bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacogenetics of a PARP inhibitor ABT-888 metabolic pathway
Authors: Li J. , Sha X. , LoRusso P. 
Published: August 2020

e14556 Background: Poly(ADP-ribose) polymerase (PARP) is essential for single-stranded DNA break repair and repair of DNA damage can lead to radio- and chemo-resistance. Thus, inhibition of PARP activity can sensitize cells to cytotoxic therapies. ABT-888 is a potent, orally bioavailable PARP inhibitor. Preclinical studies suggest that ABT-888 potentiates multiple cytotoxic agents and its efficacy is correlated with plasma/tumor drug concentrations. The objective of this study was to determine the pharmacogenetic effect of genetic variants in the ABT-888 metabolic pathway, with the aim to better understand molecular basis of the variation in ABT-888 pharmacokinetics (PK) and therapeutic outcome. Methods: The major enzymes responsible for ABT-888 metabolism were identified by in vitro metabolism studies with specific recombinant human cytochrome P450 (CYP) enzymes. The functional significance of genetic variants of the identified enzymes was assessed by examining ABT-888 metabolic kinetics by candidate variant enzymes and microsomes. The association of the functional significant genetic variants with the PK and clinical outcome is being evaluated in the context of an ongoing phase I trial in which ABT-888 is administered in combination with irinotecan in patients with advanced solid tumors. Results: ABT-888 was metabolized predominantly by human CYP2D6, to a less extent by CYP1A1, and to a negligible extent by CYP1A2, 2C9, 2C19, 3A4, and 3A5. CYP2D6*10 exhibited markedly reduced catalytic capability in ABT-888 overall metabolism and the metabolite (A-925088) formation, with in vitro maximum clearance being 31% and 5.3%, respectively, of that estimated from the wild-type CYP2D6. In human liver microsomes carrying homozygous CYP2D6*4, the rates of parent drug disappearance and metabolite formation were significantly lower than those observed in the microsomes carrying wild-type CYP2D6, P < 0.05. Conclusions: CYP2D6 is the predominant enzyme responsible for the hepatic metabolism of ABT-888. Common allelic variants CYP2D6*10 and *4 are associated with significantly reduced metabolic activity towards ABT-888. CYP2D6 polymorphisms may influence the PK and therapeutic outcome of ABT-888. Its clinical relevance remains to be determined. No significant financial relationships to disclose.
Predicting response to irinotecan/5-fluorouracil (5-FU) chemotherapy for advanced colorectal cancer based on gene expression in primary tumour
Authors: Coyle V. , Allen W. , Jithesh P. , McManus D. , Stevenson M. , Harte R. , Eatock M. , Wilson R. , Johnston P. 
Published: August 2020

e14558 Background: Despite improvements in the treatment of advanced colorectal cancer (CRC), there remains a subset of patients who fail to benefit from chemotherapy. The identification of predictive response markers has been limited by the relative scarcity of metastatic tumour samples for molecular analysis, prompting a need to consider surrogate models for generation of predictive markers. Methods: We performed gene expression profiling of archived formalin fixed paraffin-embedded (FFPE) colorectal primary tumours (dating from 2001–2007) from 40 patients who received irinotecan/5-FU chemotherapy as first line treatment for advanced disease. Patients were classified as responders/non-responders based on radiological response. Gene expression profiling was performed using the Almac Diagnostics Colorectal Disease Specific Array (DSA). Data was analysed using Genespring GX v7.3. Principal Components Analysis (PCA) was used to separate responding and non-responding patients based on the tumour- derived expression data. Predictive classifiers were constructed using several class prediction methods. The performance of the classifiers was assessed by leave-one-out cross-validation. Results: 37 samples passed data QC assessments for inclusion in predictive analysis. PCA using genes passing a t-test and 1.5-fold change filter demonstrated clear separation between responding and non-responding patients. Predictive modelling using the k-nearest neighbour and Support Vector Machine (SVM) algorithms with Fishers exact test as feature selection method each generated seven different predictive classifiers containing 5 to 35 genes; these had an average predictive accuracy of 80%. Predictive modelling of this dataset is ongoing and these encouraging initial results will be extended to a larger patient cohort. Conclusions: DNA microarray profiling has been used to generate gene signatures predictive of response to irinotecan/5-FU therapy in advanced CRC; importantly, these predictive signatures have been generated from FFPE colorectal primary tumour facilitating their independent validation in large patient cohorts and potential clinical implementation in the event of successful validation. [Table: see text]
UGT1A1,A7 and A9 genotyping and pharmacokinetics of irinotecan-containing chemotherapy in patients with advanced cancer
Authors: Valenzuela B. , Nalda R. , Duart M. , Escudero V. , Perez-Ruixo J. , Martinez-Navarro E. , Rebollo J. , Gonzalez R. , Brugarolas A. 
Published: August 2020

