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Exciting New Targets in Lung Cancer Therapy: ALK, IGF-1R, HDAC, and Hh

  • Lung Cancer
  • Published:
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Opinion statement

The anaplastic lymphoma kinase (ALK) inhibitor crizotinib will become an integral addition to the treatment of patients with non-small cell lung cancer (NSCLC) harboring genetic ALK translocations. The insulin-like growth factor receptor (IGF-1R) monoclonal antibody figitumumab, while initially promising, appears to increase toxicity and death in combination with chemotherapy in the treatment of patients with NSCLC of squamous histology; therefore, clinical development of this class of agents will need to proceed with caution. The histone deacetylation (HDAC) inhibitor vorinostat did not demonstrate an improvement in overall survival (OS) compared with placebo in a large randomized trial, but other agents in this class may have greater selectivity and efficacy. Inhibitors of the hedgehog (Hh) signaling pathways have some early clinical promise in both NSCLC and small cell lung cancer (SCLC), and larger studies using these agents are eagerly anticipated.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. American Cancer Society: Cancer Facts & Figures 2009. Atlanta: American Cancer Society; 2009

  2. Morris SW, Naeve C, Mathew P, et al.: ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin’s lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene 1997, 14(18):2175–2188.

    Article  CAS  PubMed  Google Scholar 

  3. Iwahara T, Fujimoto J, Wen D, et al.: Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene 1997, 14(4):439–449.

    Article  CAS  PubMed  Google Scholar 

  4. Morris SW, Kirstein MN, Valentine MB, et al.: Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994, 263(5151):1281–1284.

    Article  CAS  PubMed  Google Scholar 

  5. Soda M, Choi YL, Enomoto M, et al.: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007, 448(7153):561–566.

    Article  CAS  PubMed  Google Scholar 

  6. Amin HM, Lai R: Pathobiology of ALK+ anaplastic large-cell lymphoma. Blood 2007, 110(7):2259–2267.

    Article  CAS  PubMed  Google Scholar 

  7. Shaw AT, Yeap BY, Mino-Kenudson M, et al.: Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009, 27(26):4247–4253.

    Article  CAS  PubMed  Google Scholar 

  8. Rodig SJ, Mino-Kenudson M, Dacic S, et al.: Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 2009, 15(16):5216–5223.

    Article  CAS  PubMed  Google Scholar 

  9. Koivunen JP, Mermel C, Zejnullahu K, et al.: EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008, 14(13):4275–4283.

    Article  CAS  PubMed  Google Scholar 

  10. Takeuchi K, Choi YL, Soda M, et al.: Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res 2008, 14(20):6618–6624.

    Article  CAS  PubMed  Google Scholar 

  11. Mino-Kenudson M, Chirieac LR, Law K, et al.: A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res 2010, 16(5):1561–1571.

    Article  CAS  PubMed  Google Scholar 

  12. Sharma SV, Fischbach MA, Haber DA, Settleman J: “Oncogenic shock”: explaining oncogene addiction through differential signal attenuation. Clin Cancer Res 2006, 12(14 Pt 2):4392s–4395s.

    Article  CAS  PubMed  Google Scholar 

  13. Bang Y, Kwak EL, Shaw AT, et al.: Clinical activity of the oral ALK inhibitor PF-02341066 in ALK-positive patients with non-small cell lung cancer (NSCLC). J Clin Oncol 2010, 28(7s): Abstract 3

This remarkable phase I clinical trial demonstrates that patients with NSCLC and genetic translocation of the ALK gene respond to crizotinib, an oral ALK tyrosine kinase inhibitor.

  1. Li R, Morris SW: Development of anaplastic lymphoma kinase (ALK) small-molecule inhibitors for cancer therapy. Med Res Rev 2008, 28(3):372–412.

    Article  CAS  PubMed  Google Scholar 

  2. De Meyts P: Insulin and its receptor: structure, function and evolution. Bioessays 2004, 26(12):1351–1362.

    Article  PubMed  Google Scholar 

  3. Pollak M: Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 2008, 8(12):915–928.

    Article  CAS  PubMed  Google Scholar 

This is a comprehensive review of the discovery of IGF and the emerging role of this signaling pathway in cancer.

  1. Schernhammer ES, Holly JM, Hunter DJ, Pollak MN, Hankinson SE: Insulin-like growth factor-I, its binding proteins (IGFBP-1 and IGFBP-3), and growth hormone and breast cancer risk in The Nurses Health Study II. Endocr Relat Cancer 2006, 13(2):583–592.

    Article  CAS  PubMed  Google Scholar 

  2. Pollak MN, Schernhammer ES, Hankinson SE: Insulin-like growth factors and neoplasia. Nat Rev Cancer 2004, 4(7):505–518.

