bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic susceptibility to toxicity of chemotherapy in mice as pharmacokinetics-independent and drug-specific.
Authors: Dittmar Ashley J , Affronti Hayley , Sepporta Maria Vittoria , Gebuijs Elizabeth , Demant Peter 
Published: March 2020

e13549 Background: Adverse drug reactions (ADRs) are a significant obstacle in cancer chemotherapy. In spite of the advances in the development of drugs for cancer therapy, ADRs compromise their potential beneficial effects in many patients by imposing reduction of dose or cessation of treatment. Prediction of susceptibility to ADRs in individual patients could significantly improve treatment outcomes by more effectively choosing which drugs to treat with and which dose is appropriate. The pharmacokinetics (PK) of many drugs has been extensively studied and numerous enzymes and transporters that are involved in their activation and processing have been identified. However, when their role in individual susceptibility to ADRs has been tested in numerous studies, the variants of these proteins have not been able to consistently predict specific ADRs. Therefore, additional studies are required for a reliable prediction of toxicity. Methods: We used mouse strains with precisely defined limited genomic differences to evaluate genetic control of ADRs to three drugs commonly used in cancer chemotherapy - irinotecan, gemcitabine, and doxorubicin. We compared strain distribution of susceptibility to ADRs caused by each of these drugs and tested whether there is a correlation with genotypes at the major processing/transport (PK) genes that were reported in humans to affect toxicity of these drugs. Results: The major genetic differences in toxic reactions caused by these drugs do not correlate with the major PK loci and that the strain distribution pattern of susceptibility vs. resistance for each drug is different. Conclusions: This data suggests that a significant part of genetic susceptibility to ADRs is controlled by genes other than the presently known PK-related genes, and that many responsible genes are drug specific, with some possible overlaps. We hypothesize that these genes are likely involved in downstream pharmacodynamic (PD) processes and have remained largely unknown, because most studies in humans have been limited to known PK-related genes. We are proceeding towards identification of these novel genes, as they could help to optimize the selection of therapy for individual patients.
Cytotoxic effect of euphol from Euphorbia tirucalli on a large panel of human cancer cell lines.
Authors: Reis Rui Manuel , Silva Viviane Aline Oliveira , Rosa Marcela Nunes , Tansini Aline , Lima Joao Paulo Da S.N. , Jones Chris , Pianowski Luiz Francisco 
Published: March 2020

e13557 Background: The tetracyclic triterpene alcohol euphol is the main constituent found in the sap of Euphorbia tirucalli. In Brazil its latex is used as anticancer and other diseaseas folk treatment, yet, little is known about its anticancer proprieties. We aimed to study the antitumor effect of euphol on a large panel of human cancer cell lines. Methods: Anti-tumor effects of euphol in vitro were assessed using MTS assays on 77 human cancer lines from13 solid tumor models, such as breast, colon, bladder, prostate, lung, pancreas, esophagus, glioblastoma, melanoma, head and neck and cervical cancer. Additionally, we evaluate the its potential combinatorial value with temozolomide in gliomas. Ongoing experiments will identify potential drug target(s) by assessing changes in global protein expression. Results: Euphol exhibited dose and time-dependent cytotoxic effects on all cancer cell lines analyzed. Among each tumor type, the distinct cell line exhibited a heterogeneous profile of response to euphol. Esophageal squamous cell carcinoma and pancreatic carcinomas showed the most sensitive profile. In comparison with temozolomide, euphol showed a median of 30 fold higher efficacy, range 5-167 fold, in the glioma cell lines analyzed (Table). Conclusions: Euphol demonstrated potent anti-tumor activity on the majority of cancer cell lines evaluated. Our findings may provide insight into the tailoring designing of euphol-based therapies for cancer patients. [Table: see text]
Targeting the PI3K signaling cascade in PIK3CA mutated endometrial cancer in a primary human xenograft model.
Authors: Bradford Leslie Siriya , Rauh-Hain Jose Alejandro , Clark Rachel Marie , Groeneweg Jolijn W , Zhang Ling , DiGloria Celeste M , Borger Darrell R. , Growdon Whitfield Board , Schorge John O. , Foster Rosemary , Rueda Bo R 
Published: March 2020

