bluuebunny/crossref_metadata_2025_split huggingface dataset:
The value of pharmacogenomic analysis of microsatellite instability (MSI) and XPD, XRCC1 genotype polymorphisms to predict clinical outcome in metastatic colorectal carcinoma
Authors: Artac M. , Pehlivan S. , Akcan S. , Pehlivan M. , Gelen T. , Itirli G. , Aksoy N. H. , Ozdogan M. , Savas B. , Bozcuk H. S. 
Published: March 2020

13011 Background: Previous work suggests that DNA repair enzyme polymorphism and microsatellite instability (MSI) may bear prognostic value in metastatic colorectal carcinoma (MCRC), but this is either retrospective or do not involve irinotecan-based regimens. Methods: We prospectively treated 43 MCRC patients with irinotecan-based regimens (XELIRI or IFL). MSI was measured by PCR at 5 different chromosomal loci: BAT-25, BAT-26, D5S346, D2S123, and D17S250. XPD (Lys751Gln) and XRCC1 (Arg399Gln) polymorphisms were also analysed by PCR-RFLP method. Clinical outcome variables; overall survival (OAS), progression free survival (PFS) and the occurrence of grade 3 or 4 hematological and gastrointestinal (GIS) toxicities were evaluated. Results: MSI subtypes MSS, MSI-L and MSI-H were seen in 23.3%, 43.3% and 33.3% of cases. In the univariate analysis for OAS (n=43) only XPD and XRCC1 polymorphisms were significant (P=0.05 and P=0.04, respectively). After adjustment for performance status (ECOG=0, 1 vs. 2) and disease extent (single vs. multiple metastatic site), XRCC1 genotype and performance status retained significance (P=0.04, HR=2.85, and P=0.02, HR=3.19, respectively). Arg/Gln versus Arg/Arg and Gln/Gln versus Arg/Gln genotypes indicated approximately 3 times increased risk of death for each comparison. Type of presentation (metastatic versus local disease at first presentation) was the only significant predictor of PFS in the univariate analysis (n=40, P=0.003). After adjustment for performance status and disease extent, type of presentation retained its significance (P=0.003, HR=4.35). MSI was not associated with survival. Although absence of “liver only” disease was associated with the occurrence of grade 3–4 GIS toxicity, it lost significance in the multivariate analysis. None of the factors tested correlated with the likelihood of grade 3–4 hematological toxicity. Conclusions: XRCC1 genotype independently predicted overall survival in metastatic colorectal carcinoma patients treated with irinotecan-based chemotherapy. However, MSI status did not emerge as a prognostic factor in our cohort. No significant financial relationships to disclose.
Escalating weekly doses of cetuximab: A phase I trial in advanced solid tumors
Authors: Ho C. , Eisen D. , Beckett L. A. , Luciw P. , Gumerlock P. H. , Gandara D. R. , Davies A. M. 
Published: March 2020

13012 Background: Cetuximab, an IgG1 monoclonal antibody directed against the epidermal growth factor receptor (EGFR), is FDA-approved at a 400 mg/m2 loading dose, followed by 250 mg/m2 weekly maintenance. Clinical activity of cetuximab has been reported to correlate with grade of skin toxicity, and skin toxicity is reported to increase with increasing dose. We therefore examined the safety and feasibility of escalating weekly cetuximab doses. We hypothesized that increased dose would correlate with rash severity as a surrogate for tumor response. Methods: Four dose levels were tested: cetuximab loading 400 mg/m2 and 250,300,350,400 mg/m2 weekly maintenance. Dose limiting toxicity (DLT) was defined as: grade 4 platelets, grade 3 platelets with bleeding, febrile neutropenia, grade 4 cutaneous toxicity, grade 3 cutaneous toxicity necessitating holding cetuximab for > 4 weeks or any other grade ≥ 3 non-hematologic toxicity. Rash was evaluated using two additional validated dermatology methods: acne lesion counting and global acne grading scale (Int J Derml.1997;36:416–18, J Am Acad Derm.1996;35:559–65, Arch Derm.1982;118:23–25). Results: Twelve patients with advanced solid tumors were treated, including 3 H&N, 2 pancreas, 2 breast, 2 lung, 2 colorectal and 1 bladder. Patient characteristics: age range 44–84, median 62; gender: 10 M; KPS ≥80/<80=7/5; prior chemo ≤1:>1=5:7; median cycles 2 (1–8). Treatment was generally well tolerated. There were no DLTs. The most common grade 3/4 toxicities were acneiform rash (1) and lymphopenia (2). The majority of patients (6) had a Grade 2 rash. In 10 evaluable patients, there were no responses; 3 patients had stable disease. Correlative science studies are ongoing evaluating EGFR expression and polymorphisms, pEGFR, pMAPK, pAKT, Ki67, p27 levels and K-ras mutations. Conclusions: 1) Cetuximab 400 mg/m2 loading dose and 400 mg/m2 weekly maintenance is feasible and well tolerated. Doses up to 400 mg/m2 did not portend increased toxicity and a MTD was not reached on this schedule. 2) Grade of rash did not increase with increasing doses of weekly cetuximab in this limited population. 3) To date, cetuximab has not demonstrated RECIST response in this cohort of pretreated patients with solid tumors. 20 additional patients are being evaluated at the highest dose level. No significant financial relationships to disclose.
Selective inhibition of ADAM metalloproteases blocks HER-2 extracellular domain (ECD) cleavage and potentiates the anti-tumor effects of trastuzumab
Authors: Scherle P. , Liu X. , Li J. , Fridman J. , Li Y. , Yao W. , Williams W. , Levy R. , Vaddi K. , Newton R. , Friedman S. 
Published: March 2020

