2001 — 2009 |
Mcleod, Howard L |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Functional Polymorphism Analysis in Drug Pathways
Most pharmacogentic strategies to date have focused on the role of single genes in the regulation of drug activity and have made important steps towards the goal of optimizing therapy for individual patients. However, there is clear evidence that medications, like most common disease, are under the control of a network of genes each contributing to the patient's phenotype. The CREATE Pharmacogenetic Research Network (Comprehensive Research on Expressed Alleles in Therapeutic Evaluation will bring together infrastructure for the evaluation of pathways regulating drug activity This will be achieved through the coordinated efforts of investigators from Washington University and University of Southern California with expertise in the fields of genomics, Pharmacogenetics, Clinical Pharmacology, Bioinformatics/Computational Biology, Molecular Genetics, Statistical Genetics, Population Genetics, Clinical Trials, and Translational Research. Together they will evaluate the following general aims to develop validation strategies for applied pharmacokinetics. General aims: 1. Identify polymorphisms in genes that are components of pathways regulating drug activity 2. Determine the genotype-expression relationship in therapeutically relevant tissue 3. Establish the population characteristics of polymorphisms in Caucasian, Hispanic, Asian, and African American subjects 4. Provide clinical validation of polymorphisms in pathways regulating drug activity These aims will be achieved using human gastrointestinal cancer as a model system, as it is a common cause of death, has no clear prognostic tools to guide therapy, has ethnic differences in incidence and outcome, has readily accessible tissues available in the Tissue Procurement Core facilities, and is treatment with a small number of medications (three drugs). Defined gene pathways are clear for these agents and the Network will identify and evaluate a comprehensive approach to pharmacogenetics.
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1 |
2003 — 2004 |
Mcleod, Howard L |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Pharmacogenetics Advanced Colorectal Cancer
DESCRIPTION (provided by applicant): The treatment of advanced colorectal cancer offers an ideal environment for the development and evaluation of pharmacogenetics. The availability of multiple therapeutic options with clear antitumor activity requires clinical decisions to be made for individual patients and these decisions are best made with quantitative information. However, there are currently insufficient tools to guide the selection of therapy for advanced colorectal cancer. The recent FDA approval of irinotecan (CPT-11) and oxaliplatin (OXAL) for advanced colorectal cancer, in addition to the historical standard 5-fluorouracil (5FU), has led to the development of several active combination chemotherapy regimens for this disease. Indeed, the recently completed Gastrointestinal Intergroup study N9741 compared 5FU/CPT-11, 5FU/OXAL, and CPT-11/OXAL, with observed objective response rates of 28-38%. The previous reports of genetic variants associated with toxicity and/or activity from these three agents provides a promising approach for the development of a pharmacogenetic strategy to select therapy for advanced colorectal cancer. Therefore, this project will address the following Specific Aims: 1. Determine the predictive impact of genetic variants in candidate genes on severe toxicity from 5FU, CPT-11, or OXAL therapy in 575 patients from the N9741 study. 2. Define the association of genetic variants in candidate genes with response to therapy, time to progression, overall survival, and quality of life after 5FU, CPT-11, or OXAL regimens for advanced colorectal cancer. 3. Develop methods for incorporating Genetic Polymorphism Profiles into Decision Making. These aims provide a comprehensive framework for our strategy to provide the first prospective information on the integration of pharmacogenetic information into the selection of therapy for advanced colorectal cancer.
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1 |
2004 — 2008 |
Mcleod, Howard L |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Core--Pharmacology Facility
The Pharmacology Core provides analytical support for basic and clinical scientists at the Siteman Cancer Center (SCC) that would not otherwise be available. This has ranged from plasma analysis and/or pharmacokinetic modeling of arsenic trioxide, all trans retinoic acid, celecoxib, doxil, irinotecan, hydroxychloroquine, topotecan, UCN-01, cisplatin, docetaxel, paclitaxel, and PSC833 to support of preclinical and clinical studies. The core also provides the only source of support for SCC members to design and analyze novel studies of drug disposition. The core provides preclinical metabolism and elimination studies, and it plays a role in the cancer pharmacology education and training of SCC members and Barnes Jewish Hospital/Washington University clinical trainees. The Pharmacology Core offers the following services: . Pharmacology trial design and analyses . Analytical assay development and validation (HPLC) . Preclinical metabolism and elimination studies (in vitro, ex vivo, in vivo) . Pharmacokinetic/Pharmacodynamic studies . Education and training . Regional pharmacology resource for other academic institutions
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1 |
2005 — 2009 |
Mcleod, Howard L |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Core--Applied Genomics
One fundamental theme of this SCCOR proposal is the development of genetic tools for understanding the mechanistic basis for diabetes-associated cardiovascular disease. The Applied Genomics Core (AGC, Core Unit B) will provide sample processing and analytical support to the Projects detailed in this application. Specifically, the AGC will: 1) Perform DNA extraction and analysis of single nucleotide polymorphisms and other genetic variants for Projects 4 and 5 of this application. 2) Provide gene informatics expertise to mine and annotate genetic variants in candidate genes will also be conducted to support Projects 1, 4, and 5.
