New Genetic Link to Chemoresistance in Liver Cancer Identified
A new genetic link has been established between genes commonly overexpressed in human hepatocellular carcinoma and resistance to a common chemotherapeutic drug. Scientists have identified that two genes, the astrocyte elevated gene-1 (AEG-1) and the gene encoding transcription factor LSF, influence chemoresistance to drugs, such as 5-fluorouracil, which are used to treat aggressive carcinomas.
One of the most serious problems in the treatment of aggressive cancers, such as hepatocellular carcinomas, is the development of resistance to common therapeutics. Researchers have investigated whether the genetic transformation during cancer pathogenesis will be able to predict resistance. AEG-1, usually expressed in low levels in healthy tissue, is overexpressed in many aggressive cancers and therefore was an interesting candidate gene that might contribute to the development of resistance.
A team from Virginia Commonwealth University (VA, USA) studying AEG-1 expression in cancer tissue identified that the gene was overexpressed in aggressive cancers in tissues such as breast, prostate, liver and brain. They showed that this overexpression contributed to the malignant transformation of the tissue, by modulating the expression of the transcription factor LSF, which in turns controls the expression of genes that contribute to invasion, angiogenesis and metastasis.
“Since AEG-1 is a key regulator of liver cancer development and progression, understanding how this molecule works will provide profound insights into the mechanism of liver cancer development”, commented Dr Devanand Sarkar, from the Virginia Commonwealth University School of Medicine, “By understanding these molecular pathways and mechanisms, we may be able to create new drugs to inhibit the expression of AEG-1 or LSF and even develop combination drug therapies to enhance the effectiveness of 5- fluorouracil”.
They were able to show that expression of these genes was involved in chemoresistance to 5-fluorouracil, as inhibition of gene expression increased sensitivity to the drug. They analyzed the effect of siRNA-mediated gene silencing of AEG-1, LSF and another downstream gene, DPD, in human hepatocellular carcinoma cells in vitro, which increased the sensitivity of the cells to 5-fluorouracil. They were also able to noticeably inhibit tumor growth when human hepatocellular carcinoma cells were xenotransplanted onto athymic nude mice, by infecting the cells with a lentivirus carrying both 5-fluorouracil and siRNA for AEG-1. The combination of the siRNA and the drug was more effective than either approach on its own.
Sakar discussed the impact of their results “These findings may have important therapeutic implications. Based on the expression level of AEG-1 or LSF in tumor biopsy samples, a clinician might determine whether a patient would respond to 5-fluorouracil and thus design an effective chemotherapeutic protocol”.
Source: Yoo BK, Gredler R, Vozhilla N et al.: Identification of genes conferring resistance to 5-fluorouracil. Proc. Natl Acad. Sci. USA 106(31), 12938–12943 (2009).
Response to Alzheimer‘s Drug may be Affected by Common Genetic Variants Found in Many Sufferers
Scientists have found that a variant of the APOE gene combined with a polymorphism in the insulin degrading enzyme gene may influence the therapeutic efficiacy of a common Alzheimer‘s drug, AC-1202 (Axona™). The team, from Accera Inc., presented their findings at the 2009 International Conference on Alzheimer‘s Disease, Vienna, Austria in July 2009.
The etiology of Alzheimer‘s is very complex, and is thought to involve a large genetic component that may also influence treatment outcomes. Pharmacogenomic investigation into therapeutic response to common treatments may not only help to improve therapeutic efficiency but also elucidate mechanisms of the disease.
The team used data from a completed double-blind, placebo-controlled trial which compared disease progression between patients on AC-1202 and those administered a placebo for 90 days and after a two week washout period. The genetic profile of the patients was also analyzed, looking at genes that were thought to be relevant to the mechanisms of the disease. The scientists then looked to see whether any of these genes were related to the therapeutic response to AC-1202. In a previous analysis they had shown that patients with the E4 (epsilon 4) variant of the APOE gene showed decreased therapeutic response to AC-1202.
In the present study they built on these findings, and showed that a polymorphism in the insulin degrading enzyme gene also affected therapeutic response. Patients who did not carry a C/C polymorphism who were also negative for the E4 variant showed a significantly increased therapeutic response when compared with carriers of both variants. This is an encouraging finding, showing that pharmacogenomically guided dosing of AC-1202 may increase its efficacy.
Executive Director of Research at Accera, Dr Samuel Henderson commented on these important results “This pharmacogenomic finding provides both insight into the mechanism of ketone-based therapies for Alzheimer‘s disease, and also allows for the identification of patients who may respond best to therapy. This is the first scientific report on the role of insulin degrading enzyme and its interaction with APOE and effect on therapeutic efficacy in Alzheimer‘s disease patients”.