13021 Background: HER-2, a member of ErbB family of receptor tyrosine kinases, is an important regulator of cell proliferation and survival, and is a clinically validated target of therapeutic intervention in HER-2 positive metastatic breast cancer patients. In HER-2 overexpressing cells, the extracellular domain (ECD) is frequently cleaved, rendering the remaining transmembrane portion of HER-2 (p95) constitutively active. The presence of both serum ECD and cellular p95 protein have been linked to poor clinical outcome as well as reduced effectiveness of some therapeutic treatments, suggesting that signaling via p95 is clinically relevant and may represent an attractive target for therapeutic intervention. Methods: Through medicinal chemistry efforts, we have identified a series of potent, selective small molecule inhibitors of ADAM metalloproteases, exemplified here by INCB7839. These compounds were tested both in vitro and in vivo for inhibition of HER-2 ECD cleavage and anti-tumor activity in the HER-2 overexpressing BT-474 cell line. Inhibition of circulating HER-2 ECD levels was monitored in a phase I multiple dose escalation study in healthy volunteers. Results: We demonstrate that these inhibitors effectively blocked HER-2 cleavage in HER-2 overexpressing human breast cancer cell lines. When used in combination, INCB7839 dramatically enhanced the antiproliferative activity of suboptimal doses of the anti-HER-2 antibody, trastuzumab, in HER-2 overexpressing/shedding breast cancer cell lines, accompanied by reduced ERK and AKT phosphorylation. Consistent with these in vitro data, INCB7839 reduced serum ECD levels in tumor-bearing mice and enhanced the antitumor effect of trastuzumab in a xenograft tumor model derived from the HER-2 overexpressing BT-474 breast cancer cell line. In a phase I clinical trial, INCB7839 demonstrated a dose-dependent decrease in the circulating levels of HER-2 ECD present in healthy volunteers. Conclusions: Collectively, these findings suggest that blocking HER-2 cleavage with selective ADAM inhibitors, especially in combination with anti-HER-2 antibody therapy, may represent a novel approach for treating HER-2 overexpressing breast cancer patients. [Table: see text]
TYMS polymorphism analysis prediction of bolus 5-fluorouracil toxicity
Authors: Gusella M. , Bolzonella C. , Bertolaso L. , Bononi A. , Crepaldi G. , Padrini R. , Ferrazzi E. 
Published: March 2020

13022 Background: Currently there is no protocol for selecting colorectal cancer patients at risk for drug toxicity prior to 5-fluorouracil(5FU)-based chemotherapy. Thymidylate synthase (TYMS) is 5FU main molecular target and its expression is linked to cellular sensitivity or resistance to the drug. Three genetic polymorphisms have been shown to influence TYMS expression: a polymorphic tandem repeat sequence (2 or 3 repeats; 2R and 3R) and a single nucleotide polymorphism, G > C, within the promoter enhancer region and a 6 bp deletion in the 3’UTR of the gene. Methods: This prospective study endpoint was to test weather TYMS polymorphisms might predict high grade toxic events in Caucasian patients with colo- rectal carcinoma treated with adjuvant bolus 5-FU-based chemotherapy. 142 patients, 98 males, mean age 66,7±9,1 were studied at the first cycle of treatment. TYMS genotypes were determined from the peripheral blood mononuclear cells by polymerase chain reaction and restriction fragment length polymorphism. Toxic event occurrence was collected through self-administered questionnaire and physical examination and scored through WHO scales. Results: 40% of patients had no or minimal adverse events while 35% suffered grade 3–4 toxicity. At univariate analysis, there was a trend of association between 3R/3R genotype and a reduced risk of adverse events (chi test for trend, p=0.057) and again a significant association between 6bp/6bp genotype and high grade toxicity (chi test for trend, p=0.03). Analysing all the three polymorphism together, 77% of patients bearing 6bp/6bp combined with at least one 3RG allele suffered grade 3–4 toxicity, while patients bearing homozigote 6bp deletion had no or minimal side effects in 90% of cases. The other genotype combinations had an intermediate toxic risk. The differences were statistically significant (chi test p=0.02). Conclusions: TYMS combined 5’UTR and 3’UTR polymorphism analysis may help in predicting high grade toxic events in Caucasian patients treated with repeated boluses of 5-FU. Funded by AIRC-Veneto. No significant financial relationships to disclose.
Phase I trial of docetaxel, carboplatin and lenalidomide in patients with advanced solid tumors
Authors: Kalmadi S. R. , Davis M. , Dowlati A. , O’Keefe S. , Cline-Burkhardt M. , Pelley R. J. , Borden E. C. , Dreicer R. , Bukowski R. M. , Mekhail T. 
Published: March 2020

