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PGx Abstract Highlights from AACR Annual Meeting

At the annual meeting of the American Association of Cancer Research held last week in San Diego, researchers presented 44 abstracts on the latest pharmacogenomics cancer research. The following is a summary of a few select abstracts. Full versions of the abstracts are available here.

Title: Inter-ethnic genetic determinants of platinum chemotherapy toxicity susceptibility using an unbiased genome-wide approach
Authors: O'Donnell et al. University of Chicago, Chicago, Ill.
Researchers utilized well-genotyped, EBV-transformed lymphoblastoid cell lines from 45 healthy Japanese individuals in the International HapMap project to assess in vitro cisplatin and carboplatin-cytotoxicity phenotypes for use in genome-wide association studies. Drug-specific IC50s were determined using a colorimetric growth inhibition assay. Researchers produced a list of previously unidentified genes, and associated SNPs, defining the “susceptibility signature” in Japanese patients. For cisplatin, there were 6 significant SNPs (P < 0.05), all trans-acting, involving 3 target genes (FLJ12586, PHF1, LOC338612). For carboplatin, there were 11 significant trans-acting SNPs involving 8 target genes (DKFZp761O17121, NX17, LIN7B, ZBTB3, LOC284465, B4GALT3, CLCNKA, NALP11). “In summary, an unbiased genome-wide approach allowed identification of unique, population-specific cisplatin and carboplatin genetic susceptibility signatures which may be considered for clinical validation in an effort to understand the susceptibility of Asians to toxicities from these chemotherapies,” the researchers concluded.

Title: 5’ and 3’ polymorphic region of the TS gene as a prognostic marker in 5FU based chemotherapy
Authors: Pochi et al. University of Miami, Coral Gables, Fla.; University of Miami Miller School of Medicine, Miami, Fla.
Researchers hypothesized that the “simultaneous presence of three repeats at the 5’ end and 6 bp insertion at the 3’ end of the thymidylate synthase (TS) gene may increase its translational efficiency and stability. Hence the above genotypic combination may predict ‘poor’ and its absence ‘better’ response to 5FU based therapy.” To test their hypothesis, researchers determined the polymorphism by using a combination of PCR, agarose gel and RFLP analysis; analyzed IC50 values by XTT assay; and quantified mRNA levels by real time PCR using β-actin as a standard. The study found that “when TS expression was matched with the genotype; absence of 6 bp repeats in the 3’ region suggested higher TS expression under any combination of 5’ polymorphism.” The study authors said that they are “further refining this data to represent TS level as absolute quantity, which is amenable for direct comparison across cell lines. Upon establishment of a baseline TS level, using this strategy we can check the genotype of a patient and plan for individualized treatment.”

Title: CYP2D6 and SULT1A1 polymorphisms analysis in women using hormone replacement and low dose tamoxifen: A randomized low dose tamoxifen prevention trial. Seeking for the minimal active dose
Authors: Serrano et al. European Institute of Oncology, Milano, Italy; Haukeland University Hospital, Bergen, Norway; Galliera Hospital, Genoa, Italy.
After an enhancement of breast cancer risk reduction with tamoxifen treatment was observed in hormone replacement therapy users in an Italian tamoxifen trial, researchers conducted a low dose tamoxifen randomized phase II trial in 210 healthy postmenopausal women, and analyzed polymorphisms for CYP2D6 and SULT1A1 to correlate tamoxifen metabolites level. “Results showed that doses of tamoxifen £ 5 mg/day modulate favorably biomarkers of breast carcinogenesis and cardiovascular risk in HRT users,” researchers found. However, “more clinical data are needed to further understand the best dose in breast cancer prevention,” the researcher said in the abstract. “CYP2D6 and SULT1A1 polymorphisms may not significantly interfere in metabolites plasma concentrations with the reduced substrate.”

