Novel Targets for Therapeutic Agents in Small Cell Lung Cancer

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Patrick C. Ma Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medical Center, Pritzker School of Medicine, Chicago, Illinois

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Ravi Salgia Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medical Center, Pritzker School of Medicine, Chicago, Illinois

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Small cell lung cancer (SCLC) is known to have an aggressive phenotype and often presents with distant metastasis. Despite frequent initial response to chemotherapy, it inevitably relapses within 2 years in the majority of patients. Because of the poor overall prognosis of the disease and its unique tumor biology, the opportunity for improving clinical outcome of patients with development of novel therapeutics is great. This review provides current insights into the novel molecular targets in SCLC. Cellular signal transduction pathways and their relationship to cellular functions also are discussed. Discussion of the role receptor tyrosine kinases (RTKs) have in SCLC therapeutic inhibition is emphasized. In particular, the recent development of small molecule inhibitors of RTKs such as c-Kit, c-Met, and VEGF-R and the potential for clinical trials are highlighted.

Ravi Salgia is supported by an award from the American Cancer Society (Research Scholar Grant CCE-102606). Patrick C. Ma is supported by the American Association for Cancer Research (AACR)-AstraZeneca-Cancer Research and Prevention Foundation Fellowship in Translational Lung Cancer Research, and an American Cancer Society (ACS) Institutional Research Grant (American Cancer Society IRG-58-004-44).

Correspondence: Ravi Salgia, MD, PhD, Section of Hematology/Oncology, The University of Chicago Medical Center, Pritzker School of Medicine, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637. E-mail: rsalgia@medicine.bsd.uchicago.edu
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  • 1

    Jemal A, Murray T, Samuels A et al.. Cancer statistics, 2003. CA Cancer J Clin 2003;53:526.

  • 2

    Strauss GM, Kwiatkowski DJ, Harpole DH et al.. Molecular and pathologic markers in stage I non-small-cell carcinoma of the lung. J Clin Oncol 1995;13:12651279.

  • 3

    Turrisi AT 3rd, Kim K, Blum R et al.. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340:265271.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Devereux TR, Taylor JA, Barrett JC. Molecular mechanisms of lung cancer. Interaction of environmental and genetic factors: Giles F. Filley Lecture. Chest 1996;109:14S19S.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Sattler M, Salgia R. Molecular and cellular biology of small cell lung cancer. Semin Oncol 2003;30:5771.

  • 6

    Hibi K, Takahashi T, Yamakawa K et al.. Three distinct regions involved in 3p deletion in human lung cancer. Oncogene 1992;7:445449.

  • 7

    Whang-Peng J, Bunn PA Jr, Kao-Shan CS et al.. A nonrandom chromosomal abnormality, del 3p(14-23), in human small cell lung cancer (SCLC). Cancer Genet Cytogenet 1982;6:119134.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Otterson G, Lin A, Kay F. Genetic etiology of lung cancer. Oncology (Huntingt) 1992;6:97-104, 107; discussion 108, 111–102.

  • 9

    Kok K, Osinga L, Carritt B, Davis MB et al.. Deletion of a DNA sequence at the chromosomal region 3p21 in all major types of lung cancer. Nature 1987;330:578581.

  • 10

    Naylor SL, Johnson BE, Minna JD, Sakaguchi AY. Loss of heterozygosity of chromosome 3p markers in small-cell lung cancer. Nature 1987;329:451454.

  • 11

    Sozzi G, Veronese ML, Negrini M et al.. The FHIT gene 3p14.2 is abnormal in lung cancer. Cell 1996;85:1726.

  • 12

    Ji L, Fang B, Yen N et al.. Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression. Cancer Res 1999;59:33333339.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Roche J, Boldog F, Robinson M et al.. Distinct 3p21.3 deletions in lung cancer and identification of a new human semaphorin. Oncogene 1996;12:12891297.

  • 14

    Sekido R, Takagi T, Okanami M et al.. Organization of the gene encoding transcriptional repressor deltaEF1 and cross-species conservation of its domains. Gene 1996;173:227232.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Latif F, Tory K, Gnarra J et al.. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993;260:13171320.

  • 16

    Miura I, Graziano SL, Cheng JQ et al.. Chromosome alterations in human small cell lung cancer: frequent involvement of 5q. Cancer Res 1992;52:13221328.

  • 17

    Maulik G, Kijima T, Salgia R. Role of receptor tyrosine kinases in lung cancer. Methods Mol Med 2003;74:113125.

  • 18

    Kijima T, Maulik G, Salgia R. Molecular alterations in lung cancer. Impact on prognosis. Methods Mol Med 2003;75:2938.

