Strategies to Optimize the MolecularlyTargeted Anti-Cancer Agent Combinations

Yıl 2015, Cilt: 24 Sayı: 4, 432 - 451, 15.09.2015

Ayşe Erdogan Aysun Özkan

https://doi.org/10.17827/aktd.55888

Öz

Cytotoxic agents which are used in cancer chemotherapy reduced several times the number of neoplastic cells but not fully. Therefore, usage of “targeted therapeutics" which were developed with much more rational approach is increasing markedly in patients with solid cancer. Targeted therapeutics due to 'selective targets' aims cancer cells with specific molecular defect thereby, kils the cancer cells, which makes it possible to continue normal cells in a healthy environment. The rapid emergence of hundreds of new agents that modulates ever-growing list of the cancer-specific molecular targets promise great hope for cancer patients. Evaluation of the target agent individually, in combination with standard therapy and other target agents bring about important development challenges. As possible combinations of drugs number is unlimited, the identification of the most promising combinations and giving priority to assessing their strategies are very important.In this article important elements of the development strategy of the target agent combinations will be considered. Difficulties in this kind of combinations of rational pre-clinical and clinical evaluation and possible approaches to overcome these challenges will be discussed.

Anahtar Kelimeler

Molecularly targeted anti-cancer agents, cancer therapeutic targets

Moleküler Hedefli Anti-Kanser Ajan Kombinasyonlarını Optimize Etmek İçin Stratejiler

Öz

Kanser kemoterapisinde kullandığımız sitotoksik ajanlar, neoplastik hücrelerin sayılarını birkaç kat azalmakta, ancak tam olarak yok edememektedir. Bu nedenle solid kanserli hastalarda çok daha rasyonel yaklaşımla geliştirilmiş olan ‘hedeflenmiş terapötikler’in kullanımları belirgin bir şekilde artmaktadır. Hedeflenmiş terapötikler ‘seçici hedefleri’ nedeniyle ‘özgül-moleküler defekti’ olan tümor hücrelerine yönelerek kanser hücresini öldürürken normal hücrelerin sağlıklı bir ortamda devamına imkan tanımaktadır. Kansere özgü moleküler hedeflerin sürekli büyüyen listesini modüle eden yüzlerce yeni ajanların hızla ortaya çıkması kanser hastaları için büyük umut vaat etmektedir. Hedef ajanların tek olarak, standart tedaviler ile ve diğer hedef ajanları ile kombinasyonlarının değerlendirilmesi önemli gelişim zorluklarını da beraberinde getirmektedir. Olası ilaç kombinasyonlarının sayısı gerçekte sınırsız olduğundan, en umut verici kombinasyonların belirlenmesine ve bunların değerlendirilmesine öncelik verecek olan stratejiler çok önemlidir. Burada, hedef ajan kombinasyonlarının gelişim stratejilerinin önemli unsurları dikkate alınacaktır. Bu tür kombinasyonların rasyonel pre-klinik ve klinik değerlendirmelerindeki zorluklar ve bu zorlukların üstesinden gelmek için olası yaklaşımlar gözden geçirilecektir