13027 Lenalidomide (LEN) is an immunomodulatory derivative of thalidomide with significantly greater in vitro activity and different toxicity. It may interfere with the expression of angiogenic factors (TNF-alpha & IL-6), vascular endothelial growth factor (VEGF) and induce apoptosis in resistant cell lines. In preclinical trials it has shown synergy with chemotherapy. Primary objective of this study was to determine the maximum tolerated doses (MTD) of docetaxel (D) and carboplatin (Cb), combined with oral LEN. Secondary objectives were toxicity and activity. Eligibility included pathologically proven solid tumors, ≤ 2 prior chemotherapy regimens, performance status ECOG 0/1, and adequate organ function. Patients (Pts) with active brain metastases, or prior treatment with D, Cb, or LEN, were excluded. Treatment was continued for a maximum of 6 cycles, followed by optional continuation of LEN until disease progression or toxicity. MTD was defined as the dose level (dl) immediately lower than that producing dose limiting toxicity (DLT) during cycle 1 in ≥ 2 of 3–6 pts. DLT were ≥ grade (G) 3 non-hematological, or G 4 hematological toxicity. No growth factors were used during cycle 1. Four pts were treated at dl I, D 60 mg/m2, and Cb AUC 6 on Day 1, and LEN 10 mg orally daily for 14 of a 21d cycle. Dose de-escalation was done following the first cohort due to DLT. 10 pts were treated at lower dl -1, D 60 mg/m2, and Cb AUC 6 on Day 1, and LEN 5 mg orally daily for 14 of a 21d cycle. 3 of 14 pts had prior chemotherapy. Tumors included non small cell lung cancer (NSCLC) (9), and one each with thymic, rectal, apocrine carcinoma, angiosarcoma and unknown primary. The median number of cycles was 4 (range 1–6). DLTs occurred in 3 of 4 pts at dl I (G 3 electrolyte (E) (2), G 4 neutropenia (N) (1) and 1 of 10 pts at dl-1 (G 4 N). Overall G 3/4 toxicities were: N (7), thrombocytopenia (2), and E (2). There were no treatment-related deaths or irreversible toxicities. Of the evaluable pts, 5 had a partial response (5/9 NSCLC), & 5 had stable disease. D 60 mg/m2, and Cb AUC 6 on Day 1, and LEN 5 mg orally daily for 14 days of a 21 d cycle is the MTD without use of prophylactic growth factors. This combination is active and further evaluation in a phase II trial is warranted. [Table: see text]
A novel telomerase-specific oncolytic virotherapy for human cancer: preclinical evaluation of safety, biodistribution, and efficacy
Authors: Fujiwara T. , Kagawa S. , Kawamura H. , Nagai K. , Nohara R. , Tanaka N. , Urata Y. 
Published: March 2020