Title: Influence of CYP450 and UGT variants on the pharmacokinetics of 13-cis retinoic acid
Authors: Rowbotham et al. Newcastle University, Newcastle upon Tyne, UK.
Researchers evaluated the relevance to 13cisRA pharmacokinetics of 7 polymorphisms in CYP2C8, CYP3A4, CYP3A5 and CYP3A7 and 2 polymorphisms in UGT1A1 and UGT2B7 in a cohort of neuroblastoma patients receiving 13cisRA. The treatment was administered orally and plasma concentrations of parent drug and metabolites determined on days 1 and 14 of treatment by HPLC analysis. CYP2C8*3, CYP2C8*4, CYP3A5*3, CYP3A7*2 and CYP3A4*1G polymorphisms were analyzed by TaqMan, while CYP3A4*1B, CYP3A7*1C, UGT2B7*2 and UGT1A1*28 polymorphisms were analyzed by PCR-RFLP. “No associations were found between the pharmacokinetic parameters of 13cisRA or 13cisRA-4oxo and any of the studied genotypes,” the study authors concluded.

Title: Genetic variation in AKT1 and AKT2 is associated with variation in recurrence-free survival following cisplatin treatment of esophageal cancer
Authors: Hildebrandt et al. M.D. Anderson Cancer Center, Houston, Tex.
In an effort to determine if differences in response to cisplatin treatment is associated with genetic variation in the PI3K/PTEN/AKT/mTOR pathway, researchers genotyped 16 SNPs in PI3KCA, PTEN, AKT1, AKT2 and FRAP1 in 130 Caucasian esophageal cancer patients. The SNPs were analyzed for their associations with pathological response to chemotherapy, survival and recurrence-free survival. SNPs in AKT1 and AKT2 were found to be correlated with recurrence-free survival in the patient cohort. More specifically, “a highly significant association” was observed for AKT2:rs892119 (HR = 6.20; 95 percent CI - 2.45-15.69, p = 0.0001) resulting in median survival times of 40 months for patients with wild-type genotypes compared to only 12 months for those carrying at least one variant allele. “These results suggest a major role of AKT1 and AKT2 in modulating recurrence-free survival in esophageal cancer patients,” the researchers aid. “Ongoing studies are investigating the mechanistic basis for these results allowing for a comprehensive study of the relationship between genetic variation in AKT1 and AKT2 and response to cisplatin treatment of esophageal cancer.”

Title: Influence of UGT1A1 and UGT1A9 polymorphism on relative cancer risk in Korean populations
Authors: Choi et al. The Catholic University of Korea; Yonsei University Health System, Seoul, Korea.
To reveal co-occurrence of the UGT1A polymorphisms, researchers retrospectively attempted to characterize the UGT1A1-UGT1A9 haplotype structures in Koreans and gain insights on their association with increased cancer incidence. They genotyped the UGT1A1 (-3279T>G, -3156G>A, -53(TA)6>7, 211G>A and 686C>A) and UGT1A9 (-2152C>T, -275T>A and -118T9>10) variants by direct sequencing analysis in 68 cancer lung and colorectal cancer patients and 154 healthy volunteers. Overall, researchers found “no significant differences exist in the haplotype frequency between cases and controls (likelihood ratio statistic 8.56, df=15, p=0.89).” In conducting a logistic regression analysis, researchers found “a significant association between the UGT1A1-UGT1A9 diplotypes harboring four minor alleles and the incresed cancer incidence (OR 11.64, 95 percent confidence interval 1.70-79.43).” The study authors concluded that “the UGT1A genotypes might be clinically useful in predicting increased incidence of lung and colorectal cancer in Koreans.”

Title: Pharmacogenetic study of the TP53 P72R and MDM2 T309G single nucleotide polymorphisms in the human tumor cell line panel of the National Cancer Institute
Authors: Robert et al. Institut Bergonie, Bordeaux, France.
Researchers searched the panel of 60 human tumor cell lines of the National Cancer Institute to determine whether the tp53 and MDM2 polymorphisms were associated to the in vitro cytotoxicity of anticancer agents. Both SNPs have been identified in cell DNA using PCR-RFLP techniques validated by sequencing. “In the NCI-60 panel, the arg72 allele frequency of TP53 is 32 percent and the 309G allele frequency of MDM2 38 percent,” researchers reported. “The TP53 polymorphism has only a low impact on anticancer drug cytotoxicity, the cell lines with homozygous variant genotype having a lower sensitivity to some antimetabolites such as 5-fluorouracil or methotrexate, independently of the mutational status of p53. In contrast, the MDM2 polymorphism is associated to a significantly higher sensitivity of the variant homozygous cell lines to numerous alkylating and platinating agents, but this was only observed in cell lines with functional p53.” Given these findings, the researchers hypothesized that “homozygous variant cell lines for the MDM2 SNP present a lower availability of p53 for DNA repair, which would translate to higher sensitivity to DNA-damaging agents.” Additionally, “the variant MDM2 allele, because of its extra guanine, would represent a better target for alkylating agents that the common allele since these agents preferentially target N7 and O6 of guanine,” the researchers concluded.

