ZIA BC 010627 (ZIA) | |||
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Title | Clinical Pharmacogenetics | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Figg, William | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $551,199 | Project Dates | 10/01/2003 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) |
Brain (5.0%) Breast (15.0%) Nervous System (5.0%) Ovarian Cancer (15.0%) Prostate (50.0%) |
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Research Type | |||
Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors Systemic Therapies - Discovery and Development |
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Abstract | |||
Our laboratory has a strong interest in pharmacogenetics. We have been active in studying how germline genetic variants can alter pharmacokinetics, response, and toxicity of various anticancer agents, thereby contributing to interindividual variation in clinical outcomes in therapies with an already narrow therapeutic window. We have established a molecular link between these polymorphisms and their phenotype as it relates to drug treatment. Most of our work has been focused on genetic variations in drug metabolism and transporting candidate genes such as ABCB1 (P-glycoprotein, MDR1), ABCG2 (BCRP), SLCO1B3 (OATP1B3, OATP8), CYP3A4, CYP3A5, CYP1B1, CYP2C19, CYP2D6, UGT1A1, UGT1A9 and several others. Drug transporters mediate the movement of endobiotics and xenobiotics across biological membranes in multiple organs and in most tissues. As such, they are involved in physiology, development of disease, drug pharmacokinetics, and ultimately the clinical response to a myriad of medications. Genetic variants in transporters cause population-specific differences in drug transport and are responsible for considerable interindividual variation in physiology and pharmacotherapy. Thus, we are interested in studying how inherited variants in transporters are associated with disease etiology, disease state, and the pharmacological treatment of diseases. We are also interested in non-candidate gene approaches where large numbers of polymorphisms are explored to establish a relationship with clinical outcome, and experiments are conducted to validate potential causative alleles resulting from exploratory scanning. We have worked with Affymetrix to beta-test the DMET chip that contains 1,256 genetic variations in 170 drug disposition genes, and are currently establishing a clinical trial where patients treated at the NCI will be genotyped with the DMET chip to explore potential links between these genes and various treatments of several cancers. We are currently making progress in validating the results from the initial DMET chip experiments. While many of these studies have been conducted in order to explain some of the genetic influence on pharmacokinetic variability, we also have a strong interest in clarifying genetic markers of pharmacodynamics and therapeutic outcome of several major anticancer agents since this field has been rather poorly studied. We have evaluated genetic polymorphisms in the XRCC1 gene and its association with radiation therapy in prostate cancer and found that XRCC1 genetic variants may affect the outcome in patients who received radiotherapy for localized prostate cancer. We evaluated the association of ERCC1 polymorphism and its contribution to altering sensitivity to platinum-base chemotherapy. Although ERCC1 N118N (rs11615) is the most studied polymorphism, the impact of this polymorphism on platinum-based chemotherapy remains unclear. This is the first study in which the functional impact of ERCC1 N118N on gene expression and platinum sensitivity was explored. Specifically, the ERCC1 cDNA clone with either the C or T allele was introduced into an ERCC1 deficient cell line, UV20, and assayed for the effect of the two alleles on ERCC1 transcription, translation and platinum sensitivity. Both ERCC1 mRNA and protein expression levels increased upon cisplatin treatment, peaking at 4h post-treatment, however there were no differences between the two alleles. These data suggest that N118N itself is not related to the phenotypic differences in ERCC1 expression or function, but rather this polymorphism may be linked to other causative variants or haplotypes. Moreover, we also conducted the first prospective study to date in patients with metastatic castration-resistant prostate cancer that describes predictive germline polymorphisms of ERCC1 and XRCC1 for assessing the clinical activity of satraplatin. Sorafenib is an inhibitor of UGT1A1 but is metabolized by UGT1A9: Implications of genetic variants on sorafenib exposur" |