Pharmacogenetics and Individualized Therapy

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Clinical trials are needed not only to identify links between genes and treatment outcomes but also to confirm initial findings, clarify the meaning of these associations and translate them into prescribing guidelines. Nonetheless, progress in this field points toward a time when pharmacogenomics will be part of routine medical care — at least for some drugs. Mayo Clinic does not endorse companies or products.

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Sign up now. Precision medicine and pharmacogenomics Personalized medicine holds the promise that treatments will one day be tailored to your genetic makeup. By Mayo Clinic Staff. References Precision medicine. Food and Drug Administration. Accessed July 31, Godman B, et al. Personalizing health care: Feasibility and future implications. BMC Medicine. Tremblay J, et al. Role of genomics on the path to personalized medicine. Wang L, et al.

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Genomics and drug response. New England Journal of Medicine. Weinshilboum RM, et al.

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Pharmacogenomics: Precision medicine and drug response. Mayo Clinic Proceedings. Frequenty asked questions about pharmacogenomics. National Human Genome Research Institute.

Pharmacogenomics: a key component of personalized therapy

National Institute of General Medical Sciences. What you need to know about pharmacogenomic testing. Cancer pharmacogenetics allows identification of patients at risk for severe toxicity, or those likely to benefit from a particular treatment and thus helps us move toward the ultimate goal of individualized cancer therapy. There are significant differences between cancer and other disease pharmacogenomics. In cancer, both germline genome of the patient and the somatic genome of the tumor are involved. The former is responsible for the inter-individual inherited genetic differences while the latter is due to accumulation of acquired somatic mutations resulting in inconsistent responses.

Cancer pharmacogenomics also faces the problem of conducting human studies, availability of healthy volunteers for receiving cancer drugs and multigenic control of drug response. Table 1 lists some of the major biomarkers which are associated with cancer treatment toxicities while Table 2 lists some of the biomarkers associated with cancer treatments mentioned in US FDA-approved drug labels.

The prediction of cancer treatment outcome based on gene polymorphisms is becoming a reality for many classes of chemotherapy agents, and the most clinically significant examples are discussed below. Thiopurines are a family of drugs that includes 6-mercaptopurine 6-MTP which is a daily component of maintenance therapy for childhood acute lymphoblastic leukemia treatment [ 7 ], thioguanine and azathioprine.

This methylation shunts the active drug away from TGN formation. This activation is catalyzed by methylation by thiopurine methyltransferase TPMT of the thiopurine agents azathioprine, mercaptopurine, and thioguanine [ 7 , 8 ], thereby shunting drug away from TGN formation. Genetic variants present in TPMT may alter the treatment response in cases receiving chemotherapeutic drugs.

Caucasians have more prevalence of TPMT polymorphisms and a trimodal distribution of TPMT enzyme activity while southeast Asians have less prevalence and a unimodal distribution [ 15 , 16 , 17 ]. Several studies have shown that TPMT-deficient patients are at very high risk of developing severe hematopoietic toxicity if treated with conventional doses of thiopurines [ 18 , 19 ]. Studies have also been carried out to show that patients who are heterozygous at the TPMT locus are at intermediate risk of dose-limiting toxicity [ 20 , 21 ].

In one of our studies, a poor treatment response was observed in head and neck cancer patients receiving chemotherapy with cisplatin and 5-FU which might be due to the higher intracellular concentration of cisplatin due to lower or intermediate TPMT enzyme activity [ 22 ]. DPD inactivates 5-FU in the liver and has huge differences in activity among individuals leading to excessive amounts of 5-FdUMP in patients with low activity which causes gastrointestinal, hematopoietic, and neurological toxicities [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ].

A decreased DPD activity has been found to be associated with severe or fatal toxicity from standard doses of 5-FU [ 37 ]. Irinotecan, a topoisomerase I inhibitor, is used to treat various solid tumors, and requires activation by carboxylesterase to its active metabolite, SN The toxicities associated with Irinotecan, namely diarrhea and leucopenia, are due to increased levels of SN In chemotherapy, a decreased rate of glucuronidation has been shown to be an important factor in prediction of toxicity.

The rate of glucuronidation is reduced as a consequence of reduced transcription rate due to abnormal dinucleotide repeat sequences 5—8 repeats within the TATA box of the UGT1A1 gene promoter [ 40 ]. TA n TAA promoter polymorphisms are more frequent in Caucasians than in Asians which have more missense polymorphisms in the exons [ 42 ]. In another retrospective study of cancer patients treated with irinotecan, a significant proportion of the 26 patients suffered from severe diarrhea or neutropenia. Platinum agents like cisplatin, carboplatin and oxaliplatin act by inhibiting cell replication as a result of formation of DNA adducts.

