BBA - Reviews on Cancer (v.1766, #2)

Pharmacogenetics of cancer chemotherapy by Jean Abraham; Helena M. Earl; Paul D. Pharoah; Carlos Caldas (168-183).
Significant heterogeneity in the efficacy and toxicity of chemotherapeutic agents is observed within cancer populations. Pharmacogenetics (PGx) is the study of inheritance in interindividual variation in drug disposition. The allure of pharmacogenetics, in the treatment of cancer patients, comes from the potential for individualisation of cancer therapy, minimizing toxicity, while maximizing efficacy. In this review we will focus on the current and potential clinical applications of pharmacogenetics in cancer therapy by citing relevant examples and discussing the possible approaches which may be used to establish a reliable, reproducible and cost-effective test for clinically relevant genetic polymorphisms, using easily accessible biological samples (e.g., blood and tumour samples). Ideally, routine management of patients would include analysis of their single nucleotide polymorphism linkage disequilibrium (SNP-LD) profile prior to treatment, allowing stratification of patients into treatment groups, thus individualising their therapy. In order to achieve this ambition, a combination of different approaches (candidate gene, genome-wide and pathway driven) will be required from scientists and clinician scientists, as well as an increased understanding and incorporation of pharmacogenetic aims and endpoints into current and future clinical trials.
Keywords: Pharmacogenetics; Single nucleotide polymorphins; Candidate gene; Genome-wide; Pathway driven; Association studies; Cancer therapy; Toxicity;

Drug resistance, predictive markers and pharmacogenomics in colorectal cancer by Daniel B Longley; Wendy L. Allen; Patrick G. Johnston (184-196).
Resistance to chemotherapy limits the effectiveness of current cancer therapies, including those used to treat colorectal cancer, which is the second most common cause of cancer death in Europe and the United States. 5-Fluorouracil-based chemotherapy regimens are the standard treatment for colorectal cancer in both the adjuvant and advanced disease settings. Drug resistance is thought to cause treatment failure in over 90% of patients with metastatic cancer, while drug resistant micrometastic tumour cells may also reduce the impact of adjuvant chemotherapy treatment. The identification of panels of biomarkers that not only identify those patients most likely to benefit from chemotherapy treatment, but also which chemotherapies to use, would be a major advance. In this review, we describe molecular mechanisms of drug resistance that may be relevant to colorectal cancer. We also describe the results of predictive biomarker studies in this disease. Finally, we discuss how pharmacogenomics and other high through-put technologies may impact on the clinical management of colorectal cancer in the future.
Keywords: Drug resistance; Colorectal cancer; Pharmacogenomics; Predictive marker;

Chemotherapy provides variable benefit to patients with breast cancer, with usually modest but occasionally severe side effects. Hence, there is a need to identify predictive biomarkers for its efficacy. DNA arrays have been used in this setting as potential novel predictive diagnostic tools. Several gene signatures and single gene markers were proposed to predict response to chemotherapy. Although this technology offers interesting perspectives through large-scale analysis of the transcriptome, its ability to identify clinically relevant predictors is highly dependent on study design. In the present manuscript, we will review currently available results of breast cancer pharmacogenomics and focus on aspects of study design that are critical to reliably identify predictive biomarkers using DNA array technology. We will discuss whether studies should be done in the overall, unselected breast cancer population or in specific homogeneous molecular subclasses. Next, we will compare advantages and limitations of cohort-based and case-control studies. The choice of end-point to discriminate between sensitive and resistant patients will also be examined.

