Skip to main content

Advertisement

SpringerLink
Log in

Development of new targeted therapies for breast cancer

  • Conference Paper
  • Symposium: Molecular target therapy
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Clinical application of truly targeted therapy relies on identification of a specific molecular feature (the target) that is biologically relevant, reproducibly measurable and definably correlated with clinical benefit. Ideally the target should be crucial to the tumor’s malignant phenotype. The target must be easily measurable in readily obtained clinical samples. Interruption, interference or inhibition of the target should yield a clinical response in a significant proportion of patients whose tumors express the target but in few patients whose tumors do not express the target. As such, targeted therapy offers the twin hopes of maximizing efficacy while minimizing toxicity. A critical review of the hallmarks of malignancy provides a framework for considering potential targets and novel therapeutic interventions. The hallmarks of malignancy include uncontrolled proliferation, insensitivity to negative growth regulation, evasion of apoptosis, lack of senescence, invasion and metastasis, angiogenesis, and genomic elasticity. Existing therapies predominantly target proliferation either with cytotoxic agents, ionizing radiation or inhibition of estrogen receptor and HER2 growth factor signaling pathways. Further improvements in therapy must attack the other hallmarks of malignancy and will undoubtedly be accompanied by better means of individual patient selection for such therapies. Indeed, each of these hallmarks presents a therapeutic opportunity. To believe otherwise would be to assume that a feature is both biologically crucial yet therapeutically unimportant, an unlikely paradox.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Beaston G. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet. 1896;2:104–7.

    Google Scholar 

  2. Jensen E, DeSombre E, Jungblut P. Estrogen receptors in hormone responsive tissues and tumors. Chicago: University of Chicago Press; 1969.

    Google Scholar 

  3. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    Article  PubMed  CAS  Google Scholar 

  4. Ross JS, Fletcher JA, Linette GP, et al. The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist. 2003;8:307–25.

    Article  PubMed  CAS  Google Scholar 

  5. King CR, Kraus MH, Aaronson SA. Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science. 1985;229:974–6.

    Article  PubMed  CAS  Google Scholar 

  6. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.

    Article  PubMed  CAS  Google Scholar 

  7. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707–12.

    Article  PubMed  CAS  Google Scholar 

  8. Hudziak RM, Lewis GD, Winget M, et al. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol. 1989;9:1165–72.

    PubMed  CAS  Google Scholar 

  9. Pietras RJ, Fendly BM, Chazin VR, et al. Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene. 1994;9:1829–38.

    PubMed  CAS  Google Scholar 

  10. Shepard HM, Lewis GD, Sarup JC, et al. Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic. J Clin Immunol. 1991;11:117–27.

    Article  PubMed  CAS  Google Scholar 

  11. Carter P, Presta L, Gorman CM, et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A. 1992;89:4285–9.

    Article  PubMed  CAS  Google Scholar 

  12. Pietras RJ, Pegram MD, Finn RS, et al. Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs. Oncogene. 1998;17:2235–49.

    Article  PubMed  CAS  Google Scholar 

  13. Slamon DJ, Leyland-Jones B, Shak S, 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.

    Article  PubMed  CAS  Google Scholar 

  14. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–84.

    Article  PubMed  CAS  Google Scholar 

  15. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72.

    Article  PubMed  CAS  Google Scholar 

  16. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007;369:29–36.

    Article  PubMed  CAS  Google Scholar 

  17. Slamon D, Eiermann W, Robert N. Phase III trial comparing AC-T with AC-TH and with TCH in the adjuvant treatment of HER2 positive early breast cancer: first planned interim efficacy analysis (abstract 1), 28th Annual San Antonio Breast Cancer Symposium, San Antonio, TX. 2005.

  18. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006;354:809–20.

    Article  PubMed  CAS  Google Scholar 

  19. Blackwell K, Kaplan E, Franco S, et al. A phase II, open-label, multicenter study of GW572016 in patients with trastuzumab-refractory metastatic breast cancer. Proc Am Soc Clin Oncol. 2004;22:abstr 3006.

  20. Burstein H, Storniolo A, Franco S, et al. A phase II, open-label, multicenter study of lapatinib in two cohorts of patients with advanced or metastatic breast cancer who have progressed while receiving trastuzumab-containing regimens. Ann Oncol. 2004;15(suppl 3).