e14563 Background: To the best of our knowledge only one previous report in asian lung cancer patients (pts) assesed UGT1A1, A7 and A9 genotypes along with irinotecan pharmacokinetics (Han et al. JCO 2006; 24: 2237–44). We set out to evaluate UGT1A1, A7 and A9 genotypes in caucasian cancer patients and their relationship with both irinotecan toxicity and irinotecan pharmacokinetics. Methods: UGT1A1, A7 and A9 genotypes were obtained from blood genomic DNA by direct sequencing. The area under the time-concentration curve (AUC) of SN-38 and SN-38G were calculated. The ratio between these AUCs (AUC SN-38G /AUC SN-38) was also calculated. Associations between pharmacokinetics parameters and the UGT1A genotypes were assessed by univariate analysis. Toxicity was collected using standard NCI grading criteria. Statistical correlation between presence of grade III and IV toxicity and UGT1A1,A7 and A9 genotypes was done by Pearson's Chi square. At least 80 patients (with both genotype and pharmacokinetics) are needed to achieve enough statistical power. Results: At the time of writing this abstract, complete genotyping and toxicity data from 59 patients were available. Sex (females 17, males 42). Median age 60 (range 25–88). Pathology (no. pts): lung (26), colon (17), others (16). 21 pts. (35.59%) had received previous chemotherapy. All but 5 pts received doses of irinotecan between 120 and 150 mg/m2. Median no. of cycles 6 (range 1–15). The frequencies of the different UGT1A1, A7 and A9 genotypes are similar to those previously reported. At least one episode of grade III or IV leukopenia was present in 19 pts. (32.2%), and grade III diarrea in 11 pts (18.6%). No statistically significant correlation was found between presence of leukopenia grades III and IV, and the genotypes UGT1A1,A7, and A9 (P=0.687, P=0.156 and P=0.476, respectively). Diarrea grade III was not statistically significantly associated with UGT1A1 (P=0.318), A7 (P=0.318) and A9 (P=0.158). 21 out of 59 pts. had pharmacokinetics (PK) data available. In genotype-PK association analysis, UGT1A1,A7 and A9 were not statistically associated with AUC SN-38G / AUC SN-38 ratios (P=0.844, P=0.911, P=0.431, respectively). Conclusions: Patients are still being accrued to achieve the targeted size. No significant financial relationships to disclose.
Using epigenetic reprogramming to target triple-negative breast cancer
Authors: Sharma D. , Knight B. B. , Yacoub R. , Liu T. , Taliaferro-Smith L. , Nagalingam A. , O'Regan R. M. 
Published: August 2020

e14565 Background: The outcome for patients with breast cancer has been significantly improved by the use of targeted agents. The prognosis of triple negative (TN) breast cancers, which do not express hormone receptors (ER, PR) or Her2, is poor, because of an aggressive clinical course and lack of targeted therapeutic agents. Epigenetic silencing of specific genes has been observed in breast cancer and some of these genes are more important due to available targeted therapies such as ER. Since all endocrine therapies are designed to block ER function in some way, the identification of new therapies or strategies that could sensitize TN breast cancers to existing endocrine therapy could provide a revolutionary means of treating this aggressive subtype of cancer Methods: We examined the efficacy of combined treatment of HDAC inhibitor LBH589 and DNMT inhibitor decitabine to regenerate ER and PR in TN breast cancer cells using RT-PCR and immunoblotting. Changes in growth and proliferation of TN breast cancer cells in response to LBH589 and decitabine treatment were determined by XTT, BrdU incorporation and colony formation assay. Changes in apoptotic proteins were determined by western blotting. Athymic nude mice were used to establish pre-clinical models for TN breast cancer cells and effectiveness of combined treatment of LBH589 and decitabine was determined. Tumors biopsies were analyzed for ER and PR re-expression by western blot analysis and immunohistochemistry at the end of the treatment. Results: Combined treatment of LBH589 and decitabine resulted in re-expression of ER and PR in TN breast cancers in vitro and in vivo. Although re-expression of ER and PR were noted following LBH589 treatment alone, re-expression was more robust with the combination. TN breast cancer cells showing re-expressed ER can be targeted with tamoxifen. Tamoxifen inhibits growth of TN breast cancer cells re- expressing ER by triggering apoptosis. Conclusions: The importance of epigenetic events such as DNA methylation and HDAC inhibition in tumor progression is becoming increasingly evident. A trial evaluating the ability of LBH589 and decitabine to re- express ER, which can then be targeted by tamoxifen, is planned in patients with metastatic TN breast cancer. No significant financial relationships to disclose.
Cutaneous genital complications of antiangiogenic agents
Authors: Mateus C. , Massard C. , Tomasic G. , Wechsler J. , Boige V. , Le Cesne A. , Soria J. C. , Escudier B. , Robert C. 
Published: August 2020