Anahtar Kelimeler

Moleküler hedefli anti-kanser ajanları, kanser tedavi hedefleri

Kaynakça

• Beeram M, Patnaik A. Targeting intracellular signal transduction. Hematol Oncol Clin North Amer. 2002;16:1089-100.
• Chaplin DJ, Dougherty GJ. Tumour vasculature as a therapeutic strategy for cancer. Cancer Metastasis Rev. 1990;9:267.
• Bicknell R, Harris AL. Anticancer strategies involving the vasculature: vascular targeting and the inhibition of angiogenesis. Semin Cancer Biol. 1992;3:399-407.
• Goss G, Gauthier I. Targeted therapies: promising a better future for patients. Signal. 2004;5:2.
• Kansu E. Hedeflenmiş tedavilerde “Hedef” moleküller. ANKEM Derg. 2005;19(Ek 2): 112-6.
• Dancey JE, Chen HE. Strategies for optimizing combinations of molecularly targeted anticancer agents. Nat Rev Drug Discov. 2006;5:649-58.
• Druker BJ, Moshe T, Resta DJ, Peng B, Buchdunger E, Ford JM et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344;1031–7.
• 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;344:783–92.
• Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial-INTACT 2. J Clin Oncol. 2004;22:785–94.
• Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial-INTACT 1. J Clin Oncol. 2004;22:777–84.
• Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005;23: 5892–9.
• Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S et al. Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG]. J Clin Oncol ASCO Ann Mtg Proc. 2005;23:A1.
• 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;350:2335–42.
• Miller K et al. First-line bevacizumab and paclitaxel in patients with locally recurrent or metastatic breast cancer: a randomized, phase III trial coordinated by the Eastern Cooperative Oncology Group (E2100). Eur J Cancer Suppl ECCO 13 Abstract Book. 2005;3:77 A275.
• Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005;23:792–9.
• Sandler AB, Gray R, Brahmer J, Dowlati A, Schiller JH, Perry MC, Johnson DH. Randomized phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial- E4599. J Clin Oncol. 2005;24:A4.
• Kirkwood JM, Bedikian AY, Millward MJ, Conry RM, Gore ME, Pehamberger HE et al. Long-term survival results of a randomized multinational phase 3 trial of dacarbazine (DTIC) with or without Bcl-2 antisense (oblimersen sodium) in patients (pts) with advanced malignant melanoma (MM). J Clin Oncol. 2005;24:A7506.
• Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 2005;23:8646–54.
• 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;354:567–78.
• De Soto JA, Bowen D, Davis JH, Southerland WM, Hawkins MJr. Sequence- and timedependent antagonism between raloxifene and methotrexate in human breast cancer cells. AntiCancer Res. 2002;22:1007–9.
• Osborne CK, Kitten L, Arteaga CL. Antagonism of chemotherapy-induced cytotoxicity for human breast cancer cells by antiestrogens. J Clin Oncol. 1989;7:710–7.
• Albain K, Gren SJ, Ravdin PM, Cobau CD, Levine EG, Ingle JN et al. Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol. 2002;21:A143.
• Tabernero J, Schoffski P, Rojo F, de Brujin E, Ramos FJ, Dumez H et al. Combined anti-EGFR blockade: A Phase I pharmacokinetic and molecular pharmacodynamic study of cetuximab (Erbitux) and gefitinib (Iressa) in patients with advanced colorectal, head and neck and non-small cell lung cancer expressing the EGFR. Clin Cancer Res. 2005;11:8990s Abs. A107.
• Milton DT, Kris MG, Azzoli CG, Gomez JE, Helan R, Krug LM et al. Phase I/II trial of gefitinib and RAD001 (Everolimus) in patients (pts) with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2005;24:A7104.
• Reardon DA, Quinn JA, Vredenburgh JJ,Gururangan S, Friedman AH, Desjardins A et al. Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res. 2006;12:860–8.
• Moulder SL, Arteaga CL. A Phase I/II trial of trastuzumab and gefitinib in patients with Metastatic Breast Cancer that overexpresses HER2/neu (ErbB-2). Clin Breast Cancer. 2003;4:142–5.
• Britten CD, Pegram M, Rosen P, Finn RS, Wax A, Bosseman L et al. Targeting ErbB receptor interactions: A phase I trial of trastuzumab and erlotinib in metastatic HER2+ breast cancer. J Clin Oncol. 2004;22:A3045.