    Article  CAS  PubMed  Google Scholar 

  3. Chan JM, Stampfer MJ, Ma J, et al.: Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. J Natl Cancer Inst 2002, 94(14):1099–1106

    Google Scholar 

  4. Spitz MR, Barnett MJ, Goodman GE, Thornquist MD, Wu X, Pollak M: Serum insulin-like growth factor (IGF) and IGF-binding protein levels and risk of lung cancer: a case-control study nested in the beta-Carotene and Retinol Efficacy Trial Cohort. Cancer Epidemiol Biomarkers Prev 2002, 11(11):1413–1418.

    CAS  PubMed  Google Scholar 

  5. Lee YJ, Imsumran A, Park MY, et al.: Adenovirus expressing shRNA to IGF-1R enhances the chemosensitivity of lung cancer cell lines by blocking IGF-1 pathway. Lung Cancer 2007, 55(3):279–286.

    Article  PubMed  Google Scholar 

  6. Guix M, Faber AC, Wang SE, et al.: Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest 2008, 118(7):2609–2619.

    CAS  PubMed  Google Scholar 

  7. Iwasa T, Okamoto I, Suzuki M, et al.: Inhibition of insulin-like growth factor 1 receptor by CP-751, 871 radiosensitizes non-small cell lung cancer cells. Clin Cancer Res 2009, 15(16):5117–5125.

    Article  CAS  PubMed  Google Scholar 

  8. Karp DD, Pollak MN, Cohen RB, et al.: Safety, pharmacokinetics, and pharmacodynamics of the insulin-like growth factor type 1 receptor inhibitor figitumumab (CP-751, 871) in combination with paclitaxel and carboplatin. J Thorac Oncol 2009, 4(11):1397–1403.

    Article  PubMed  Google Scholar 

  9. Karp DD, Paz-Ares LG, Novello S, et al.: Phase II study of the anti-insulin-like growth factor type 1 receptor antibody CP-751, 871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. J Clin Oncol 2009, 27(15):2516–2522.

    Article  CAS  PubMed  Google Scholar 

  10. Jassem J, Langer CJ, Karp DD, et al.: Randomized, open label, phase III trial of figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC). J Clin Oncol 2010, 28(7s):Abstract 7500

  11. Gualberto A, Dolled-Filhart MP, Hixon ML, et al.: Molecular bases for sensitivity to figitumumab (CP-751, 871) in NSCLC. J Clin Oncol 2009, 27(15s):Abstract 8091

    Google Scholar 

  12. Olmos D, Postel-Vinay S, Molife LR, et al.: Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751, 871) in patients with sarcoma and Ewing’s sarcoma: a phase 1 expansion cohort study. Lancet Oncol 2010, 11(2):129–135.

    Article  CAS  PubMed  Google Scholar 

  13. Lindsay CR, Chan E, Evans TR, et al.: Phase I dose escalation study of continuous oral dosing of OSI-906, an insulin like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor, in patients with advanced solid tumors. J Clin Oncol 2009, 27(18s): Abstract 2559

    Google Scholar 

  14. Gregory PD, Wagner K, Horz W: Histone acetylation and chromatin remodeling. Exp Cell Res 2001, 265(2):195–202.

    Article  CAS  PubMed  Google Scholar 

  15. Schrump DS: Cytotoxicity mediated by histone deacetylase inhibitors in cancer cells: mechanisms and potential clinical implications. Clin Cancer Res 2009, 15(12):3947–3957.

    Article  CAS  PubMed  Google Scholar 

  16. Gu W, Roeder RG: Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 1997, 90(4):595–606.

    Article  CAS  PubMed  Google Scholar 

  17. Patel JH, Du Y, Ard PG, et al.: The c-MYC oncoprotein is a substrate of the acetyltransferases hGCN5/PCAF and TIP60. Mol Cell Biol 2004, 24(24):10826–10834.

    Article  CAS  PubMed  Google Scholar 

  18. Kovacs JJ, Murphy PJ, Gaillard S, et al.: HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 2005, 18(5):601–607.

    Article  CAS  PubMed  Google Scholar 

  19. Olsen EA, Kim YH, Kuzel TM, et al.: Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 2007, 25(21):3109–3115.

    Article  CAS  PubMed  Google Scholar 

  20. Traynor AM, Dubey S, Eickhoff JC, et al.: Vorinostat (NSC# 701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network phase II study. J Thorac Oncol 2009, 4(4):522–526.

    Article  PubMed  Google Scholar 

  21. Ramalingam SS, Parise RA, Ramanathan RK, et al.: Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin Cancer Res 2007, 13(12):3605–3610.

    Article  CAS  PubMed  Google Scholar 

  22. Ramalingam SS, Maitland ML, Frankel P, et al.: Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J Clin Oncol 2010, 28(1):56–62.

