Target Based Drug Discovery and Telomerase Validation

Despite significant advances in recent years in our understanding of the cellular and molecular mechanisms underpinning cancer progression, mortality rates remain unac-ceptably high for most common malignancies, and effective treatment options are often unavailable. Therefore, drug development remains a major goal of cancer research. Drug discovery begins with exploratory research to identify potential molecular targets, followed by preclinical target validation, assay development, compound screening, hit identification and confirmation, lead identification and optimization, and in vitro and in vivo efficacy and toxicity studies (Sams-Dodd 2005) (Fig. 13.1). Therefore, preclinical development alone requires significant financial, intellectual, and manpower investment. Assuming that a new lead meets acceptance criteria in all assays, and subject to relevant regulatory and ethical approval, clinical testing may begin. At this point in development, both costs and risk increase substantially as a candidate progresses through clinical trials (DiMasi and Grabowski 2007, DiMasi et al. 2003).

W. Nicol Keith

Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, Bearsden, Glasgow, United Kingdom email: [email protected]

K.L. Rudolph (ed.), Telomeres and Telomerase in Ageing, Disease, and Cancer. © 2008 Springer-Verlag Berlin Heidelberg

Fig. 13.1 Key stages in the preclinical drug discovery paradigm. Clinical development is preceded by target identification through exploratory research and sequential/iterative phases comprising target validation, assay development, and screening, hit confirmation, lead optimization, and confirmation of efficacy in well-validated in vitro and in vivo models

Fig. 13.1 Key stages in the preclinical drug discovery paradigm. Clinical development is preceded by target identification through exploratory research and sequential/iterative phases comprising target validation, assay development, and screening, hit confirmation, lead optimization, and confirmation of efficacy in well-validated in vitro and in vivo models

Both small-molecule drugs and more complex biotherapeutics pass through similar pipelines to demonstrate specificity and efficacy (Hermiston and Kirn 2005). Attrition rates of all drugs in clinical testing are high, partly reflecting the fact that target complexity in the human setting is frequently underestimated. Failure late in the development process incurs massive costs, and the recent overall trend toward escalating development costs and falling approval rates for new drugs implies that creative, target-specific solutions must be applied to streamline all phases of drug development (Hoos et al. 2007, Keith et al. 2004, Kummar et al. 2006, Kummar et al. 2007, Lesko 2007, Michaelis and Ratain 2006, Nicol Keith et al. 2001). However, it is also critical that only the best leads progress to clinical trials. Therefore, the most appropriate targets must be identified and prioritized by extensive characterization. Good targets should associate in a frequent and causal way with disease etiology in relevant tissues and should be in some way druggable.

By these criteria, telomerase is a suitable target for drug development. We will not review the molecular regulation of telomerase in detail in this chapter. However, a brief reminder of the attributes of telomerase as a cancer target is useful. Telomerase is minimally composed of the core RNA (hTERC) and catalytic (hTERT) subunits (see Dillin and Karlseder, this volume), both of which are selectively overexpressed in cancer cells relative to most somatic cells (see Rudolph, this volume), with the tumor-selective expression profile encompassing the entire spectrum of human malignancy (Downey et al. 2001, Keith et al. 2002, Sarvesvaran et al. 1999, Shay and Bacchetti 1997, Soder et al. 1998, Soder et al. 1997, Wisman et al. 2000). Transcriptional activation of both genes is the primary mechanism by which telomerase is turned on, and the cloned promoter regions also show selective activity in cancer cells (Keith et al. 2004). Telomerase acts to oppose telomere attrition by reverse transcription of new telomere repeats from an exposed single-stranded template sequence in hTERC (see Allsopp, this volume). It is clear that telomere maintenance is essential for cancer cell immortality (Keith et al. 2002, Keith et al. 2004, Lavelle et al. 2000, Nicol Keith et al. 2001, Shay and Wright 2006, White et al. 2001). Telomerase inhibition in cancer cells generally results in progressive cell division-dependent telomere shortening and delayed onset senescence and/or apoptosis, induced by DNA damage signaling at critically short or uncapped telomeres (d'Adda di Fagagna et al. 2003, Takai et al. 2003). Therefore, telomerase has high prevalence, selective expression. and mechanistic importance in many cancer types.

Telomerase targeting strategies can be defined as immunotherapy, gene therapy, and inhibition either by oligonucleotides or small molecules (Fig. 13.2). However, few published approaches have entered clinical testing. Each therapeutic approach has its own advantages and limitations, and the different mechanisms of action must be taken into account in order to design appropriate preclinical models for each approach and identify appropriate endpoints for clinical trials. For example, because of the "phenotypic lag" (the theoretical requirement for continued cell division and substantial telomere shortening to occur prior to the onset of senescence or apoptosis under telomerase inhibition), clinical studies using telomerase inhibitors may need to incorporate alternative phase II endpoints such as time-to-progression rather than assessment of objective tumor response. In contrast, efficacy of approaches such as gene therapy may be able to be assessed more easily by a classic phase II design. Since the ultimate validation of any therapeutic target is the successful completion of clinical trials leading to a new drug approval, it is timely to critically assess the state of the development pipelines for the various classes of telomerase-directed therapeutics. In this chapter we review the substantial preclinical and existing clinical data in support of targeting telomerase, highlighting future challenges, opportunities, and development gaps.

Immunotherapy Gene therapy

Immunotherapy Gene therapy

Fig. 13.2 Targets in telomerase-specific therapeutics development. Most strategies have focused on the areas of immunotherapy, gene therapy using the telomerase promoters, and inhibition by oligo-nucleotides or small molecules. However, the unique function of telomerase, the complexity of its regulation, and the large number of factors implicated in telomere length regulation suggests that there is still scope for development of new therapeutic strategies targeting immortality

Oligonucleotides Small molecules

Fig. 13.2 Targets in telomerase-specific therapeutics development. Most strategies have focused on the areas of immunotherapy, gene therapy using the telomerase promoters, and inhibition by oligo-nucleotides or small molecules. However, the unique function of telomerase, the complexity of its regulation, and the large number of factors implicated in telomere length regulation suggests that there is still scope for development of new therapeutic strategies targeting immortality

0 0

Post a comment