Genomic Fingerprint May be Able to Predict Chemotherapy Survivors
Cancer cell chemosensitivity revealed by genomic signature analysis
The wide range of chemosensitivity often shown by cancer cells poses an obstacle to achieving the most effective treatment pathway from the outset. A research team from the Institute of Statistical Science (Taipei, Taiwan) has recently carried out a study that may lead to the alleviation of this problem. This study has shed light on the genetic basis underlying the variation in chemotherapy response and therefore may have provided the starting point for the development of a more personalized chemotherapeutic approach.
The researchers pinpointed invasion-associated (IA) genes by correlating invasion-profiling data, from an invasion assay on the NCI-60 panel, with Affymetrix (CA, USA) gene expression data. Focusing on theIA genes, they investigated the gene–drug correlation, utilizing relatively new chemosensitivity data of 99 anticancer drugs. In order to validate their compound response predictions, they gathered data from four independent drug-testing experiments. Finally, the performance of the gene signature in patient outcome prediction was assessed using recently published clinical and molecular data from two recent adjuvant chemotherapy cohorts, one on lung cancer and one on breast cancer.
The invasion–gene expression correlation study uncovered a total of 633IA genes. A subset of these was revealed that was characterized by correlations between expression levels and drug-sensitivity profiles. This subset included eight genes:EGFR,ITGA3, MYLK, RAI14, AHNAK, GLS, IL32 andNNMT, which all showed gene–drug correlations with paclitaxel, docetaxel, erlotinib, everolimus and dasatinib. The investigators validated this chemosensitivity prediction of the eight-gene signature using 107 drug tests on 78 tumor cell lines. Remarkably, the eight-gene signature predicted relapse-free survival for both the lung and breast cancer patients. Notably, this eight-gene signature features the cancer hallmarkEGFR and other genes that are involved in typically tumorigenic activities, such as cell adhesion, migration and invasion, as well as tumor growth and progression.
By investigating the three-way interplay among gene expression, invasion and compound sensitivity, the researchers were able to identify a unique signature that is predictive of chemotherapy response, in both lung and breast cancer. This study may lead to advancements in chemosensitivity analysis, something which is crucial if the personalization of chemotherapy is to be realized. The genomic signature in this study was an eight-gene signature. However, ultimately, if the field of personalized chemotherapy is to progress, the focus must be on expansion, with genomic signatures much larger than eight genes. Larger, more descriptive signatures will naturally be more individualized, which will enable researchers to confidently assign patients specific and tailor-made treatment plans.
Source: Hsu YC, Chen HY, Li KC et al. Genome-wide analysis of three-way interplay among gene expression, cancer cell invasion and anticancer compound sensitivity. BMC Med. 11, 106 (2013).
Sofosbuvir Therapy has High Cure Rate in Patients with Particular Hepatitis C Genotypes
Sofosbuvir proves to be an effective treatment for hepatitis C patients who have previously had no other option
A research team led by Ira Jacobson of Weill Cornell Medical College (NY, USA) has recently tested the efficacy of the drug sofosbuvir in the treatment of hepatitis C virus (HCV) infections. The impetus of this study was the desire to move away from interferon use – the current mainstay HCV treatment – as HCV patients with genotypes 2 and 3, comprising 25% of all HCV patients, show no response to this treatment. For these patients, there is currently no alternative treatment option and, therefore, the need to develop new drugs is rather pressing. In addition to these nonresponders, the move away from interferon use is being driven by the negative side effects associated with the drug.
The researchers investigated the performance of sofosbuvir by conducting two randomized, Phase III studies with patients with chronic HCV genotype 2 or 3 infection. In one trial, patients for whom peginterferon was not an option, received either oral doses of sofosbuvir and ribavirin (207 patients), or a matching placebo (71) over the course of 12 weeks. In a second trial, patients who had been treated previously with interferon but who had not shown any response were given oral doses of sofosbuvir and ribavirin for 12 (103 patients) or 16 weeks (98 patients).
The results of the study, which were published in theNew England Journal of Medicine, showed that sofosbuvir and ribavirin elicited a sustained virologic response of 78% in patients for whom treatment with peginterferon was not an option, as compared with 0% with placebo. Patients who had been previously treated with interferon had a 50% response rate with 12 weeks of treatment. Upon extension of treatment time to 16 weeks, the response rate in this group increased to 73%.