e14568 Background: Multikinase inhibitors targeting VEGFR, i.e. sorafenib and sunitinib are associated with various cutaneous side effects (1). Five cases of scrotal skin lesions were recently reported in male patients treated with sunitinib (2). Our observations of 8 patients presenting with genital inflammatory lesions during various anti-VEGFR therapies show that this side effect is linked to VEGFR blockade and not specifically to sunitinib and that it can also occur in women. Results: Six men and two women were seen for a genital eruption. They were treated with sorafenib (3 pts), sunitinib (5 pts), and a new pan-HER and VEGFR inhibitor (BMS 514, EVRI) (1 pt) for renal cell cancer (4 pts), hepatocellular carcinoma (2 pts), lung cancer (1 pt) and sarcoma (1 pt). Genital lesions occurred during the first six weeks of treatment. They appeared as a painful erythematous and squamous inguinal, intergluteal, and perianal rash rapidly involving all genital areas in 4 patients. Lesions became erosive in 3 cases. Four men presented more limited, pruriginous and lichenoid penile papules which were associated with a genital erythema for 3 of them. In one patient, penile inflammation resulted in a phimosis. One patient successively treated with sunitinib, sorafenib and once again with sunitinib experienced genital side effects with both agents. Patients taking sequential sunitinib treatment reported symptoms improvement during treatment interruptions and recurrences during the weeks on therapy. Microbiological samples were negative. Pathology of erythematous and squamous lesions showed a psoriasiform or a lichenoid aspect. Topical steroids were efficient for 5 patients but 3 patients had to interrupt anti-VEGF therapy because of their genital rash. Conclusions: Polymorphous genital inflammatory rash is a new skin side effect that can be associated with any cancer therapies targeting VEGFR in men and in women. Its frequency is unknown and probably underestimated because many patients might not report this side effect and its mechanism is still obscure. Physicians should be aware of this side effect and should inquire as to whether the patients have noticed such symptoms in order to avoid worsening thereof by symptomatic measures. No significant financial relationships to disclose.
Gastrin-releasing peptide receptors in the tumor vascular bed of various human cancers: high incidence in urinary tract cancers
Authors: Fleischmann A. M. , Waser B. , Reubi J. C. 
Published: August 2020

e14575 Background: Tumoral Gastrin-releasing peptide (GRP) receptors are potential targets for diagnosis and therapy using radiolabeled or cytotoxic GRP analogs. GRP-receptor overexpression has been detected in cancer cells and, more recently, also in the vascular bed of selected tumors. More information on vascular GRP-receptors in cancer is required to asses their potential for vascular targeting applications. Methods: Frequent human cancers from the breast (n=134), lung (n=57), prostate (n=50), kidney (n=32), colon (n=46), urinary tract (n=26) and biliary tract (n=23) were analyzed using in vitro GRP-receptor autoradiography on tissue sections with the 125I-[Tyr4]-bombesin radioligand and/or the universal radioligand 125I-[D-Tyr6, ß-Ala11, Phe13, Nle14]-bombesin(6–14). GRP-receptor expressing tumoral vessels were evaluated in each tumor group for prevalence, quantity (vascular score) and GRP-receptor density. Results: Prevalence of vascular GRP-receptors is variable, ranging from 13% (prostate cancer) to 92% (urinary tract cancer). Different tumor-types within a given site may have divergent prevalence of vascular GRP-receptors (e.g. lung: small cell cancer: 0%; adenocarcinoma: 59%; squamous carcinoma: 83%). Also the vascular score varies widely, with highest score in urinary tract cancer (1.69), moderate scores in lung (0.91), colon (0.88), kidney (0.84) and biliary tract (0.69) cancers and low scores in breast (0.39) and prostate (0.14) cancers. Vascular GRP-receptors are expressed in the muscular vessel wall in moderate to high densities. Normal non- neoplastic control tissues from these organs lack vascular GRP-receptors. Conclusions: Tumoral vessels in all evaluated sites overexpress GRP-receptors, suggesting a major biological function of GRP-receptors in the tumor vascular bed. Vascular GRP-receptor expression varies between the tumor-types indicating tumor-specific mechanisms in their regulation. Urinary tract cancers express vascular GRP-receptors so abundantly, that they are promising candidates for vascular targeting applications. No significant financial relationships to disclose.
Can [F-18]FDG PET imaging predict early response to chemotherapy in breast cancer patients?
Authors: John C. S. , Madabushi R. , Farah C. , Lubas C. , Williams G. 
Published: August 2020