e13564 Background: Alterations in the PI3K pathway are highly prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. Given these data, we investigated the anti-tumor activity of the PI3K inhibitor NVP-BKM120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model. Methods: NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were randomly divided into two- and four-arm cohorts with equivalent tumor volumes. Three single agent experiments tested the effectiveness of NVP-BKM120 against two endometrioid (PIK3CA wild type and H1047L mutant) and one carcinosarcoma (PIK3CA R88Q mutant) endometrial cancer. Three four arm experiments tested NVP-BKM120 alone and in combination with paclitaxel and carboplatin (P/C) in two endometrioid tumors (both R88Q) and one carcinosarcoma (no PIK3CA mutation detected). Following in vivo study, tumors from the NVP-BKM120 , P/C, P/C+ NVP-BKM120 and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation. Wilcoxan rank sum analysis was utilized to compare tumor growth across all treatment experiments. Results: In endometrioid single agent experiments, NVP-BKM120 resulted in tumor growth suppression starting at days 5-10 compared to the linear growth observed in vehicle treated tumors (p<0.04 in all experiments). In all experiments, tumor resurgence manifested between days 14-25 (p<0.03). When combined with P/C, the NVP-BKM120 resistance pattern failed to develop in all three xenograft lines (p<0.05) while synergistic tumor growth suppression (p< 0.05) of only one xenograft tumor harboring the R88Q mutation was observed. Acute treatment with NVP-BKM120 led to a decrease in pAKT, whereas, there was no difference in pAKT levels following chronic therapy compared to vehicle. Conclusions: These data suggest that NVP-BKM120 mediated inhibition of the PI3K pathway in endometrial tumors with and without a PIK3CA mutation precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.
Effect of pan-PI3K and HER2 blockade on antitumor activity in preclinical models of breast cancer resistance to trastuzumab therapy.
Authors: De Pradip , Sun Yuliang , Friedman Lori , Dey Nandini , Leyland-Jones Brian 
Published: March 2020

e13570 Background: PI3K-AKT-mTOR pathway signaling is important for the oncogenic function of HER2. Activating alterations of this pathway are frequently observed in HER2-enriched breast cancer and generally herald a poor response and resistance to trastuzumab (T). Targeting the PI3K-AKT-mTOR pathway is an attractive strategy in HER2+ breast cancer that is refractory to trastuzumab. The hypothesis is that the suppression of this pathway by pan-PI3K inhibitor, GDC-0941 may lead to overcome trastuzumab-resistance. Methods: The antiproliferative and HER2-mediated cellular signaling (pAKT, pP70S6K, pS6RP, p4EBP1 and p-ERK) effects of GDC-0941 alone and in combination with T were evaluated in HER2 amplified T-sensitive (BT474), T-resistant (BT474HR), and HER2 amplified/PIK3CA mutated (HCC1954, UACC893) BT cell lines by MTT assay and Western blots. Athymic mice bearing BT474 and BT474HR xenograft tumors were treated with GDC-0941 and T (alone and in combination). Results: (1) GDC-0941 exhibited in vitro cell killing activity in MTT assay with IC50’s ranging from 0.35 µM to 1 µm and potency was augmented by the addition of T, (2) inhibition of phosphorylation of AKT(S473, T308), P70S6K, S6RP, and 4EBP1(T37/46, T70) was observed following GDC-0941 treatment, and the combination of GDC-0941 and T more effectively blocked the PI3K-AKT-mTOR pathway, (4) GDC-0941 dose-dependently blocked 3D-ON-TOP clonogenic growth of HER2+ cells. This effect was potentiated in the presence of T and (5) xenograft data show that the combination of GDC-0941 and T has strongly enhanced anti-tumor effect in both sensitive (82%) and resistant models (79%), something that cannot be achieved by either monotherapy. Conclusions: Our data suggest that 1) therapeutic targeting of the PI3K-AKT-mTOR signaling should be effective in abrogating resistance to T therapy in HER2+ BT, and 2) targeting both the HER2 and the PI3K signaling pathways is an attractive strategy to enhance the clinical activity of T therapy, as well as to prevent or delay the development of resistance.
Pharmacokinetic study of aldoxorubicin in solid tumor patients.
Authors: Natale Ronald B. , Mita Alain C. , Wolin Edward M. , Laabs Brenda , Dinh Hillary , Wieland Scott , Levitt Daniel , Mita Monica M. 
Published: March 2020