However, sometimes the effect of platinum agents is compromised as a result of decreased drug accumulation, detoxification, reduced or no DNA adduct formation and an increased activity of DNA repair system. One of the factors that can influence response to platinum chemotherapy agents is polymorphisms in glutathione GSH -dependent enzymes.

Glutathione-S-transferases GSTs catalyze the conjugation of GSH to platinum agents, forming less toxic and more water-soluble conjugates. Studies from our laboratory have shown association of polymorphism in drug metabolizing cytochrome Ps CYPs and GSTs with head and neck cancer [ 46 ]. Studies also revealed significant increase in head and neck cancer risk in cases with null genotypes of GSTM1 or GSTT1, though inconsistent reports are also available.

Likewise, no consistent data is available on the association of GSTP1 polymorphism with head and neck cancer risk [ 47 ]. Further, site specificity is also reported in the expression of GSTs in the squamous mucosa of head and neck which may lead to the differences in the susceptibility when analyzed according to the tumor location. In contrast, no site specific differences in the distribution of GST variant forms have also been observed in few studies [ 48 ]. The null genotypes for GSTM1 or GSTT1 were associated with a reduction in risk of relapse in several tumor types treated with chemotherapy such as acute lymphoblastic leukemia, acute myeloblastic leukemia, breast cancer, ovarian cancer, and lung cancer.

Women with the low-activity VV genotype had better survival upon cyclophosphamide-based chemotherapy [ 49 ]. The substitution of isoleucine with valine at position reduces enzyme activity against alkylating agents.

Pharmacogenomic Testing – Nicole's Story

Anticancer agents act by causing DNA damage in tumor cells which is subsequently repaired by the DNA repair machinery of the cell. Thus, more the active DNA repair system, less will be the treatment outcome. It was reported that the allele results in high rate of sister chromatid exchange after exposure to ionizing radiation in human lymphocytes.

Pharmacogenomics and “Individualized Drug Therapy” | SpringerLink

There are also reports which suggest the role of XRCC1 GA ArgGln polymorphism in development of lower grade of fibrosis as a result of radiotherapy in 60 nasopharyngeal cancer patients [ 56 ]. Excision-repair cross-complementing 1 ERCC1 gene encodes a helicase which is required for the nucleotide excision repair pathway.

Studies have shown that patients homozygous for the ERCC1 C allele demonstrated a significantly better survival. The patients having KK homozygotes responded more frequently to chemotherapy and lived significantly longer than did heterozygotes or QQ homozygotes [ 62 ].

Time to progression was significantly higher in cisplatinum-treated patients with non-small cell lung cancer harboring the KQ ERCC2 genotype than those harboring the KK genotype. A nonsynonymous SNP, altering a lysine to glutamine at codon of the XPD protein, was significantly associated with treatment outcome in patients with metastatic colorectal cancer [ 62 ]. The current pharmacogenetics approaches face many stumbling blocks. Candidate gene-based approaches do not provide a reliable prediction of tumor drug response and normal tissue toxicity because of a lack of understanding of the precise role of all participating factors.

A number of other issues plague SNP genotyping in the clinical settings such as quality control which is due phenotypic heterogeneity, a long duration involved in validation of pharmacogenetic markers in experimental settings, the combined effects of many low-risk polymorphisms, selection of the most appropriate panel of SNPs, analyzing the correlation between genotype, gene expression, and enzyme activity, criteria for risk assessment and thresholds, consideration of ethnic variations as the distribution and frequency of SNPs vary among different ethnic groups which makes it difficult to extrapolate the findings of one group on another [ 65 ].

Newer targeted therapies are also gaining popularity. Trastuzumab herceptin , a humanized recombinant monoclonal antibody IgG targets Human Epidermal Growth Factor Receptor 2 HER2 , Gefitinib Iressa inhibits the tyrosine kinase activity of the Epidermal Growth Factor Receptor, Bevacizumab Avastin is an anti-angiogenesis agent, the addition of which to standard chemotherapy regimens has shown improved response rates and survival rates in the treatment of metastatic colorectal cancer [ 66 ].

Likewise, Cetuximab Erbitux , a monoclonal antibody, targeting EGFR has also shown promising results in colorectal cancer and head and neck cancers.

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Future developments in some key areas will play a critical role in deciding the overall influence of pharmacogenetics data on therapeutic decisions. Improvements are needed in genome-wide technologies such as development of gene expression arrays, high throughput technologies, SNP chips, genome-wide scans which could potentially identify previously unidentified, functionally important candidate genes and SNPs.

Mouse models could be used for genome-wide scans in offspring from phenotypically distinct mice from resistant and susceptible strains. Knockout and transgenic techniques could also be used for establishing the key elements that contribute to drug response and disposition.

Candidate gene approach could be enhanced by knowledge gained from genome wide techniques and by incorporating a metabolic pathway approach.

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