Methods and biomarkers for the diagnosis and prognosis of cancer and other diseases: Towards personalized medicine

Abstract

The rapid development of new diagnostic procedures, the mapping of the human genome, progress in mapping genetic polymorphisms, and recent advances in nucleic acid-and protein chip technologies are driving the development of personalized therapies. This breakthrough in medicine is expected to be achieved largely due to the implementation of "lab-on-the-chip" technology capable of performing hundreds, even thousands of biochemical, cellular and genetic tests on a single sample of blood or other body fluid. Focusing on a few disease-specific examples, this review discusses selected technologies and their combinations likely to be incorporated in the "lab-on-the-chip" and to provide rapid and versatile information about specific diseases entities. Focusing on breast cancer and after an overview of single-nucleotide polymorphism (SNP)-screening methodologies, we discuss the diagnostic and prognostic importance of SNPs. Next, using Duchenne muscular dystrophy (DMD) as an example, we provide a brief overview of powerful and innovative integration of traditional immuno-histochemistry techniques with advanced biophysical methods such as NMR-spectroscopy or Fourier-transformed infrared (FT-IR) spectroscopy. A brief overview of the challenges and opportunities provided by protein and aptamer microarrays follows. We conclude by highlighting novel and promising biochemical markers for the development of personalized treatment of cancer and other diseases: serum cytochrome c, cytokeratin-18 and -19 and their proteolytic fragments for the detection and quantitation of malignant tumor mass, tumor cell turn-over, inflammatory processes during hepatitis and Epstein-Barr virus (EBV)-induced hemophagocytic lymphohistiocytosis and apoptotic/necrotic cancer cell death.

Genome-wide DNA copy number predictors of lapatinib sensitivity in tumor-derived cell lines

“…Finally, as noted above, genetic aberrations are faithfully represented in cell lines, allowing for hypotheses to be generated and tested in vitro. Limitations of arraybased copy number analysis include the requirement of sufficient tissue material, the relative expense of the technique, and the lack of availability of array equipment in the clinical setting (17,57,58). In addition, copy number analyses will obviously not discover specific mutations (e.g., EGFR and KRAS) relevant to drug responsiveness.…”

“…Although genomewide expression profiling is currently the most widespread platform for pharmacogenomic studies, the mapping of specific DNA copy number alterations to multiple pathways is also effective in delineating markers associated with the responsiveness to targeted therapy (reviewed in ref. 17). Fixed genetic alterations such as DNA copy number gains and losses are appealing for clinical study because (a) they are relatively stable in vivo over time, and (b) they are faithfully modeled in cell lines in vitro (18,19).…”

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

“…Many novel small molecule approaches integrating peptides or peptidomimetics are being constructed to mimic the proapoptotic function of the BH3 domain, a fundamental target model whose function, in excess, can overcome the molecular roadblocks impeding the success of conventional chemotherapy (Mendoza et al, 2005). Pharmacological optimization of BH3-peptides and derived mimics using "hydrocarbon stapling" to produce stable, protease-resistant ␣-helices (Anderson et al, 2006;Kroczak et al, 2006;Walensky et al, 2004) or conjugation to cell penetrating peptides, such as the membrane translocation domain of the Antennapedia (Ant) protein to enhance membrane permeability (Hauff et al, 2005;Mendoza et al, 2005;Vieira et al, 2002), are proving to be efficacious methods in the design of potential drug candidates both in vitro and in vivo. The sophisticated dual role of the Bcl2 family members in the intricate regulation of apoptosis and the cell cycle makes them ideal therapeutic targets in diseases characterized by deregulated apoptotic pathways.…”

TRAIL receptor-targeted therapeutics: Resistance mechanisms and strategies to avoid them

“…that influence TRAIL sensitivity and which might be useful to select patients who are most likely to benefit from treatment. The practical issue, that will need to be determined in the case of TRAIL-receptor targeted therapeutics is similar to those for other current classes of (targeted) agents (Anderson et al, 2006), namely whether one or two of these markers will provide sufficient information to make informed treatment decisions or whether we will need to assess a large panel of such markers to optimize patient selection. Another question to be answered is, whether these markers will be associated with resistance or sensitivity to the various different drugs that could be used.…”