Predictive biomarker discovery through the parallel integration of clinical trial and functional genomics datasets

Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK. .
Genome Medicine (Impact Factor: 5.34). 08/2010; 2(8):53. DOI: 10.1186/gm174
Source: PubMed


The European Union multi-disciplinary Personalised RNA interference to Enhance the Delivery of Individualised Cytotoxic and Targeted therapeutics (PREDICT) consortium has recently initiated a framework to accelerate the development of predictive biomarkers of individual patient response to anti-cancer agents. The consortium focuses on the identification of reliable predictive biomarkers to approved agents with anti-angiogenic activity for which no reliable predictive biomarkers exist: sunitinib, a multi-targeted tyrosine kinase inhibitor and everolimus, a mammalian target of rapamycin (mTOR) pathway inhibitor. Through the analysis of tumor tissue derived from pre-operative renal cell carcinoma (RCC) clinical trials, the PREDICT consortium will use established and novel methods to integrate comprehensive tumor-derived genomic data with personalized tumor-derived small hairpin RNA and high-throughput small interfering RNA screens to identify and validate functionally important genomic or transcriptomic predictive biomarkers of individual drug response in patients. PREDICT's approach to predictive biomarker discovery differs from conventional associative learning approaches, which can be susceptible to the detection of chance associations that lead to overestimation of true clinical accuracy. These methods will identify molecular pathways important for survival and growth of RCC cells and particular targets suitable for therapeutic development. Importantly, our results may enable individualized treatment of RCC, reducing ineffective therapy in drug-resistant disease, leading to improved quality of life and higher cost efficiency, which in turn should broaden patient access to beneficial therapeutics, thereby enhancing clinical outcome and cancer survival. The consortium will also establish and consolidate a European network providing the technological and clinical platform for large-scale functional genomic biomarker discovery. Here we review our current understanding of molecular mechanisms driving resistance to anti-angiogenesis agents, the current limitations of laboratory and clinical trial strategies and how the PREDICT consortium will endeavor to identify a new generation of predictive biomarkers.

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    • "Another exciting new avenue of research into prognostic markers in RCC comes from a prospective study investigating individual RCC tumour genomes in nephrectomy specimens from the patients who were treated before surgery with the approved anti-angiogenic targeted therapies, sunitinib and everolimus. That study hoped to identify new biomarkers predicting drug response or resistance, and potentially discover new therapeutic targets in RCC [62]. Recent data from a similar study correlating germline polymorphisms to the outcomes in patients with RCC receiving pazopanib, an oral anti-angiogenic targeted therapeutic agent, identified a specific polymorphism in the IL-8 gene which predicted disease progression, and another polymorphism in HIF-1a that predicted the response rate to therapy [63]. "
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    ABSTRACT: Objectives Increased knowledge about the molecular pathways involved in tumorigenesis has led to the discovery of new prognostic molecular markers and development of novel targeted therapies for renal cell carcinoma (RCC). In this review we describe the prognostic markers of RCC and highlight the areas of recent discovery with a focus on the mammalian target of rapamycin (mTOR) pathway.Methods We reviewed previous reports, using PubMed with the search terms ‘renal cell carcinoma’, ‘molecular markers’, ‘prognosis’, ‘outcomes’ and ‘mammalian target of rapamycin pathway’ published in the last two decades. We created a library of 100 references and focused on presenting the recent advances in the field.ResultsGrowing evidence suggests that mTOR deregulation is associated with many types of human cancer, including RCC. Consequently, temsirolimus and everolimus, which target mTOR, are approved for treating advanced RCC. There is a demand to integrate clinical, pathological and molecular markers into accurate prognostic models to provide patients with the most personalised cancer care possible.Conclusions The mTOR pathway is highly implicated in RCC tumorigenesis and progression, and its constituents might represent a promising prognostic tool and target for treating RCC. Combining newly discovered molecular markers with classic clinicopathological prognostics might potentially improve the management of RCC.
    Arab Journal of Urology 06/2012; 10(2):110–117. DOI:10.1016/j.aju.2012.02.005
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    • ", Huang , Y . , Jia , W . such as those used by the Personalized RNA interference to Enhance the Delivery of Individualized Cytotoxic and Targeted therapeutics ( PREDICT ) consortium ( Swanton et al. , 2010 ) are required , but are often complex and demanding in terms of human and financial resources . The mechanisms of resistance to anti - VEGF and anti - mTOR treatments in mRCC are incompletely understood , but an obvi - ous question which arises from regional genomic variability in tumors is whether intra - tumoural heterogeneity itself fosters treatment resistance and therapeutic fail - ure ( Carter et al . "

    Frontiers in Oncology 05/2012; 2:49. DOI:10.3389/fonc.2012.00049
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    • "There is an increasing understanding of mechanisms of resistance, which may include vascular resistance through activation of alternative pro-angiogenic pathways [154], and hypoxia resistance [153]. Resistance to mTOR inhibition is less well understood but preclinical models suggest that negative feedback loops and parallel signalling pathways such as the Ras-mitogen-activated protein kinase (MAPK) pathway play an important role [153]. Again, routine tissue collection at important clinical time-points (such as pre-treatment, and at the time of progressive disease) is likely to add to the mounting body of evidence delineating resistance pathways. "
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    ABSTRACT: Recent years have seen major advances in the management of metastatic renal cell carcinoma (mRCC). The tyrosine kinase and mammalian target of rapamycin inhibitors have resulted in disease control and improved survival for many patients with mRCC, but they have not led to preventive, predictive or personalised medicine (PPPM). Failure to achieve this rests ultimately with inadequate knowledge of tissue and molecular heterogeneity; discovery of these drugs was based upon identification of pathogenic molecular pathways in RCC, but research into molecular factors which underpin drug response, resistance and selection of therapy for individual patients has lagged well behind clinical trials of drug development. This review will provide an overview of the development of targeted drug therapies for mRCC, will discuss the challenges which currently impede the delivery of PPPM, including identification of biomarkers, drug resistance and molecular heterogeneity, and will propose research methodologies and technologies required to overcome these obstacles.
    EPMA Journal, The 12/2011; 3(1):1. DOI:10.1007/s13167-011-0137-3
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