Consensus Statement

in Endocrine-Related Cancer
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Following the discovery of potential targets, anti-cancer drug development through preclinical investigation and the establishment of clinical studies and trials are essential processes in cancer research. The major goal of the recent 2nd Tenovus/AstraZeneca Workshop in Cardiff (comprising various talks from International experts supplemented by a poster session and discussion) was to define ‘where we are now’ with regards to these processes for several signalling targets known to contribute to cancer growth and progression. A second aim was to describe how our knowledge of the increasingly complex signal transduction pathways associated with drug response and resistance is beginning to mould the next generation of anti-cancer agents and future clinical strategies. The Workshop, culminating in 12 articles within this Supplement, sought to describe the present state of affairs both for well-established and for relatively new targets, where lessons learned from the past regarding response and resistance should influence how we proceed in the future. Session 1 focused around oestrogen receptor-α (ERα) as an old target that has recently spawned the exciting third generation of aromatase inhibitors and where new knowledge of the molecular actions of the ER is providing novel avenues for drug exploitation. The articles from the research groups of Professors R Santen (Song et al. 2006) and R Schiff (Massarweh & Schiff 2006) examine recent findings regarding the non-genomic and genomic activity of the ERα, exploring its crosstalk with growth factor-signalling pathways (including erbB, insulin-like growth factor I receptor (IGF-IR) and downstream kinases), its relevance to endocrine resistance, and therapeutic implications for treating this state and for reinstating response. The article from Prof. D McDonnell’s group (Stein & McDonnell 2006) outlines another potential disease target, the orphan nuclear receptor oestrogen-related receptor α (ERRα) that interplays with, and modifies, ERα signalling. Session 2 explored several drugs targeting classical growth factor receptors for which extensive clinical data are now emerging, and also inhibitors of more novel signalling mechanisms that are rapidly moving towards clinical development, where possible, encompassing resistance mechanisms. The article from Dr V Macaulay’s group (Riedemann & Macaulay 2006) focuses on IGF-IR signalling and its inhibitory strategies, where the authors are beginning to monitor the impact of alternative tyrosine kinase receptor signalling (notably epidermal growth factor receptor (EGFR)) on therapeutic response. Jones et al.(2006) subsequently detail the complex signalling interplay between different classes of tyrosine kinase receptors that may limit response to anti-EGFR agents, such as gefitinib. This article introduces a recurring theme of the Workshop, that of drug-induction of alternative signalling (in this instance, type II receptors) that can limit therapeutic efficacy, and which suggests that combined targeting of the induced mechanism alongside the anti-EGFR agent to subvert resistance will have superior anti-tumour effects. Combined treatment (in this instance, to dually subvert invasive behaviour and growth) is also a theme for Hiscox et al.(2006) in the context of targeting Src kinase signalling alongside anti-growth factors in resistant breast cancer. Prof. A Harris’s article (Patiar & Harris 2006) focuses on regulation and inhibition of a further target of emerging interest in cancer biology, hypoxia-inducible factor 1α (HIF-1α). The final session explored, in detail, the new concept of ‘compensatory’ drug-induced signalling that may limit full effectiveness of anti-cancer agents and ultimately promote and maintain resistance as suggested by the mechanistic and gene profiling data being amassed from various model systems. These include induction of several tyrosine kinase receptors during treatment with anti-hormones that may promote growth and tumour aggressive behaviour (Gee et al. 2006), promotion of IGF-IR/insulin receptor substrate 1 (IRS1) signalling by anti-EGFR agents (Hutcheson et al. 2006), induction of erbB signalling by radiotherapy (Yacoub et al. 2006) and chemotherapy interplay with stress response pathways (Tiligada 2006).

It is clear from the various presented data that cancer cells exhibit a remarkable ability to recruit alternative signalling pathways for growth and progression. However, future rational targeting of therapy-induced elements alongside primary therapy (or alternatively use of inhibitors that target multiple signalling pathways, as exemplified by Prof. P Workman (Powers & Workman 2006) holds much promise for improving clinical anti-tumour effect. Indeed, preclinical data reveal such strategies can delay, and even prevent, the development of resistance with its associated undesirable features of progression. There remains much to learn as to how we best design and use therapies to target the alternative signalling recruited by cancer cells. Integral to such success, however, will be increasing the access to, and concerted profiling of, clinical disease to confirm mechanism, in parallel with continued evaluation of likely outcome of the proposed therapeutic strategies in appropriate cancer model systems.

This Workshop was dedicated to Dr Alan Wakeling who has been a tremendous friend of the Tenovus Centre for Cancer Research for over 20 years. Dr Wakeling who has recently retired from AstraZeneca, not only made an immense contribution to clinical anti-cancer drug development in the UK, but also through his work has provided basic scientists worldwide with the anti-hormone and anti-growth factor pharmacological tools necessary to accurately decipher and understand cancer biology.

References

  • Gee JMW, Shaw VE, Hiscox SE, McClelland RA, Rushmere NK & Nicholson RI 2006 Deciphering antihormone-induced compensatory mechanisms in breast cancer and their therapeutic implications. Endocrine-Related Cancer 13 (Suppl 1) S77–S88.

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  • Hiscox S, Morgan L, Green T & Nicholson RI 2006 Src as a therapeutic target in anti-hormone/anti-growth factor resistant breast cancer. Endocrine-Related Cancer 13 (Suppl 1) S53–S59.