Title: Polymorphisms in folate-metabolizing enzymes and response to 5-fluorouracil among stage II or III rectal cancer patients (SWOG 9304).
Authors: Holmes et al. Fred Hutchinson Cancer Research Center, Seattle, Wash.; Southwest Oncology Group Statistical Center, Seattle, Wash.; Olathe Regional Oncology Center, Olathe, Kan.; Oregon Health & Science University, Portland, Ore.; University of Southern California, Los Angeles, Calif.
Researchers studied two functional germline polymorphisms in MTHFR (A1298C and C677T) and one in RFC (RFC1 G80A) and a deletion polymorphism in DHFR in a cohort of stage II or III rectal cancer patients enrolled in a phase III adjuvant clinical trial of three regimens of 5-FU and radiation therapy. Taqman assays were used to genotype MTHFR and RFC polymorphisms in 425 patients' tumor samples. GeneScan size-dependent separation was employed to assess the DHFR deletion polymorphism in normal tissue collected using laser-capture microdissection. “Analyses of the three polymorphisms in folate-metabolizing enzymes MTHFR and RFC showed no significant differences across genotypes in overall survival, disease-free survival, or overall toxicity,” researchers reported. “For the DHFR deletion, we observed a significant increase in overall survival for subjects with heterozygous genotype versus those with homozygous wild type genotype (adjusted HR 0.44, 95 percent CI 0.21-0.89). We observed differences in flu-like symptoms across genotypes of A1298C (p=0.04), in dermatologic toxicity across genotypes of RFC1 G80A (p=0.03), and in hematologic toxicity across genotypes of DHFR (p=0.02).” According to the study authors, the preliminary analyses “suggest differences in survival and in toxicity by folate-related genotype.” Future studies will include additional patients from this trial and will be adjusted for toxicity results by treatment arm.

Title: ABCB1 genetic variation influences the toxicity and clinical outcome of patients treated with docetaxel
Authors: Sissung et al. National Cancer Institute, Bethesda, Md.; Georgetown University Medical Center, Washington, DC; St. Jude Children's Research Hospital, Memphis, Tenn.
Patients with androgen independent prostate cancer (AIPC) treated with docetaxel alone (n=23), or docetaxel and thalidomide (n=50), were genotyped for the ABCB1 1236C>T, 2677 G>T/A, and 3435 C>T alleles by direct sequencing. Researchers then compared this data to duration to onset of peripheral neuropathy, neutropenia grade, and survival after docetaxel. For patients receiving docetaxel alone, individuals carrying a diplotype consisting of the 1236C-2677G-3435C-linked alleles had improved overall survival after treatment. Patients treated with docetaxel and thalidomide carrying a diplotype consisting of the 2677T-3435T haplotype had a shorter median survival. In both treatment arms, individuals with the 2677GG genotype had a longer time-to-neuropathy and for patients carrying the 2677TT-3435TT diplotype there was a strong trend toward having higher grades of neutropenia. “The data suggest that docetaxel-induced neuropathy, neutropenia grade, and overall survival could be linked to ABCB1 allelic variants with ensuing negative implications for docetaxel treatment in patients carrying ABCB1 variant genotypes,” the researchers concluded.