  21. Kaplan E, Jones C, Berger M, et al. A phase II, open-label, multicenter study of GW572016 in patients with trastuzumab refractory metastatic breast cancer. 2003;22. Proc Am Soc Clin Oncol. 2003;22:abstr 981.

  22. Blackwell K, Burstein H, Pegram M, et al. Determining relevant biomarkers from tissue and serum that may predict response to single agent lapatinib in trastuzumab-refractory metastatic breast cancer. Proc Am Soc Clin Oncol. 2005;24:abstr 3004.

  23. Spector N, Blackwell K, Hurley J, et al. EGF 103009, a phase II trial of lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): clinical activity and biologic predictors of response. Proc Am Soc Clin Oncol. 2006;25:abstr 502.

  24. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733–43.

    Article  PubMed  CAS  Google Scholar 

  25. Moy B, Goss PE. Lapatinib: current status and future directions in breast cancer. Oncologist. 2006;11:1047–57.

    Article  PubMed  CAS  Google Scholar 

  26. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;85:1182–6.

    Google Scholar 

  27. Relf M, LeJeune S, Scott PA, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 1997;57:963–9.

    PubMed  CAS  Google Scholar 

  28. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocrinol Rev 1997, 1997.

  29. Cobleigh M, Miller K, Langmuir V, et al. Phase II dose escalation trial of Avastin (bevacizumab) in women with previously treated metastatic breast cancer. Breat Cancer Res Treat. 2001;69:301.

    Google Scholar 

  30. Miller KD, Chap LI, Holmes FA, 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.

    Article  PubMed  CAS  Google Scholar 

  31. Miller KD. E2100: a phase III trial of paclitaxel versus paclitaxel/bevacizumab for metastatic breast cancer. Clin Breast Cancer. 2003;3:421–2.

    Article  PubMed  CAS  Google Scholar 

  32. Miller K, Burstein H, Elias A, et al. Phase II study of SU11248, a multitargeted tyrosine kinase inhibitor in patients with previously treated metastatic breast cancer. Breast Cancer Res and Treat. 2005;95(Suppl 1):abstr 1006.

  33. Campbell I, Russell S, Choong D, et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 2004;64:7678–81.

    Article  PubMed  CAS  Google Scholar 

  34. Xu Y, Yu Q. Angiopoietin-1, unlike angiopoietin-2, is incorporated into the extracellular matrix via its linker peptide region. J Biol Chem. 2001;276:34990–8.

    Article  PubMed  CAS  Google Scholar 

  35. Chan S, Scheulen M, Johnston S, et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol. 2005;23:5314–22.

    Article  PubMed  CAS  Google Scholar 

  36. Chow L, Sun Y, Jassem J, et al. Phase 3 study of temsirolimus with letrozole or letrozole alone in postmenopausal women with locally advanced or metastatic breast cancer. Breast Cancer Res and Treat 2006;100(Suppl 1):S286.

    Google Scholar 

  37. Herbert BS, Wright WE, Shay JW. Telomerase and breast cancer. Breast Cancer Res. 2001;3:146–9.

    Article  PubMed  CAS  Google Scholar 

  38. Mueller C, Riese U, Kosmehl H, et al. Telomerase activity in microdissected human breast cancer tissues: association with p53, p21 and outcome. Int J Oncol. 2002;20(2):385–90.

    PubMed  CAS  Google Scholar 

  39. Shpitz B, Zimlichman S, Zemer R, et al. Telomerase activity in ductal carcinoma in situ of the breast. Breast Cancer Res and Treat. 1999;58:65–9.

    Article  CAS  Google Scholar 

  40. Mokbel KM, Parris CN, Ghilchik M, et al. Telomerase activity and lymphovascular invasion in breast cancer. Eur J Surg Oncol. 2000;26:30–3.

    Article  PubMed  CAS  Google Scholar 

  41. Bieche I, Nogues C, Paradis V, et al. Quantitation of hTERT gene expression in sporadic breast tumors with a real-time reverse transcription-polymerase chain reaction assay. Clin Cancer Res. 2000;6:452–9.