13057 Background: Replication-selective tumor-specific viruses present a novel approach for treating neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We constructed an adenovirus 5 vector (Telomelysin [OBP-301]), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an IRES. Methods: We examined the antitumor effect of Telomelysin as a single agent or in combination with systemic administration of chemotherapeutic drugs such as docetaxel in tumor xenograft models. IND-supporting preclinical toxicology and pharmacodynamic studies were also performed to characterize the safety, pharmacokinetics and biological activity of Telomelysin. Results: Telomelysin replicated efficiently and induced marked cell killing in a panel of human cancer cell lines derived from various organs, whereas replication as well as cytotoxicity was highly attenuated in normal human cells lacking telomerase activity. In nu/nu mice carrying subcutaneous human tumor xenografts, intratumoral injection of Telomelysin resulted in a significant inhibition of tumor growth, which was significantly enhanced in combination with systemic administration of docetaxel. Moreover, Telomelysin replication in the distant, un-injected tumors was demonstrated. Viral DNA was identified in tissues outside of the injection site; however, toxicology studies including pathological examinations in mice and cotton rats demonstrated that local injection of Telomelysin could be well-tolerated with an acceptable safety profile. Conclusions: The hTERT promoter confers competence for selective replication of Telomelysin in human cancer cells, an outcome that has important implications for the treatment of human cancers. Telomelysin has been already manufactured under GMP conditions for initial clinical trials. Upon FDA approval, a phase I dose-escalation study of intratumoral injection of Telomelysin for various solid tumors will be started. [Table: see text]
Thymidylate synthase gene expression in solid tumors predicts for response to pemetrexed in vitro
Authors: Eismann U. , Oberschmidt O. , Ehnert M. , Fleeth J. , Lüdtke F. , Struck S. , Schulz L. , Blatter J. , Ma D. , Hanauske A. 
Published: March 2020

13058 Background: Pemetrexed (P) is a novel antifolate which targets thymidilate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). The aim of the present study was to identify gene expression thresholds for these enzymes in human tumor specimens in order to separate P-sensitive from P-resistant patients. Methods: Soft-agar cloning assays were performed on freshly biopsied tumor cells exposed one hour to clinically achievable concentrations of P. In parallel, RNA was isolated, transcribed to cDNA and subsequently used for multiplex real-time PCR. Gene expression data were normalized against beta-actin transcripts followed by correlation against cloning assay results. Iterative calculations (fourfold analysis) were done for each enzyme separately to find the best cutoff for prediction of sensitivity to P. Results: Sensitive and resistant tumor samples were statistically significant different in gene expression of TS, DHFR, and GARFT (p < 0.003). 81% of all tumors with a TS copy number < 144 (related to 104 copies β-actin) were sensitive to P in vitro. (specificity = 0.69; chi2 = 14.14). Statistical tests demonstrated that gene expression of TS, DHFR, and GARFT are dependent variables and that TS transcription is the leading variable. The combination of TS, DHFR, and GARFT expression data was not superior to TS alone. Conclusions: TS expression is the most meaningful predictor for sensitivity (≤ 144 copies) or resistance (> 144 copies) to Pemetrexed in fresh tumor tissue. This observation forms a rationale for clinical trials using TS expression as predictor for clinical response. No significant financial relationships to disclose.
A pharmacogenetic study of irinotecan: Genetic polymorphisms in the coding region of UGT1A1 gene and SN-38 glucuronidation in the body
Authors: Araki K. , Fujita K. , Ando Y. , Nagashima F. , Yamamoto W. , Endou H. , Miya T. , Kodama K. , Narabayashi M. , Sasaki Y. 
Published: March 2020

13078 Background: Pharmacogenetic testing of UGT1A1*28, a promoter variant of UGT1A1 gene, for estimating a risk of irinotecan toxicity has been introduced into clinical practice. Purpose: To elucidate clinical significance of UGT1A1*6 and UGT1A1*27, the variants in exon 1 that are found mostly in Asians. Methods: Pharmacogenetic relationships were explored between the genotyping results and ratio of area under the concentration-time curve (AUC) of SN-38 and its glucuronide (SN-38G) as a surrogate for a UGT1A1 activity (AUCSN-38/AUCSN-38G) in 36 Japanese patients who received various regimens of irinotecan chemotherapy at doses from 50 to 180 mg/m2. Results: No patients were homozygous for UGT1A1*28 and none had UGT1A1*27. One was heterozygous for UGT1A1*28. Two were homozygous and ten heterozygous for UGT1A1*6, all of whom were wild type with respect to UGT1A1*28. Two patients were simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 that existed on the different chromosomes. The remaining 21 patients did not have any variants studied. The 2 patients who was simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 and the 2 patients who were homozygous for UGT1A1*6 had significantly higher AUCSN-38/AUCSN-38G than the others (P = 0.004). Conclusions: Concurrence of the two UGT1A1 variants, UGT1A1*28 and UGT1A1*6 even in their heterozygous statuses, remarkably altered drug disposition of irinotecan and could enhance susceptibility to the drug. Patients who are homozygous for UGT1A1*6 should also be monitored cautiously. Genotyping of UGT1A1 polymorphisms in the coding region together with UGT1A1*28 is necessary for predicting irinotecan toxicity at least for Asian patient population. [Table: see text] [Table: see text]
A phase I trial of bexarotene and docetaxel in patients with advanced solid tumors
Authors: Pishvaian M. J. , Firozvi K. , Hwang J. J. , Marshall J. L. , Ramzi P. , Malik S. 
Published: March 2020