  • 19

    Reeve JG, Payne JA, Bleehen NM. Production of immunoreactive insulin-like growth factor-I (IGF-I) and IGF-I binding proteins by human lung tumours. Br J Cancer 1990;61:727731.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Minuto F, Del Monte P, Barreca A et al.. Evidence for an increased somatomedin-C/insulin-like growth factor I content in primary human lung tumors. Cancer Res 1986;46:985988.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Yu H, Spitz MR, Mistry J et al.. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis. J Natl Cancer Inst 1999;91:151156.

  • 22

    Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 1997;390:465471.

  • 23

    Matthews W, Jordan CT, Wiegand GW et al.. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell 1991;65:11431152.

  • 24

    Ashman LK. The biology of stem cell factor and its receptor c-Kit. Int J Biochem Cell Biol 1999;31:10371051.

  • 25

    Linnekin D. Early signaling pathways activated by c-Kit in hematopoietic cells. Int J Biochem Cell Biol 1999;31:10531074.

  • 26

    Micke P, Basrai M, Faldum A et al.. Characterization of c-Kit expression in small cell lung cancer: prognostic and therapeutic implications. Clin Cancer Res 2003;9:188194.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Krystal GW, Honsawek S, Litz J, Buchdunger E. The selective tyrosine kinase inhibitor STI571 inhibits small cell lung cancer growth. Clin Cancer Res 2000;6:33193326.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Wang WL, Healy ME, Sattler M et al.. Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571. Oncogene 2000;19:35213528.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Kijima T, Maulik G, Ma PC et al.. Regulation of cellular proliferation, cytoskeletal function, and signal transduction through CXCR4 and c-Kit in small cell lung cancer cells. Cancer Res 2002;62:63046311.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Ma PC, Kijima T, Maulik G et al.. c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res 2003;63:62726281.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Krystal GW, Honsawek S, Kiewlich D et al.. Indolinone tyrosine kinase inhibitors block Kit activation and growth of small cell lung cancer cells. Cancer Res 2001;61:36603668.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Krystal GW, DeBerry CS, Linnekin D, Litz J. Lck associates with and is activated by Kit in a small cell lung cancer cell line: inhibition of SCF-mediated growth by the Src family kinase inhibitor PP1. Cancer Res 1998;58:46604666.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Soria JC, Johnson BE, Chevalier TL. Imatinib in small cell lung cancer. Lung Cancer 2003;41(Suppl 1):S49S53.

  • 34

    Ma PC, Maulik G, Christensen J, Salgia R. c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev 2003;22:309325.

  • 35

    Maulik G, Kijima T, Ma PC et al.. Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. Clin Cancer Res 2002;8:620627.

  • 36

    Stella MC, Comoglio PM. HGF: a multifunctional growth factor controlling cell scattering. Int J Biochem Cell Biol 1999;31:13571362.

  • 37

    Rygaard K, Nakamura T, Spang-Thomsen M. Expression of the proto-oncogenes c-met and c-kit and their ligands, hepatocyte growth factor/scatter factor and stem cell factor, in SCLC cell lines and xenografts. Br J Cancer 1993;67:3746.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Ma PC, Bharti A, Maulik G et al.. Alpha-Haptoglobin and hepatocyte growth factor can potentially serve as tumor markers in small cell lung cancer [Abstr]. Lung Cancer 2003;41:S87.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Sattler M, Pride YB, Ma P et al.. A novel small molecule MET inhibitor induces apoptosis in cells transformed by the oncogenic TPR-MET tyrosine kinase. Cancer Res 2003;63:54625469.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Christensen JG, Schreck R, Burrows J et al.. A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res 2003;63:73457355.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Carpenter CL, Cantley LC. Phosphoinositide kinases. Curr Opin Cell Biol 1996;8:153158.

  • 42

    Rameh LE, Cantley LC. The role of phosphoinositide 3-kinase lipid products in cell function. J Biol Chem 1999;274:83478350.

  • 43

    Moore SM, Rintoul RC, Walker TR et al.. The presence of a constitutively active phosphoinositide 3-kinase in small cell lung cancer cells mediates anchorage-independent proliferation via a protein kinase B and p70s6k-dependent pathway. Cancer Res 1998;58:52395247.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev 1999;13:29052927.

  • 45

    Brazil DP, Hemmings BA. Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 2001;26:657664.

  • 46

    Kops GJ, Burgering BM. Forkhead transcription factors: new insights into protein kinase B (c-Akt) signaling. J Mol Med 1999;77:656665.

