Network-targeted combination therapy : a new concept in cancer treatment

Toxicity is a major concern for anti-neoplastic drugs, with much of the existing pharmacopoeia being characterized by a very narrow therapeutic index. ‘Network-targeted’ combination therapy is a promising new concept in cancer therapy, whereby therapeutic index might be improved by targeting multiple nodes in a cell's signaling network, rather than a single node. Here, we examine the potential of this novel approach, illustrating how therapeutic benefit could be achieved with smaller doses of the necessary agents.

[1]  J Verweij,et al.  Dosing strategies for anticancer drugs: the good, the bad and body-surface area. , 2002, European journal of cancer.

[2]  Samuel Singer,et al.  PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors , 2003, Science.

[3]  R P Araujo,et al.  A mathematical model of combination therapy using the EGFR signaling network. , 2005, Bio Systems.

[4]  P. Cohen Protein kinases — the major drug targets of the twenty-first century? , 2002, Nature reviews. Drug discovery.

[5]  Chi-Ying F. Huang,et al.  Ultrasensitivity in the mitogen-activated protein kinase cascade. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[6]  M. Broggini,et al.  New molecules and strategies in the field of anticancer agents. , 2004, Current medicinal chemistry. Anti-cancer agents.

[7]  B. Kholodenko,et al.  Quantification of Short Term Signaling by the Epidermal Growth Factor Receptor* , 1999, The Journal of Biological Chemistry.

[8]  P. Harari,et al.  Combining EGFR inhibitors with radiation or chemotherapy: will preclinical studies predict clinical results? , 2004, International journal of radiation oncology, biology, physics.

[9]  M. Barthelemy,et al.  Connectivity distribution of spatial networks. , 2003, Physical review. E, Statistical, nonlinear, and soft matter physics.

[10]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[11]  B. Duenweg,et al.  散逸粒子動力学:平衡および非平衡分子動力学シミュレーションのための有用なサーモスタット(原標題は英語) , 2003 .

[12]  C. Langer,et al.  Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC. , 2004, International journal of radiation oncology, biology, physics.

[13]  G. Fontanini,et al.  Oral administration of a novel taxane, an antisense oligonucleotide targeting protein kinase A, and the epidermal growth factor receptor inhibitor Iressa causes cooperative antitumor and antiangiogenic activity. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[14]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[15]  L. Mirny,et al.  Protein complexes and functional modules in molecular networks , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  N. Saba,et al.  Molecular biological design of novel antineoplastic therapies , 2004, Expert opinion on investigational drugs.

[17]  Katherine C. Chen,et al.  Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. , 2003, Current opinion in cell biology.

[18]  M. Piccart,et al.  New anticancer agents and therapeutic strategies in development for solid cancers: a clinical perspective , 2004, Expert review of anticancer therapy.

[19]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[20]  J. Fletcher,et al.  Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs) , 2004, Oncogene.

[21]  N. Saijo,et al.  Synergistic interaction between the EGFR tyrosine kinase inhibitor gefitinib (“Iressa”) and the DNA topoisomerase I inhibitor CPT‐11 (irinotecan) in human colorectal cancer cells , 2004, International journal of cancer.

[22]  S. Shankar,et al.  Enhancement of therapeutic potential of TRAIL by cancer chemotherapy and irradiation: mechanisms and clinical implications. , 2004, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[23]  Nils Blüthgen,et al.  How robust are switches in intracellular signaling cascades? , 2003, Journal of theoretical biology.

[24]  J. Baselga,et al.  Clinical trial design and end points for epidermal growth factor receptor-targeted therapies: implications for drug development and practice. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[25]  U Alon,et al.  Generation of oscillations by the p53-Mdm2 feedback loop: a theoretical and experimental study. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[26]  A. D. Van den Abbeele,et al.  Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  M. Ranson ZD1839 (Iressa): for more than just non-small cell lung cancer. , 2002, The oncologist.

[28]  E. Sausville,et al.  In vitro Combination Treatment with Perifosine and UCN-01 Demonstrates Synergism against Prostate (PC-3) and Lung (A549) Epithelial Adenocarcinoma Cell Lines , 2004, Clinical Cancer Research.

[29]  B. Kholodenko,et al.  Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades. , 2000, European journal of biochemistry.

[30]  P. Bunn,et al.  ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, alone and in combination with radiation and chemotherapy as a new therapeutic strategy in non-small cell lung cancer. , 2002, Seminars in oncology.

[31]  Michael Veit [New strategies for drug development]. , 2004, Berliner und Munchener tierarztliche Wochenschrift.