Related Experiment Videos
Pharmacogenetics of anticancer drug sensitivity in non-small cell lung cancer
Romano Danesi1, Filippo de Braud, Stefano Fogli
1Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy. r.danesi@med.unipi.it
Abstract:
In mammalian cells, the process of malignant transformation is characterized by the loss or down-regulation of tumor-suppressor genes and/or the mutation or overexpression of proto-oncogenes, whose products promote dysregulated proliferation of cells and extend their life span. Deregulation in intracellular transduction pathways generates mitogenic signals that promote abnormal cell growth and the acquisition of an undifferentiated phenotype. Genetic abnormalities in cancer have been widely studied to identify those factors predictive of tumor progression, survival, and response to chemotherapeutic agents. Pharmacogenetics has been founded as a science to examine the genetic basis of interindividual variation in drug metabolism, drug targets, and transporters, which result in differences in the efficacy and safety of many therapeutic agents. The traditional pharmacogenetic approach relies on studying sequence variations in candidate genes suspected of affecting drug response. However, these studies have yielded contradictory results because of the small number of molecular determinants of drug response examined, and in several cases this approach was revealed to be reductionistic. This limitation is now being overcome by the use of novel techniques, i.e., high-density DNA and protein arrays, which allow genome- and proteome-wide tumor profiling. Pharmacogenomics represents the natural evolution of pharmacogenetics since it addresses, on a genome-wide basis, the effect of the sum of genetic variants on drug responses of individuals. Development of pharmacogenomics as a new field has accelerated the progress in drug discovery by the identification of novel therapeutic targets by expression profiling at the genomic or proteomic levels. In addition to this, pharmacogenetics and pharmacogenomics provide an important opportunity to select patients who may benefit from the administration of specific agents that best match the genetic profile of the disease, thus allowing maximum activity.
Insights
Cancer involves genetic changes affecting cell growth. Pharmacogenetics and pharmacogenomics study genetic variations to improve drug efficacy and safety, enabling personalized cancer treatment strategies.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Malignant transformation in mammalian cells involves tumor-suppressor gene loss and proto-oncogene activation, leading to uncontrolled cell proliferation and survival.
- Genetic abnormalities in cancer are crucial for predicting tumor progression, patient survival, and response to chemotherapy.
- Pharmacogenetics investigates genetic variations influencing drug metabolism, targets, and transporters, impacting drug efficacy and safety.
Purpose of the Study:
- To explore the evolution from pharmacogenetics to pharmacogenomics for a comprehensive understanding of genetic influences on drug response.
- To highlight the role of novel techniques like high-density arrays in genome- and proteome-wide tumor profiling.
- To emphasize the potential of pharmacogenomics in identifying novel therapeutic targets and enabling personalized medicine in cancer treatment.
Main Methods:
- Traditional pharmacogenetics relies on analyzing sequence variations in candidate genes.
- Novel techniques such as high-density DNA and protein arrays enable genome- and proteome-wide tumor profiling.
- Pharmacogenomics utilizes a genome-wide approach to assess the collective impact of genetic variants on drug responses.
Main Results:
- Traditional candidate gene approaches in pharmacogenetics have yielded contradictory results due to limited scope.
- Genome- and proteome-wide profiling offers a more comprehensive understanding of molecular determinants of drug response.
- Pharmacogenomics accelerates drug discovery by identifying new therapeutic targets through expression profiling.
Conclusions:
- Pharmacogenomics represents an advancement over pharmacogenetics by considering the cumulative effect of all genetic variants on drug response.
- High-throughput technologies are essential for advancing pharmacogenomic research and application.
- Pharmacogenetics and pharmacogenomics offer significant opportunities for patient stratification and personalized therapeutic strategies in cancer care.