511/.
  79. 79.
    Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006;38(7):787–93. doi: 10.1038/ng1834.CrossRefPubMedGoogle Scholar
  80. 80.
    Study of Imprime PGG® in Combination With Cetuximab in Subjects With Recurrent or Progressive KRAS Wild Type Colorectal Cancer (PRIMUS). 2011. https://clinicaltrials.gov/ct2/show/NCT01309126.

Copyright information

© Springer Japan 2018

Authors and Affiliations

  1. 1.Department of Medicine (Oncology)Stanford University Comprehensive Cancer CenterStanfordUSA
  2. 2.Department of Surgery (Colorectal)Stanford University Comprehensive Cancer CenterStanfordUSA

Personalised recommendations