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  • Hutcheson IR, Knowlden JM, Jones HE, Burmi RS, McClelland RA, Barrow D, Gee JMW & Nicholson RI 2006 Inductive mechanisms limiting response to anti-epidermal growth factor receptor therapy. Endocrine-Related Cancer 13 (Suppl 1) S89–S97.

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  • Jones HE, Gee JMW, Hutcheson IR, Knowlden JM, Barrow D & Nicholson RI 2006 Growth factor receptor interplay and resistance in cancer. Endocrine-Related Cancer 13 (Suppl 1) S45–S51.

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  • Massarweh S & Schiff R 2006 Resistance to endocrine therapy in breast cancer: exploiting ER/growth factor signaling crosstalk. Endocrine-Related Cancer 13 (Suppl 1) S15–S24.

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  • Patiar S & Harris AL 2006 Role of HIF-1alpha as a cancer therapy target. Endocrine-Related Cancer 13 (Suppl 1) S61–S75.

  • Powers MV & Workman P 2006 Targeting of multiple signalling pathways by HSP90 molecular chaperone inhibitors. Endocrine-Related Cancer 13 (Suppl 1) S125–S135.

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  • Riedemann J & Macaulay VM 2006 IGF1R signaling and its inhibition. Endocrine-Related Cancer 13 (Suppl 1) S33–S43.

  • Stein R & McDonnell DP 2006 Estrogen-related receptor alpha as a therapeutic target in cancer. Endocrine-Related Cancer 13 (Suppl 1) S25–S32.

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  • Song RX-D, Fan P, Yue W, Chen Y & Santen RJ 2006 Role of receptor complexes in the extra-nuclear actions of ERalpha in breast cancer. Endocrine-Related Cancer 13 (Suppl 1) S3–S13.

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  • Tiligada E 2006 Chemotherapy: induction of stress responses. Endocrine-Related Cancer 13 (Suppl 1) S115–S124.

  • Yacoub A, Miller A, Caron RW, Qiao L, Hagan MP, Grant S & Dent P 2006 Radiotherapy-induced signal transduction. Endocrine-Related Cancer 13 (Suppl 1) S99–S114.

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  • Gee JMW, Shaw VE, Hiscox SE, McClelland RA, Rushmere NK & Nicholson RI 2006 Deciphering antihormone-induced compensatory mechanisms in breast cancer and their therapeutic implications. Endocrine-Related Cancer 13 (Suppl 1) S77–S88.

    • Search Google Scholar
    • Export Citation
  • Hiscox S, Morgan L, Green T & Nicholson RI 2006 Src as a therapeutic target in anti-hormone/anti-growth factor resistant breast cancer. Endocrine-Related Cancer 13 (Suppl 1) S53–S59.

    • Search Google Scholar
    • Export Citation
  • Hutcheson IR, Knowlden JM, Jones HE, Burmi RS, McClelland RA, Barrow D, Gee JMW & Nicholson RI 2006 Inductive mechanisms limiting response to anti-epidermal growth factor receptor therapy. Endocrine-Related Cancer 13 (Suppl 1) S89–S97.

    • Search Google Scholar
    • Export Citation
  • Jones HE, Gee JMW, Hutcheson IR, Knowlden JM, Barrow D & Nicholson RI 2006 Growth factor receptor interplay and resistance in cancer. Endocrine-Related Cancer 13 (Suppl 1) S45–S51.

    • Search Google Scholar
    • Export Citation
  • Massarweh S & Schiff R 2006 Resistance to endocrine therapy in breast cancer: exploiting ER/growth factor signaling crosstalk. Endocrine-Related Cancer 13 (Suppl 1) S15–S24.

    • Search Google Scholar
    • Export Citation
  • Patiar S & Harris AL 2006 Role of HIF-1alpha as a cancer therapy target. Endocrine-Related Cancer 13 (Suppl 1) S61–S75.

  • Powers MV & Workman P 2006 Targeting of multiple signalling pathways by HSP90 molecular chaperone inhibitors. Endocrine-Related Cancer 13 (Suppl 1) S125–S135.

    • Search Google Scholar
    • Export Citation
  • Riedemann J & Macaulay VM 2006 IGF1R signaling and its inhibition. Endocrine-Related Cancer 13 (Suppl 1) S33–S43.

  • Stein R & McDonnell DP 2006 Estrogen-related receptor alpha as a therapeutic target in cancer. Endocrine-Related Cancer 13 (Suppl 1) S25–S32.

    • Search Google Scholar
    • Export Citation
  • Song RX-D, Fan P, Yue W, Chen Y & Santen RJ 2006 Role of receptor complexes in the extra-nuclear actions of ERalpha in breast cancer. Endocrine-Related Cancer 13 (Suppl 1) S3–S13.

    • Search Google Scholar
    • Export Citation
  • Tiligada E 2006 Chemotherapy: induction of stress responses. Endocrine-Related Cancer 13 (Suppl 1) S115–S124.

  • Yacoub A, Miller A, Caron RW, Qiao L, Hagan MP, Grant S & Dent P 2006 Radiotherapy-induced signal transduction. Endocrine-Related Cancer 13 (Suppl 1) S99–S114.

    • Search Google Scholar
    • Export Citation