13085 Background: Retinoids have been used to treat a wide variety of malignancies. Bexarotene is a synthetic retinoid that binds preferentially to the RXR subclass of retinoid receptors. In the initial phase I trial of bexarotene, a subset of patients with non-small cell lung cancer (NSCLC) had prolonged stabilization of disease and survival. In vitro evidence suggests that the effects of retinoids may be enhanced when used in conjunction with taxanes. This is a phase I trial designed to determine the maximum tolerated dose of docetaxel in combination with a fixed dose of bexarotene. Methods: Patients with pathologically confirmed solid tumors for whom no standard therapies exist, who have an ECOG performance status ≤2, adequate organ function and normal serum triglycerides were eligible. Each cycle was 4 weeks long. Oral bexarotene was given at 400 mg/m2 daily. Docetaxel was given weekly for 3 out of 4 weeks at two dose levels, 25 or 30 mg/m2, for up to 6 cycles. For patients exhibiting disease stabilization or response, treatment with bexarotene was continued until disease progression. Restaging studies were performed after every 2 cycles. Results: To date 10 patients have been enrolled, half of whom had NSCLC - 7 male, mean age = 61 (range 37–73), 100% PS = 0 or 1. 29 cycles were completed (range 1 to 8). 7 patients have been treated at 25 mg/m2 and 3 at 30 mg/m2 of docetaxel. Hypothyroidism, hypertriglyceridemia, and fatigue were common but generally mild. Two patients experienced grade III fatigue, and 1 each experienced grade III hypertriglyceridemia, neutropenia, and cough. There were no grade IV toxicities. Two patients were taken off study because of non-fatal radiation recall pneumonitis that was controlled with steroids. In this heavily pretreated population, of 8 patients assessable for response, 5 had stable disease for at least 2 cycles. One patient with NSCLC had a partial response that persisted for 6 cycles. Conclusions: Bexarotene and docetaxel (at a minimum of 25 mg/m2) can be safely coadministered. Care should be taken in patients who have been previously irradiated. Enrolment and dose escalation for the phase I trial is still ongoing. A phase II trial of the combination as second line therapy in NSCLC is planned. [Table: see text]
Preclinical evaluation of the dual specific Src/Abl kinase inhibitor AZD0530 in lung cancer
Authors: Gautschi O. , Purnell P. , Evans C. P. , Yang J. C. , Holland W. S. , Bold R. J. , Virudachalam S. , Lara P. N. , Gandara D. R. , Gumerlock P. H. 
Published: March 2020

13108 Background: AZD0530 is a highly selective, orally available, dual specific Src/Abl kinase inhibitor in clinical development. We tested this agent in multiple lung cancer cell lines in vitro. We hypothesized that activity of AZD0530 may depend on the level of activated (pY416-)Src, and that Src inhibition may decrease Bcl-xL protein levels and lower the barrier to apoptosis. Methods: NSCLC (A549, Calu-1, Calu-6) and SCLC (H69, H526) cells were incubated with 0.001–100 μM AZD0530 for 1–72hrs. Proliferation (MTT), DNA-content (flow cytometry), and protein levels of Src, pY416-Src, PARP, and Bcl-xL (Western blotting) were assessed. Results: Basal pY416-Src was detectable in most cell lines except H526. AZD0530 decreased pY416-Src levels at submicromolar concentrations in pY416-Src positive cells. In A549, Calu-1 and Calu-6, AZD0530 blocked cell growth in a time- and dose-dependent way (IC50 = 7–25 μM) by arrest in G1, retaining a cytostatic effect at submicromolar concentrations in A549 and Calu-1. AZD0530 induced apoptosis in 10–22% of these cells at micromolar concentrations, accompanied by a decrease of Bcl-xL protein in A549 and Calu-1. In H69 and H526, growth inhibition by AZD0530 was limited (IC50 >100 μM). Conclusions: 1) AZD0530 induced apoptosis at micromolar concentrations, and inhibited cell growth at micromolar to submicromolar concentrations in some cell lines. 2) pY416-Src is a potential marker for drug responsiveness, but other factors should also be tested. 3) Decrease of Bcl-xL by AZD0530 may render cancer cells more sensitive to chemotherapy. These data suggest that Src kinase inhibitors merit further testing in lung cancer, both alone and in combination with other agents. (Support: Swiss National Science Foundation, Swiss Cancer League, AstraZeneca). [Table: see text]