e14577 Background: The purpose of this study was to perform a meta-analysis of literature data and see if [F-18]FDG and PET imaging can be used to predict the early response to chemotherapy based upon the measure of standard uptake value (SUV) or drug uptake ratio (DUR; a measure of glycolytic index) in breast cancer patients. This intervention may identify the responders for continued therapy or identify the non- responders for change of therapy. Methods: A literature search determined the number of studies that used PET-FDG imaging to monitor the response of various chemotherapies in breast cancer patients. A total of nine studies have been reviewed that used SUV/DUR as a measure of glycolytic activity of the primary tumors. The percent decrease of SUV over baseline was determined for chemotherapy cycle 1 and for subsequent cycles. A paired t-test was performed to see the statistical significance of the SUV decrease. Results: Five (n=158) studies presented the data in % mean reduction in SUV and four (n=59) studies presented SUV values for the individual patient. The average decrease in SUV in responders were 29% and 51% after first and second cycle, respectively. The non responders did not show significant change in SUV as compared to responders. Conclusion: The preliminary data mining and analysis strongly implies that PET imaging using [F-18]FDG may be used to monitor the progress of chemotherapy in breast cancer patients. This study was supported by a grant from OWH, FDA. The results do not represent official FDA position. No significant financial relationships to disclose.
The antitumor effects of OSU-HDAC42, a novel histone deacetylase inhibitor, in HER-2-positive breast cancer
Authors: Weng S. , Wu E. , Kulp S. K. , Wang D. , Chen C. , Yee L. D. 
Published: August 2020

e14587 Background: Elevated HER-2/neu expression in primary breast tumors is associated with frequent relapse and poor prognosis. For this reason, HER-2/neu has been actively pursued as a target for novel therapeutic agents. Histone deacetylase inhibitors (HDACi), a new class of antitumor drugs, can downregulate HER2 through hyperacetylation of heat shock protein 90 (hsp90), an important ATP-dependent chaperone that mediates the stability and maturation of a variety of important oncogenic proteins, including HER2, Akt and ERα. In this study, we assess the effects of OSU-HDAC42, a novel orally bioavailable phenylbutyrate-based HDAC inhibitor, on hsp90 and HER2 downregulation. Methods: OSU-HDAC42 was tested for effects on the human breast cancer cell lines BT474, SKBR3, MDA-MB-231 and MCF-7. Assays of cell viability, cell cycle, apoptosis, HER2 expression, phosphorylation, and hsp90 acetylation were performed. Tumor growth was assessed in an orthotopic HER2+ mammary tumor model, using diets ± OSU-HDAC42. Results: SKBR3 (HER2+, ERα-) was the most susceptible to the antiproliferative effects of OSU-HDAC42 after 72 hours of treatment (IC50 = 0.025 μmol/L), followed by BT474 (HER2+, ERα+), MCF-7 (HER2-, ERα+) and MDA-MB-231 (HER2-, ERα-) cells with IC50 values calculated at 0.16, 0.19 and 0.2 μmol/L, respectively, which correlated with the level of inhibition of Hsp90 client protein expression (HER2, Akt). OSU-HDAC42 yields 43- or 65- fold greater cell killing than suberoylanilide hydroxamic acid (SAHA; vorinostat) or MS-275, respectively, and more potently suppresses the levels of Hsp90 client proteins (HER2, ERα and Akt) and induction of apoptosis in HER2+ breast cancer cells. In vivo administration of OSU-HDAC42 resulted in reductions of 76% and 82% in NT5 (HER2+,ER-) tumor mass and volume, respectively, concomitant with tubulin hyperacetylation, increased PARP cleavage, and decreased HER2 levels in OSU-HDAC42 treated mouse tumors. Conclusions: OSU-HDAC42 is a potent inhibitor of HER2+ breast cancer, mediated in part through hsp90 downregulation. As an orally bioavailable HDAC inhibitor with greater potency than other clinically available HDACi agents, OSU- HDAC42 warrants evaluation in clinical trials as a novel therapy for HER2+ breast cancer. [Table: see text]
Single nucleotide polymorphisms of TSER, ATM, RecQ1 genes association with survival in pancrease cancer
Authors: Weekes C. , Nallapareddy S. , Jimeno A. , Hidalgo M. , Laheru D. , Rudek M. A. , Baker S. , Redlinger C. , Murphy K. , Messersmith W. 
Published: August 2020