Source: Accera Press Release www.accerapharma.com/2009/news34.html
Genetic Variant Shown to Influence Response to a Common Antiseizure Drug
A genetic polymorphism has been shown to influence the dosing requirements of carbamazepine, a common antisezuire medication, according to scientists from Glasgow University, UK.
Considerable variation in individual dosing requirements for carbamazepine has been shown, and it is thought that this variation may have a genetic component. The team investigated various candidate genes thought to be involved in the metabolism of the drug, to identify whether they could identify any variants that influenced the variation in therapeutic response.
The team demonstrated that while no single genetic variant significantly affected the dose, a multivariate model taking into account specific variations in the microsomal epoxide hydrolase gene (EPHX1) (c.337T>C and c.416A>G) and the patient‘s age and sex was significantly associated with carbamazepine maintenance dose. The study will hopefully stimulate further research into the influence of genetic variation on the maintenance dose of the drug, looking at more genes that influence the pharmacokinetics and dynamics of carbamazepine. The authors of the study have called for further large-scale, prospective studies.
Source: Makmor-Bakry M, Sills GJ, Hitiris N, Butler E, Wilson EA, Brodie MJ: Genetic variants in microsomal epoxide hydrolase influence carbamazepine dosing. Clin. Neuropharmacol. (2009) (Epub ahead of print).
Genetic Biomarker Associated with Survival Rates in Breast Cancer may also Predict Treatment Response
A genomic grade index designed for the histological grading of tumors may also be able to predict response to chemotherapy. The team from The University of Texas MD Anderson Cancer Center, TX, USA, as well as scientists from Belgium and Germany, have examined whether the grade index, which has ready been shown to predict survival rates, is able to predict the response to neoadjuvant chemotherapy in breast cancer patients.
The discovery of biomarkers for cancer diagnosis, prognosis and treatment outcomes is vital for the progression of cancer research and treatment. The genomic grade index, for example, which was developed as a grade scale for cancer pathology, has also been used to successfully predict prognosis and survival rates. A high index score was associated with a worse relapse-free survival rate in HER-2 normal breast cancer. The team decided to look at whether the genomic grade index could be used not only as a biomarker for prognosis but also as a biomarker for treatment outcome.
“We are fascinated by the observation that the same biomarker can interact with multiple different clinical end points, often to an opposing effect”, Dr Lajos Pusztai, Associate Professor at The University of Texas MD Anderson Cancer Center, discussed the rationale behind the research, “For example, genomic grade index (GGI) interacts with chemotherapy sensitivity and higher GGI is associated with higher probability of response to chemotherapy, however, GGI also interacts with prognosis even in the absence of any systemic therapy and higher GGI is predictive of worse survival. We started to systematically map interactions between various gene-expression based markers and these clinical outcome variables including prognosis, chemosensitivity and endocrine sensitivity in the major subtypes of breast cancers.”
In the present study they looked at whether the 97-gene grade index could be used to predict response to neoadjuvant chemotherapy with paclitaxel, fluorouracil, doxorubicin and cyclophosphamide in patients with HER-2 normal breast cancer. They collected gene-expression data from 229 biopsies collected prospectively before chemotherapy was started, using fine-needle aspiration. They assed the response to therapy using the residual cancer burden, which calculates a score based on different parameters including the largest two dimensions (mms) of the residual tumor bed, the number of positive (metastatic) lymph nodes, percentage of tumor bed containing carcinoma, the percentage containing carcinoma in situ and the largest diameter (mm) of the largest nodal metastasis.
The results were very interesting. They showed that a high score indicated increased sensitivity to neoadjuvant chemotherapy in both ER-negative and ER-positive patients; however, the index was a better predictor of response on ER-positive subjects. They also confirmed that the index does predict worse relapse-free survival rates in ER-negative patients, and validated the use of the index in an independent laboratory.
The researchers hope that the study will influence future research, “We hope that investigators will increasingly recognize that the same biomarker, GGI in this instance, can have different degrees of predictive value in the different clinical and molecular subsets of breast cancer and start developing and validating markers separately for the different types of breast cancers (i.e., ER-positive disease or triple negative disease)” commented Dr Pusztai.
Source: Liedtke C, Hatzis C, Symmans WF et al.: Genomic grade index is associated with response to chemotherapy in patients with breast cancer. J. Clin. Oncol. 27(19), 3185–3191 (2009).
Acknowledgement
With thanks to Dr Pusztai for his comments.