BRCA1—A good predictive marker of drug sensitivity in breast cancer treatment? by Paul B. Mullan; Julia J. Gorski; D. Paul Harkin (205-216).
There are currently only two predictive markers of response to chemotherapy for breast cancer in routine clinical use, namely the Estrogen receptor-α and the HER2 receptor. The breast and ovarian cancer susceptibility gene BRCA1 is an important genetic factor in hereditary breast and ovarian cancer and there is increasing evidence of an important role for BRCA1 in the sporadic forms of both cancer types. Our group and numerous others have shown in both preclinical and clinical studies that BRCA1 is an important determinant of chemotherapy responses in breast cancer. In this review we will outline the current understanding of the role of BRCA1 as a determinant of response to DNA damaging and microtubule damaging chemotherapy. We will then discuss how the known functions of this multifaceted protein may provide mechanistic explanations for its role in chemotherapy responses.
Keywords: BRCA1; Predictive marker; Chemotherapy; Response;

The EGFR is a validated anticancer target whose successful exploitation has added novel agents to our current treatment protocols. Subsets of patients have shown to benefit the most from these therapies, and though these differential responses have yet to be completely defined, they are mostly of genetic nature. Egfr amplifications have shown to increase sensitivity to both small molecule inhibitors and specific monoclonal antibodies targeting the EGFR. A somatic/germline egfr intron 1 CA repeat sequence polymorphism has shown to have an important role in the control of EGFR protein expression, and has been linked to an increased risk of familial breast cancer, a worse outcome in patients with colorectal cancer, and anti-EGFR treatment efficacy in preclinical models. Egfr activating mutations have been recently described in lung cancer linking a cluster of genotypes with sensitivity to EGFR tyrosine kinase pharmacological inhibition. Despite the initial excitement that this discovery elicited, follow-up reports have not unequivocally confirmed this finding, and these drugs have been solidly efficacious both in individual patients and in diseases generally lacking egfr mutations such as pancreas cancer. We are witnessing exciting developments in the field of the pharmacogenomics of cancer, and this has particularly evolved in the area pertaining EGFR tyrosine kinase inhibitors. This review will discuss the background and currently available preclinical and clinical data.
Keywords: Pharmacogenomics; EGFR; Tyrosine kinase inhibitors; Targeted therapies;

Emerging applications for phospho-proteomics in cancer molecular therapeutics by Michael F. Moran; Jiefei Tong; Paul Taylor; Robert M. Ewing (230-241).
Protein phosphorylation is a key mechanism of cell regulation in normal and cancer cells. Various new cancer drugs and drug candidates are aimed at protein kinase targets. However, selecting patients likely to respond to these treatments, even among individuals with tumors expressing validated kinase targets remains a major challenge. There exists a need for biomarkers to facilitate the monitoring of modulation of drug-targeted kinase pathways. Phospho-proteomics involves the enrichment of phosphorylated proteins from tissue, and the application of technologies such as mass spectrometry (MS) for the identification and quantification of protein phosphorylation sites. It has potential to provide pharmacodynamic readouts of disease states and cellular drug responses in tumor samples, but technical hurdles and bioinformatics challenges will need to be addressed.
Keywords: Phospho-peptide; Mass spectrometry; Protein kinase; Phosphorylation; Biomarker; Epidermal growth factor;

Assessing responses to cancer therapy using molecular imaging by André A. Neves; Kevin M. Brindle (242-261).
Tumor responses to therapy in the clinic are still evaluated primarily from non-invasive imaging measurements of reductions in tumor size. This approach, however, lacks sensitivity and can only give a delayed indication of a positive response to treatment. Major advances in our understanding of the molecular mechanisms responsible for cancer, combined with new targeted clinical imaging technologies designed to detect the molecular correlates of disease progression and response to treatment, are set to revolutionize our approach to the detection and treatment of the disease. We describe here the imaging technologies available to image tumor cell proliferation and migration, metabolism, receptor and gene expression, apoptosis and tumor angiogenesis and vascular function, and show how measurements of these parameters can be used to give early indications of positive responses to treatment or to detect drug resistance and/or disease recurrence. Special emphasis has been placed on those applications that are already used in the clinic and those that are likely to translate into clinical application in the near future or whose use in preclinical studies is likely to facilitate translation of new treatments into the clinic.
Keywords: Diagnostic imaging; Cancer therapy; MRI; PET; Nuclear imaging; Metabolism; Angiogenesis; Gene expression; Apoptosis; Immunotherapy; Receptor imaging; Staging; Recurrence;