e14590 Background: Pancreatic cancer (PaCa) is the 4th leading cause of cancer-related mortality in the U.S . We tried to determine whether ATM, RecQ1 gene polymorphisms correlate with gemcitabine (G) and TSER gene polymorphism with capecitabine (C) response and over all survival(OS). We also tested the hypothesis that PaCa pts homozygous for the S/S variant of the TSER will have a higher 6-month survival with C compared to historical controls. TS expression is regulated by a polymorphism in the TSER and has been shown that pts with S/S variant have high response rate and increased toxicity in colon cancer pts. ATM and recQ1 genes are involved with DNA damage response and repair and correlate with G response. Methods: DNA isolated from peripheral blood samples in 82 pts with Stage IV pancreatic cancer was tested for the TSER, ATM and RecQ1 gene polymorphisms. All patients were treated with G 1,000mg/m2 wkly for 3/4 wks. Pts homozygous for the S/S variant were treated with C, 2,000 mg/m2/day for 14 /21days. Pts were evaluated for response to therapy according to the RECIST. Results: 16 pts (19.5%) were positive for S/S variant of TSER, but only 4 (4.8%) were treated. The reasons for declining treatment were geographic, logistic or progression issues. Only 1 pt was evaluable, receiving at least 3 cycles of C . All pts needed dose reductions due to toxicities. Grade 3 hand foot syndrome, diarrhea and vomiting were dose limiting toxicities. No complete or partial responses were seen. The pt who received 3 cycles came off study due to progressive disease and the other 3 pts came of the study due to toxicities. TSER polymorphism was correlated to OS and only S/S variant was significant with a trend towards improved OS by log rank test and Kaplan Meier plot. ATM and RecQ1 gene polymorphisms subtypes did not correlate with G response and OS ( not statistically significant). Conclusions: Our study represents an initial effort to apply pharmacogenetics to PaCa therapy. 19.5% of pts had the S/S variant of the TSER polymorphism, but only 4.8% enrolled. C administration was associated with excess toxicity. The toxicities observed in this study appear to outweigh the benefit of using C in this pt population. There is no correlation between ATM and RecQ1 genotypes with OS. However the sample size is too small to draw conclusions. [Table: see text]
Population pharmacokinetics of CNTO 95, a human anti-αv integrin antibody, in patients with solid tumors
Authors: Ling J. , Zhang Y. , Hu C. , Jiao T. , Lang Z. , Foster B. , Marini J. , Zhong B. , Puchalski T. , Zhou H. 
Published: August 2020

e14593 Background: CNTO 95 is a human anti-αv integrin antibody. The dose-dependent antitumor effect of CNTO 95 has been demonstrated in multiple preclinical studies. The objective of these analyses was to characterize the population pharmacokinetics (PPK) in solid tumor cancer patients treated with CNTO 95 with and without dacarbazine. Methods: Approximately 140 patients with solid tumors from two phase I and one phase II studies were included in this analysis. CNTO 95 was administered via intravenous infusion, with 11 different regimens ranging from 0.1 to 20 mg/kg every 1–4 weeks. Serum CNTO 95 concentrations were determined using a validated enzyme-linked immunosorbent assay. Serum CNTO 95 concentration data were analyzed using noncompartmental analysis (NCA) and a PPK approach. Results: The NCA results indicated that total clearance of CNTO 95 decreased as the dose of CNTO95 increased and approached saturation at 10 mg/kg. Based on the NONMEM analysis, data were best described by a 2-compartment model with dual clearance pathways (linear and nonlinear elimination). The nonlinear elimination process is likely due to the receptor-mediated clearance. Mean estimates of central volume, peripheral compartment volume, intercompartmental clearance and linear clearance, as well as an additional nonlinear clearance, were in agreement with antibodies targeting membrane-bound receptors. No differences in the PPK of CNTO 95 were found in patients treated with and without co-administered dacarbazine. Interindividual variability was moderate (<50%). Conclusions: A PPK model could adequately describe serum CNTO 95 concentration-time profiles. Extensions of this model can be used to assist in the selection of doses in diverse oncology patient populations. [Table: see text]