    Article  CAS  PubMed  Google Scholar 

  23. Belani C, Ramalingam S, Kalemkerian G, et al.: Randomized, double-blind phase II/III study of first-line paclitaxel (P) plus carboplatin (C) in combination with vorinostat or placebo in patients with advanced non-small-cell lung cancer (NSCLC). Eur J Cancer Suppl 2009, 7(2):507, Abstract O-9007

    Google Scholar 

  24. Witta SE, Gemmill RM, Hirsch FR, et al.: Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res 2006, 66(2):944–950.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang W, Peyton M, Xie Y, et al.: Histone deacetylase inhibitor romidepsin enhances anti-tumor effect of erlotinib in non-small cell lung cancer (NSCLC) cell lines. J Thorac Oncol 2009, 4(2):161–166.

    Article  PubMed  Google Scholar 

  26. Ho L, Stojanovski A, Whetstone H, et al.: Gli2 and p53 cooperate to regulate IGFBP-3- mediated chondrocyte apoptosis in the progression from benign to malignant cartilage tumors. Cancer Cell 2009, 16(2):126–136.

    Article  CAS  PubMed  Google Scholar 

  27. Bigelow RL, Chari NS, Unden AB, et al.: Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1. J Biol Chem 2004, 279(2):1197–1205.

    Article  CAS  PubMed  Google Scholar 

  28. Oliver TG, Grasfeder LL, Carroll AL, et al.: Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc Natl Acad Sci USA 2003, 100(12):7331–7336.

    Article  CAS  PubMed  Google Scholar 

  29. Gorlin RJ: Nevoid basal cell carcinoma (Gorlin) syndrome. Genet Med 2004, 6(6):530–539.

    Article  PubMed  Google Scholar 

  30. Gailani MR, Stahle-Backdahl M, Leffell DJ, et al.: The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet 1996, 14(1):78–81.

    Article  CAS  PubMed  Google Scholar 

  31. Xie J, Murone M, Luoh SM, et al.: Activating smoothened mutations in sporadic basal-cell carcinoma. Nature 1998, 391(6662):90–92.

    Article  CAS  PubMed  Google Scholar 

  32. Reifenberger J, Wolter M, Knobbe CB, et al.: Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol 2005, 152(1):43–51.

    Article  CAS  PubMed  Google Scholar 

  33. Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA, Baylin SB: Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003, 422(6929):313–317.

    Article  CAS  PubMed  Google Scholar 

  34. Vestergaard J, Pedersen MW, Pedersen N, et al.: Hedgehog signaling in small-cell lung cancer: frequent in vivo but a rare event in vitro. Lung Cancer 2006, 52(3):281–290.

    Article  PubMed  Google Scholar 

  35. Yuan Z, Goetz JA, Singh S, et al.: Frequent requirement of hedgehog signaling in non-small cell lung carcinoma. Oncogene 2007, 26(7):1046–1055.

    Article  CAS  PubMed  Google Scholar 

  36. Yauch RL, Gould SE, Scales SJ, et al.: A paracrine requirement for hedgehog signalling in cancer. Nature 2008, 455(7211):406–410.

    Article  CAS  PubMed  Google Scholar 

  37. Zhao C, Chen A, Jamieson CH, et al.: Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 2009, 458(7239):776–779.

    Article  CAS  PubMed  Google Scholar 

  38. Chen JK, Taipale J, Cooper MK, Beachy PA: Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 2002, 16(21):2743–2748.

    Article  CAS  PubMed  Google Scholar 

  39. Stanton BZ, Peng LF, Maloof N, et al.: A small molecule that binds Hedgehog and blocks its signaling in human cells. Nat Chem Biol 2009, 5(3):154–156.

    Article  CAS  PubMed  Google Scholar 

  40. Hyman JM, Firestone AJ, Heine VM, et al.: Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade. Proc Natl Acad Sci USA 2009, 106(33):14132–14137.

    Article  CAS  PubMed  Google Scholar 

  41. Rudin CM, Hann CL, Laterra J, et al.: Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 2009, 361(12):1173–1178.

    Article  CAS  PubMed  Google Scholar 

  42. Von Hoff DD, LoRusso PM, Rudin CM, et al.: Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 2009, 361(12):1164–1172.

    Article  Google Scholar 

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Authors and Affiliations

  1. Stanford Cancer Center, 875 Blake Wilbur Drive, Stanford, CA, 94305, USA

    Joel W. Neal MD, PhD

  2. Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA, 02114, USA

    Lecia V. Sequist MD, MPH

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  1. Joel W. Neal MD, PhD
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Correspondence to Joel W. Neal MD, PhD.

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Neal, J.W., Sequist, L.V. Exciting New Targets in Lung Cancer Therapy: ALK, IGF-1R, HDAC, and Hh. Curr. Treat. Options in Oncol. 11, 36–44 (2010). https://doi.org/10.1007/s11864-010-0120-6

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