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Targeted cancer therapy

Abstract

Disruption of the normal regulation of cell-cycle progression and division lies at the heart of the events leading to cancer. Complex networks of regulatory factors, the tumour microenvironment and stress signals, such as those resulting from damaged DNA, dictate whether cancer cells proliferate or die. Recent progress in understanding the molecular changes that underlie cancer development offer the prospect of specifically targeting malfunctioning molecules and pathways to achieve more effective and rational cancer therapy.

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Figure 1: Cancer pathways and targeted therapy.

References

  1. Sawyers, C. L. Opportunities and challenges in the development of kinase inhibitor therapy for cancer. Genes Dev. 17, 2998–3010 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Sordella, R., Bell, D. W., Haber, D. A. & Settleman, J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305, 1163–1167 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Stephens, P. et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431, 525–526 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Bardelli, A. et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300, 949–950 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Cools, J. et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N. Engl. J. Med. 348, 1201–1214 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Rubin, B. P. et al. Molecular targeting of platelet-derived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J. Clin. Oncol. 20, 3586–3591 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. De Angelo, D. J. et al. Phase I clinical results with MLN518, a novel FLT3 antagonist: tolerability, pharmacokinetics, and pharmacodynamics. Blood 102 (65a), Abstr. 219 (2003).

    Google Scholar 

  11. Stone, R. M. et al. Oral PKC 412 has activity in patients (pts) with mutant FLT3 acute myeloid leukemia (AML): a phase II trial. Proc. Am. Soc. Clin. Oncol. Abstr. 22, 563 (2003).

    Google Scholar 

  12. Smith, B. D. et al., Single agent CEP-701, a novel FLT3 inhibitor, shows initial response in patients with refractory acute myeloid leukemia. Proc. Am. Soc. Clin. Oncol. Abstr. 22, 194 (2003).

    Google Scholar 

  13. Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876–880 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Shah, N. P. et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2, 117–125 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Branford, S. et al. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood 99, 3472–3475 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Shah, N. P. et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305, 399–401 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Romer, J. T. et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/−)p53(−/−) mice. Cancer Cell 6, 229–240 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Wolfel, T. et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269, 1281–1284 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Williams, M. E., Swerdlow, S. H. & Meeker, T. C. Chromosome t(11;14)(q13;q32) breakpoints in centrocytic lymphoma are highly localized at the bcl-1 major translocation cluster. Leukemia 7, 1437–1440 (1993).

    CAS  PubMed  Google Scholar 

  20. Sawyers, C. L. Will mTOR inhibitors make it as cancer drugs? Cancer Cell 4, 343–348 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Hughes, T. P. et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N. Engl. J. Med. 349, 1423–1432 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Graham, S. M. et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99, 319–325 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Bhatia, R. et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 101, 4701–4707 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Chu, S. et al. Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood published online 2 September 2004 (doi: 10.1182/blood-2004-03-1114).

  25. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Yang, J. C. et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 349, 427–434 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ratain et al. ASCO annual meeting proceedings (post-meeting edn). J. Clin. Oncol. 22, (no. 14 suppl.) 4501 (2004).

    Article  Google Scholar 

  28. Motzer et al. ASCO annual meeting proceedings (post-meeting edn). J. Clin. Oncol. 22, (no. 14 suppl.) 4500 (2004).

    Article  Google Scholar 

  29. Kaelin, W. G., Jr Molecular basis of the VHL hereditary cancer syndrome. Nature Rev. Cancer 2, 673–682 (2002).

    Article  CAS  Google Scholar 

  30. Bhowmick, N. A. et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303, 848–851 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  31. Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

    CAS  PubMed  Google Scholar 

Download references

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Sawyers, C. Targeted cancer therapy. Nature 432, 294–297 (2004). https://doi.org/10.1038/nature03095

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