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1 |
2005 — 2006 |
Mcleod, Howard L |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Ovarian Cancer Pharmacogenetics @ University of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): It is an exciting time for the treatment of ovarian cancer. The availability of multiple therapeutic options with clear antitumor activity requires clinical decisions to be made for individual patients and these decisions are best made with quantitative information. However, there are currently insufficient tools to guide the selection of therapy for ovarian cancer. The recently completed SCOTROC1 Phase III clinical trial compared paclitaxel/carboplatin and docetaxel/carboplatin, with a 29% complete response rate observed in both arms. The incidence and type of toxicity differed significantly between the two therapies. This offers the opportunity to apply human genomic information to develop predictive markers to guide therapy selection. Therefore, this project will address the following Specific Aims: 1. Determine the predictive impact of variants in taxane/platinum candidate genes on severe toxicity in patients on the SCOTROC1 study. 2. Define the association of genetic variants in taxane/platinum candidate genes with tumor response and progression-free survival after treatment for ovarian cancer. 3. Identify genotypes associated with favorable risk-benefit for taxane/platinum therapy in ovarian cancer. This study will take advantage of DNA collected from 914 patients on the SCOTROC1 Phase III clinical trial. Samples from both treatment arms will be assessed for the presence of multiple polymorphisms in genes of relevance to taxane and platinum activity and efficacy. Single polymorphism and haplotype associations with toxicity and response will be performed to address Specific Aims 1-3. The availability of uniform information on toxicity, tumor response, and patient survival makes this study a powerful framework with which to answer pharmacogenetic questions. Significant associations will provide the basis for future genotype-directed clinical trials in ovarian cancer.
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1 |
2005 — 2009 |
Mcleod, Howard L |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Pharmacogenetics of Post-Acs Therapy
Acute Coronary Syndrome (ACS) is a major cause of morbidity and mortality in the Western World. Multiple patient characteristics, including genetic constitution and metabolic status (in particular diabetes), have significant influence on patient outcome. The last decade has seen major advances in post-ACS treatment, including the administration of beta adrenergic receptor antagonists (beta blockers; BB) and angiotensin converting enzyme (ACE) inhibitors to prevent post-ACS complications. The avaiiabiiity of multiple therapeutic options with clear benefit post-ACS requires that clinical decisions must be made for individual patients. However, there are currently insufficient tools to guide the selection of post-ACS therapy in an objective and evidenced-based manner. The expansion of human genomic information has led to exciting new opportunities for the application of pharmacogenetics to improve the selection of post-ACS therapy. There is a growing list of published examples where a genetic variant in the metabolism, transport, or cellular target of a drug is clearly associated with patient toxicity or clinical outcome. The greatest obstacle to the integration of pharmacogenetics into clinical practice is the paucity of quantitative data on the predictive ability of genetics in the selection of drug therapy. Accordingly, we seek to address the need for quantitative assessment of the predictive impact of relevant genetic variants in the context of modern post-ACS therapy. Recent findings by investigators of this SCCOR proposal and others implicate genes of the PPAR gene regulatory complex as candidate modifiers of metabolic and cardiovascular disease states. This project will address the following Specific Aims: 1) To determine if a homozygous SNP genotype in PPAR complex genes (PPARalpha, PPARgamma, PGC1alpha) involved in cardiac metabolism will predict improved efficacy of ACE-I or BB therapy in preventing MACE or improving symptom score in patients with ACS; 2) To perform gene-environment interaction analyses to ascertain the impact of diabetes on the predictive power of PPAR complex genes for improved efficacy of ACE-I or BB therapy in preventing MACE or improving symptom score in patients with ACS; and 3) To develop a polygenic panel of SNPs in multiple genes regulating myocardial metabolism to predict improved efficacy of ACE-I or BB in preventing MACE or improving symptom score among patients with ACS. These aims provide a comprehensive framework for our strategy to generate prospective information on the predictive power of metabolic genes on the selection of therapy for ACS. The resulting tools will allow for more precise selection of post-ACS therapy for individual patients.
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1 |
2012 — 2019 |
Krauss, Ronald M (co-PI) [⬀] Mcleod, Howard L Motsinger-Reif, Alison [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetic Etiology of Cancer Drug Response @ North Carolina State University Raleigh
DESCRIPTION (provided by applicant): Important progress continues to be made in the treatment of most common cancers, but therapeutic benefit remains difficult to predict and severe or fatal adverse events occur frequently. The Human Genome Project has fueled the notion that genetic information can produce effective and cost-efficient selection of therapies for individual patients, but validated genetic signatures that predict response to most chemotherapy regimens remain to be identified. Numerous genes potentially influence drug response, but current candidate-gene approaches are limited by the requirement of a priori knowledge about the genes involved and the moderate size of most clinical trials often limits the power of in vitro genome wide association studies (GWAS) for cancer pharmacogenomics discovery. In response to these limitations, we have undertaken a thorough, pharmacogenomic assessment of cytotoxic effect of the majority of FDA approved anti-cancer compounds using an ex vivo model system to determine the heritability of drug-induced cell killing to prioritize drugs for pharmacogenomic mapping. These results are an important first step, and while high heritability of a trait does not guarantee successful association mapping results, it represents an important first step and the results will be used to prioritize drugs with high heritabilities for genome-wide association mapping. In the current proposal, GWAS mapping of cytotoxic agents will be performed in a European American population, and then replication GWAS mapping will be performed in an East Asian population. In addition to discovering and validating genetic variants that predict drug response, the wealth of data collected will be used to dissect the underlying etiology of drug response traits, including assessing the relative contribution of genetic, environmental, and interaction components of variation. These results will provide crucial insight to prioritize genetic variants for follow-up in precious clinical population resources, and potentially reveal new insight into the overall etiology of drug responses. PUBLIC HEALTH RELEVANCE: We will build on our previous work to conduct ex vivo GWAS studies in two large, independent population cohorts on drug response phenotypes, and use cutting-edge statistical approaches to dissect the genetic etiology of these traits. Our overall goal is to identify high interest genes and characterize the trait etiology of these drug response outcomes so that they may be further investigated in future studies. This application leverages previously completed genome-wide genotyping for efficient association mapping, and will evaluate genetic associations in two independent cohorts.
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0.937 |