  • 47

    Scott PH, Brunn GJ, Kohn AD et al.. Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc Natl Acad Sci USA 1998;95:77727777.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Nave BT, Ouwens M, Withers DJ et al.. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 1999;344(Pt 2):427431.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49

    Stolovich M, Tang H, Hornstein E et al.. Transduction of growth or mitogenic signals into translational activation of TOP mRNAs is fully reliant on the phosphatidylinositol 3-kinase-mediated pathway but requires neither S6K1 nor rpS6 phosphorylation. Mol Cell Biol 2002;22:81018113.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50

    Grunwald V, DeGraffenried L, Russel D et al.. Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Res 2002;62:61416145.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51

    Seufferlein T, Rozengurt E. Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells. Cancer Res 1996;56:38953897.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52

    Dancey JE. Clinical development of mammalian target of rapamycin inhibitors. Hematol Oncol Clin North Am 2002;16:11011114.

  • 53

    Yan JJ, Chen FF, Tsai YC, Jin YT. Immunohistochemical detection of Bcl-2 protein in small cell carcinomas. Oncology 1996;53:611.

  • 54

    Reed JC. Bcl-2: prevention of apoptosis as a mechanism of drug resistance. Hematol Oncol Clin North Am 1995;9:451473.

  • 55

    Rudin CM, Otterson GA, Mauer AM et al.. A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer. Ann Oncol 2002;13:539545.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    Rudin C, Kosloff M, Edelman MJ et al.. Phase I study of G3139 (oblimersen sodium), carboplatin, and etoposide in previously untreated extensive stage small cell lung cancer (SCLC) (Abstract No: 2538). Proc Am Soc Clin Oncol 2003;22:631.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57

    Grant SC, Kris MG, Houghton AN, Chapman PB. Long survival of patients with small cell lung cancer after adjuvant treatment with the anti-idiotypic antibody BEC2 plus Bacillus Calmette-Guerin. Clin Cancer Res 1999;5:13191323.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58

    Frankel AE, Rossi P, Kuzel TM, Foss F. Diphtheria fusion protein therapy of chemoresistant malignancies. Curr Cancer Drug Targets 2002;2:1936.

  • 59

    Lynch TJ Jr. Immunotoxin therapy of small-cell lung cancer. N901-blocked ricin for relapsed small-cell lung cancer. Chest 1993;103:436S439S.

  • 60

    Lynch TJ Jr, Lambert JM, Coral F et al.. Immunotoxin therapy of small-cell lung cancer: a phase I study of N901-blocked ricin. J Clin Oncol 1997;15:723734.

  • 61

    Cuttitta F, Carney DN, Mulshine J et al.. Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer. Nature 1985;316:823826.

  • 62

    Kelley MJ, Linnoila RI, Avis IL et al.. Antitumor activity of a monoclonal antibody directed against gastrin-releasing peptide in patients with small cell lung cancer. Chest 1997;112:256261.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63

    McCaffery M, Yao TJ, Williams L et al.. Immunization of melanoma patients with BEC2 anti-idiotypic monoclonal antibody that mimics GD3 ganglioside: enhanced immunogenicity when combined with adjuvant. Clin Cancer Res 1996;2:679686.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64

    Nasi ML, Meyers M, Livingston PO et al.. Anti-melanoma effects of R24, a monoclonal antibody against GD3 ganglioside. Melanoma Res 1997;7(Suppl 2):S155162.

  • 65

    Salven P, Ruotsalainen T, Mattson K, Joensuu H. High pretreatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in small-cell lung cancer. Int J Cancer 1998;79:144146.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66

    Ogawa S, Oku A, Sawano A et al.. A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain. J Biol Chem 1998;273:3127331282.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67

    Ortega N, Jonca F, Vincent S et al.. Systemic activation of the vascular endothelial growth factor receptor KDR/flk-1 selectively triggers endothelial cells with an angiogenic phenotype. Am J Pathol 1997;151:12151224.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 68

    Presta LG, Chen H, O'Connor SJ et al.. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997;57:45934599.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69

    Rosen LS. Clinical experience with angiogenesis signaling inhibitors: focus on vascular endothelial growth factor (VEGF) blockers. Cancer Control 2002; 9:3644.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70

    Gordon MS, Margolin K, Talpaz M et al.. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001;19:843850.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71

    Wedge SR, Ogilvie DJ, Dukes M et al.. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 2002;62:46454655.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72

    Adler V, Yin Z, Tew KD, Ronai Z. Role of redox potential and reactive oxygen species in stress signaling. Oncogene 1999;18:61046111.

  • 73

    Kamata H, Hirata H. Redox regulation of cellular signaling. Cell Signal 1999;11:114.

  • 74

    Rahman I, MacNee W. Role of oxidants/antioxidants in smoking-induced lung diseases. Free Radic Biol Med 1996;21:669681.

  • 75

    Huang P, Feng L, Oldham EA et al.. Superoxide dismutase as a target for the selective killing of cancer cells. Nature 2000;407:390395.

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