• Saltz LB, Lenz HJ, Hochster H, Wadler S, Hoff P, Kemeny N et al. Randomized Phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan- refractory colorectal cancer. Proc Am Soc Clin Oncol. 2005;24:A3508.
• Hainsworth JD, Somsan JA, Spigel DR, Edwards DL, Baughman C, Greco A. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol. 2005;23:7889–96.
• Herbst RS, Johnson DH, Mininberg E, Carbone DP, Henderson T, Kim ES et al. Phase I/II trial evaluating the antivascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/ epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent nonsmall-cell lung cancer. J Clin Oncol 2005;23:2544–55.
• Posadas EM, Kwitkowski V, Lie M, Kotz H, Minasian L, Sarosy G et al. Clinical synergism from combinatorial VEGF signal transduction inhibition in patients with advanced solid tumors-early results from a Phase I study of sorafenib (BAY 43–9006) and bevacizumab. Eur J Cancer. 2005;3 (Suppl.):A1450.
• Moulder SL, Arteaga CL. A Phase I/II trial of trastuzumab and gefitinib in patients with Metastatic Breast Cancer that overexpresses HER2/neu (ErbB-2). Clin Breast Cancer. 2003;4:142–5.
• Genentech, Inc. Genentech announces preliminary results from randomized Phase II trial of Avastin and Tarceva in kidney cancer. Press Release October [online] 2005, oryid=4>.
• Normanno N, Campiglio M, De LA, Somenzi G, Maiello M, Ciardiello F et al. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. Ann Oncol. 2002;13:65–72.
• Baselga J, Albanell J, Ruiz A, Lluch A, Gascón P, Guillém V. et al. Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol. 2005;23:5323–333.
• Kelland LR. Of mice and men: values and liabilities of the athymic nude mouse model in anticancer drug development. Eur J Cancer. 2004;40:827–36.
• Shinn C, Larsen D, Suarez JR. Flavopiridol sensitivity of chronic lymphocytic leukemia (CLL) cells in vitro varies based upon species specific drug protein binding. Blood. 2000;96:294b.
• Gitler MS, Monks A, Sausville EA. Preclinical models for defining efficacy of drug combinations: mapping the road to the clinic. Mol Cancer Ther. 2003;2:929–32.
• Reynolds CP, Maurer BJ. Evaluating response to antineoplastic drug combinations in tissue culture models. Methods Mol Med. 2005;110:173–83.
• Houghton PJ, Stewart CF, Cheshire PJ, Richmond LB, Kirstein MN, Poquette CA et al. Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine- DNA methyltransferase and mismatch repair phenotypes in xenograft models. Clin Cancer Res. 2000;6:4110–8.
• Meco D, Colombo T, Ubezio P, Zucchetti M, Zaffaroni M, Riccardi A et al. Effective combination of ET-743 and doxorubicin in sarcoma: preclinical studies. Cancer Chemother Pharmacol. 2003;52:131–8.
• Tan M, Fang HB, Tian GL, Houghton PJ. Experimental design and sample size determination for testing synergism in drug combination studies based on uniform measures. Stat Med. 2003;22:2091–100.
• Ferguson PJ, Cheng YC. Phenotypic instability of drug sensitivity in a human colon carcinoma cell line. Cancer Res. 1989;49:1148–53.
• Smith A, van Haaften-Day C, Russell P. Sequential cytogenetic studies in an ovarian cancer cell line. Cancer Genet Cytogenet. 1989;38:13–24.
• Ciardiello F, Bianco R, Caputo R, Caputo R, Damiano V, Troiani T et al. Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy. Clin Cancer Res. 2004;10:784–93.
• Jones HE, Goddard L, Gee JM, Hiscox S, Rubini M, Barrow D et al. Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer. 2004;11:793–814.
• Solit DB, She Y, Lobo J, Kris MG, Scher HI, Rosen N et al. Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumors to paclitaxel. Clin Cancer Res. 2005;11:1983–9.
• Kaelin WG Jr. The concept of synthetic lethality in the context of anticancer therapy. Nature Rev Cancer. 2005;5:689–98.
• Siemann DW, Chaplin DJ, Horsman MR. Vascular targeting therapies for treatment of malignant diseases. Cancer. 2004;100:2491-9.
• Correspondence Address / Yazışma Adresi