    PubMed  CAS  Google Scholar 

  42. Kyo S, Takakura M, Kanaya T, et al. Estrogen activates telomerase. Cancer Res. 1999;59:5917–21.

    PubMed  CAS  Google Scholar 

  43. Wang Z, Kyo S, Takakura M, et al. Progesterone regulates human telomerase reverse transcriptase gene expression via activation of mitogen-activated protein kinase signaling pathway. Cancer Res. 2000;60:5376–81.

    PubMed  CAS  Google Scholar 

  44. Izbicka E, Wheelhouse R, Raymond Eea. Effects of cationic porphyrins as G-quadruplex interactive agents in human tumor cells. Cancer Res. 1999;59:639–44.

    Google Scholar 

  45. Muller A, Saretzki G, von Zglinicki T, et al. Telomerase inhibition by induced expression of antisense RNA. Adv Exp Med Biol. 1998;451:23–6.

    PubMed  CAS  Google Scholar 

  46. Xu D, Wang Q, Gruber A, et al. Downregulation of telomerase reverse transcriptase mRNA expression by wild type p53 in human tumor cells. Oncogene. 2000;19:5123–33.

    Article  PubMed  CAS  Google Scholar 

  47. Ludwig A, Saretzki G, Holm PS, et al. Ribozyme cleavage of telomerase mRNA sensitizes breast epithelial cells to inhibitors of topoisomerase. Cancer Res. 2001;61:3053–61.

    PubMed  CAS  Google Scholar 

  48. Kossakowska AE, Huchcroft SA, Urbanski SJ, et al. Comparative analysis of the expression patterns of metalloproteinases and their inhibitors in breast neoplasia, sporadic colorectal neoplasia, pulmonary carcinomas and malignant non-Hodgkin’s lymphomas in humans. Br J Cancer. 1996;73:1401–8.

    PubMed  CAS  Google Scholar 

  49. Monteagudo C, Merino MJ, San-Juan J, et al. Immunohistochemical distribution of type IV collagenase in normal, benign, and malignant breast tissue. Am J Pathol. 1990;136:585–92.

    PubMed  CAS  Google Scholar 

  50. Zucker S, Lysik RM, Zarrabi MH, et al. M(r) 92,000 type IV collagenase is increased in plasma of patients with colon cancer and breast cancer. Cancer Res. 1993;53:140–6.

    PubMed  CAS  Google Scholar 

  51. Sledge GW Jr, Qulali M, Goulet R, et al. Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. J Natl Cancer Inst 1995;87:1546–50.

    Article  PubMed  CAS  Google Scholar 

  52. Bramhall S, Rosemurgy A, Brown P, et al. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol. 2001;19:3447–55.

    PubMed  CAS  Google Scholar 

  53. Hidalgo M, Eckhardt SG. Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst. 2001;93:178–93.

    Article  PubMed  CAS  Google Scholar 

  54. Shepard F, Giaccone G, Debruyne C, et al. Randomized double-blind placebo-controlled trial of marimastat in paitents with small cell lung cancer following response to first-line chemotherapy: an NCIC-CTG and EORTC study. Proc Am Soc Clin Oncol. 2001;20:4a.

    Google Scholar 

  55. Sparano JA, Bernardo P, Gradishar W, et al. Randomized phase II trial of marimastati versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: an Eastern Cooperative Oncology Group trial (E2196). Proc Am Soc Clin Oncol. 2002;21:44a.

    Google Scholar 

  56. Miller KD, Gradishar W, Schuchter L, et al. A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer. Ann Oncol. 2002;13:1220–4.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Indiana University School of Medicine, Indianapolis, IN, USA

    Danielle M. Doyle & Kathy D. Miller

  2. Indiana Cancer Pavilion, 535 Barnhill Drive, RT-473, Indianapolis, IN, 46202, USA

    Kathy D. Miller

Authors
  1. Danielle M. Doyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kathy D. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathy D. Miller.

Additional information

This article is based on a keynote address of Symposium 3, “Molecular target therapy: basics and clinical application,” held on 30 June 2007 at the 15th Annual Meeting of the Japanese Breast Cancer Society in Yokohama.

About this article

Cite this article

Doyle, D.M., Miller, K.D. Development of new targeted therapies for breast cancer. Breast Cancer 15, 49–56 (2008). https://doi.org/10.1007/s12282-007-0003-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-007-0003-2

Keywords

Search

Navigation