Title: Genome-wide screening for sensitivity to etoposide and other topoisomerase II targeting drugs.
Authors: Stepanov et al. St. Jude Children's Research Hospital, Memphis, Tenn.
Topoisomerase II is a target for clinically important anticancer drugs such as s. Most of these drugs act as topoisomerase poisons, converting topoisomerase into a DNA damaging agent. Little is known about repair of this damage and genetic alterations responsible for enhanced sensitivity of tumor cells to topoisomerase targeting drugs.
In order to investigate the mechanism of topoisomerase II as a clinically important target for anticancers drugs, such as etoposide, doxorubicin and others, researches looked at a set of 4800 yeast strains that precisely delete each of the open reading frames present in the yeast genome. Researchers analyzed deletion set strains for sensitivity to the topoisomerase II poisons etoposide, doxorubicin, and mAMSA and identified more than 200 yeast genes that alter sensitivity to Top2 poisons. “As expected, genes defective in double strand break repair such as genes required for homologous recombination (e.g., RAD52 and MRE11) non-essential genes required for checkpoint induction (e.g., RAD9 and TOF1), DNA repair functions (e.g. TDP1 and MMS4/MUS81), and cell cycle regulators (such as CLB5, SIC1, and casein kinase II subunits) confer high levels of sensitivity to Top2 targeting agents,' the study authors reported. “Importantly, we have identified yeast genes that confer hypersensitivity to Top2 targeting drugs but do not significantly affect sensitivity to the Top1 targeting drug camptothecin ... These results provide an important tool for understanding repair of a unique type of DNA damage and will also be useful as a source of candidate genes that may predict drug sensitivity in human tumors.”

Title: Predicting sensitivity to temozolomide in melanoma: genomic and molecular profiling to identify prevailing resistance mechanisms
Authors: Augustine et al. Durham VA Medical Center, Duke University Medical Center, N.C.
Utilizing a panel of human melanoma-derived cell lines, researchers measured temozolomide (TMZ) sensitivity, O6-alkylguanine-DNA alkyltransferase (MGMT) activity and expression, proficiency of the mismatch repair (MMR) pathway, expression of base excision repair (BER) genes, promoter methylation status of MGMT and expression of 38k genes using the Affymetrix gene-microarray platform for each cell line. “Despite the broad spectrum of response to TMZ, the expression of genes important in BER varied little across these melanoma cell lines and showed no correlation with response to TMZ,” researchers found. “In contrast, there was a marked correlation between TMZ response and MGMT activity (p<0.0001) and expression (p<0.001).” Meanwhile, “MGMT expression was significantly correlated with MGMT activity (p<0.0001) and high MGMT expression was associated with little to no promoter methylation while low MGMT expression was associated with a high level of promoter methylation.” Given these results, researchers concluded that the study demonstrated that “melanoma resistance to temozolomide is almost exclusively conferred by MGMT activity and that MGMT expression alone appears to be the most accurate predictor of response to TMZ.”

Title: Application of cellular pharmacogenomics and systems biology to identify contexts of vulnerability and guide the clinical development of brostallicin
Authors: Keifer, et al. Translational Genomics Research Institute; Systems Medicine LLC, Scottsdale, Ariz.
Researchers attempted to identify molecular determinants of brostallicin response that could inform clinical development and conducted an integrated cellular pharmacogenomics study using response data from NCI's 60 human tumor cell lines. “Gene set enrichment analysis (GSEA) revealed unique associations between the brostallicin sensitivity gene set signature and distinct gene sets representing a number of specific molecular concepts, including significant associations with defined cancer types and aspects of DNA repair,” the study authors reported. Next, researchers prioritized a set of approximately 100 candidate genes to design a focused siRNA library to supplement a larger siRNA library representing 7,000 druggable gene targets across the human genome, and used the data to a high-throughput RNA interference (HT-RNAi) phenotype profiling analysis of the A2780 cell line treated with brostallicin. “Chemical-lethal sensitizing phenotypes representing potential genes and pathways that may play a role in regulating brostallicin sensitivity are being confirmed and validated,” researchers said. “The results of the integrated systems biology and cellular pharmacogenomics analysis will be presented as lists of prioritized candidate predictive biomarkers, putative synergistic combinations, and actionable biological insights that represent new hypotheses and molecular contexts of vulnerability that will support the clinical development of brostallicin.”

Title: Integrative approaches to investigate the molecular basis of the in vivo activity of NVP-BEZ235, a dual pan-PI3K / mTOR inhibitor
Authors: Marrer et al. Novartis Pharma AG; Novartis Institutes for Biomedical Research, Basel, Switzerland.
Researchers investigated the molecular basis of the target-related activity of NVP-BEZ235 — a dual pan-PI3K/mTOR inhibitor — in preclinical models, in an effort to understand the molecular links between glucose deregulation and pathways involved in NVP-BEZ235 target-related activities. They performed transcriptional profiling and yielded results demonstrating “the feasibility of effectively blocking the PI3K/PKB pathway in vivo with manageable effects on glucose regulation,” researchers reported.

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