It was also notable that patients with genotype 3 demonstrated a lower response rate than those with genotype 2, in both trials. Another observation was that among patients with genotype 3, those with cirrhosis displayed a lower response than those without. Sofosbuvir elicited some adverse reactions, of which the most common included headache, fatigue, nausea and insomnia. However, despite these, the overall rate of discontinuation was low (1–2%).
The researchers were able to conclude from these two studies that sofosbuvir and ribavirin is an effective HCV treatment for patients who show no response to pegineterferon or for whom treatment with peginterferon is not an option.
Thus, the study has revealed some very appealing aspects of sofosbuvir, especially when compared with interferon; it offers the same or higher cure rates, a faster response time and has a better safety profile. The researchers predict that these studies may pave the way for a much-needed paradigm shift in the treatment of HCV. This study may also herald the renewal of hope for patients with genotypes 2 and 3, as it is the first treatment to elicit a response in this typically nonresponsive subgroup.
Source: Jacobson IM, Gordon SC, Kowdley KV et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N. Engl. J. Med. 368(20), 1867–1877 (2013).
Genome Study Fuels the Drive to Personalize Pulmonary Fibrosis Treatment
A recent genome-wide association study carried out by a research team headed by David Schwartz of National Jewish Health (CO, USA) revealed multiple genetic regions that are associated with pulmonary fibrosis (PF). This study may be regarded as the long-awaited ‘light at the end of the tunnel‘ breakthrough for PF, a disease for which there is currently no successful treatment.
The investigators used a cohort of 1616 non-Hispanic, white individuals with fibrotic idiopathic interstitial pneumonias and 4683 matched controls to perform a genome-wide association study. As well as confirming the previously known associations between PF andTERT, andMUC5B, they found seven novel genetic associations with fibrotic idiopathic interstitial pneumonias;FAM13A, DSP, OBFC1, ATP11A, DPP9 and chromosomal regions 7q22 and 15q14–15. The researchers investigated the functionality of the genes revealed, many of which they found to be involved in cellular activities such as host defense, cell–cell adhesion and DNA repair, giving us insights into the disease mechanism. The study also strengthened the tenuous link between telomere length and PF. Two rare genetic mutations in telomeric regions were previously associated with PF. However, due to their rarity, these mutations were not a viable focus for research. This study uncovered common variants in close proximity to these two genes, thus providing us with a more feasible research point with a much wider patient catchment potential.
The vast multiplicity of PF-associated loci revealed by this study suggests that ‘different genes in different people‘ may be responsible for PF. It is crucial, therefore, that research maintains a broad genetic focus, rather than homing in on one particular variant. This strategy will avoid the risk of narrowing the treatment possibilities for many patient subgroups and prevent premature and superficial treatment individualization.
Source: Fingerlin TE, Murphy E, Schwartz DA et al. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat. Genet. doi:10.1038/ng.2609 (2013) (Epub ahead of print).
Individualized Treatment for Cardiac Rhythm Disorders May be just a Heartbeat away
A recent genome-wide association study led by collaborators from the Medical Research Council (Cambridge, UK) and Icahn School of Medicine at Mount Sinai (NY, USA) has provided us with a genetic viewpoint of cardiovascular disease, as the researchers uncovered 14 new genetic loci associated with heart rate. As heart rate is a strong predictor of cardiovascular disease and cardiac health in general, this finding may encourage the treatment of cardiac problems by genetic targeting, rather than the current ‘blanket‘ approach.
The joint research team performed a two-stage meta-analysis, using data from 181,171 patients from 65 studies from 2009 to 2012. The study took a hypothesis-free stance as they aimed to capture all genetic variation that has an effect, even slight, on heart rate. Their results proved to be very fruitful, yielding three-times the number of genetic variations that were known to be associated with heart rate. Furthermore, they attempted to elucidate some of the mechanisms underlying the associations by manipulating the expression of such genes in a follow-up study. They were thus able to attribute some of these variants to more specific aspects in the control and/or influence of heart rate, such as: signal transmission, embryonic development of the heart, cardiomyopathy, congenital heart failure and sudden heart failure.
Cardiac research has now been given a robust genetic foundation, which may support further understanding of heart-rate regulation. This knowledge may promote the development of cardiac therapies that are more genetically focused.
Source: den Hoed M, Eijgelsheim M, Loos RJ et al. Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nat. Genet. doi:10.1038/ng.2610 (2013) (Epub ahead of print).
– All stories written by Katie Lockwood