e13572 Background: Aldoxorubicin consists of doxorubicin conjugated to a pH sensitive linker that binds covalently to circulating albumin. Previous studies demonstrated that aldoxorubicin can be administered at doses up to 350 mg/m2 (260 mg/m2doxorubicin equivalents, DE) every 21 days for up to 8 cycles. We have investigated aldoxorubicin pharmacokinetics, including albumin-bound and free doxorubicin and doxorubicinol after administration of 2 dose levels of aldoxorubicin in patients with advanced solid tumors. Methods: Patients with solid tumors and no standard therapy were eligible. Other entry criteria: ECOG PS 0-2, LVEF > 45% of predicted normal for the site, adequate hematological status. Patients were administered either 230 mg/m2 aldoxorubicin (165 mg/m2 DE) or 350 mg/m2 aldoxorubicin (260 mg/m2 DE) iv over 30 minutes on day 1 of cycles 1 and 3. Blood samples were taken prior to administration and at multiple time points up to 72 hr post administration. Serum concentrations of albumin-bound doxorubicin, unbound doxorubicin and doxorubicinol were analyzed. Results: As of January 31, 7 subjects have been entered in the study. 6 subjects have received 230 mg/m2 aldoxorubicin and 1 subject has received 350 mg/m2 aldoxorubicin. No serious adverse events have been reported. Grade 3 or 4 adverse events include neutropenia, thrombocytopenia and anemia. A minor response (20% decrease) was observed in one subject (230 mg/m2aldoxorubicin) with small cell lung cancer who had received 3 prior chemotherapy regimens. For the 230 mg/m2 cohort during cycle 1, median results for albumin-bound doxorubicin include Cmax= 64 µg/mL, tmax= 0.25 hr, t1/2= 19.7 hr, AUC t-∞= 1500 h*µg/mL, CLpred= 0.153 L/h/m2, Vss pred= 3.91 L/m2. Results were similar for cycle 3. Free doxorubicin accounted for only 0.8% of total doxorubicin detected, and doxorubicinol less than 0.0007% of total drug. Results from the 350 mg/m2 cohort are pending. Data from all 12 subjects will be available at presentation. Conclusions: Aldoxorubicin binds rapidly to albumin and is cleared slowly from the circulation. It possess a relatively narrow volume of distribution. These characteristics distinguish aldoxorubicin from published PK data for doxorubicin. Clinical trial information: NCT01706835.
Risk of pneumonitis with mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus.
Authors: Ranpura Vishal Navnitray , Wu Shenhong 
Published: March 2020

e13573 Background: Pneumonitis is associated with the use of mTOR inhibitors, everolimus and temsirolimus, which have been used widely in cancer therapeutics and clinical trials. Currently, the overall risk of pneumonits in patients treated with mTOR inhibitors has not been defined. We performed a systematic review and meta-analysis of published clinical trials to assess the risk of pneumonitis in cancer patients treated with mTOR inhibitors. Methods: Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology conferences until May 2012 were searched to identify relevant studies. Eligible studies included prospective clinical trials in which patients received treatment with everolimus or temsirolimus as a single agent or in combination with other agents. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated employing a fixed- or random-effects model based upon the heterogeneity of the included studies. Results: A total of 2,303 patients with a variety of tumors from 18 studies (everolimus: 12, temsirolimus: 6) were included for the analysis. The overall incidences of all-grade and high-grade pneumonitis with mTOR inhibitors were 6.5% (95% CI: 3.7-11.1%) and 2.5% (95% CI 1.2-5.4%) respectively. The risk of all-grade pneumonitis did not vary significantly with tumor types (P=0.079), but vary significantly with their combination with other agents (P<0.001). There was no significant difference between everolimus and temsirolimus in the incidence of all-grade (P=0.22) and high-grade (P=0.28) pneumonitis. In comparison with controls, mTOR inhibitors significantly increased the risk of all-grade (RR=5.2, 95% CI: 2.09-12.93, P<0.001) but not high-grade pneumonits (RR=2.63, 95% CI: 0.66-10.40, P=0.41). Conclusions: The risk of pneumonitis is increased in cancer patients receiving mTOR inhibitors without significant difference between everolimus and temsirolimus.
Phase Ib study of safety, tolerability, and efficacy of R1507 a monoclonal antibody to IGF-1R in combination with multiple standard chemotherapy regimens in patients with advanced solid malignancies.
Authors: Mahadevan Daruka , Sutton Gregory Ryan , Arteta-Bulos Rafael , Bowden Chris J. , Miller Paul J. E. , Swart Rachel Elizabeth , Walker Mark S. , Munster Pamela N. , Dees Elizabeth Claire , Marshall John , Hamid Omid , Kurzrock Razelle 
Published: March 2020

e13574 Background: R1507 is a human IgG1 Mab that binds to the insulin-like growth factor-1 receptor (IGF-1R), implicated in the pathogenesis of several solid tumor types. IGF-1 or IGF-2 activate the IGF-1R and promote anchorage independent growth of malignant cells. A phase 1b study was conducted to establish the safety, tolerability and efficacy of R1507 in combination with multiple standard oncology regimens. Methods: This was an open-label, multi-center study in advanced stage cancer patients (pts). R1507 (3, 5, 9, 10 and 16 mg/kg IV, Q2W or Q3W) was added to 6 treatment regimens: gemcitabine + erlotinib (GE); paclitaxel + bevacizumab (PB); carboplatin + etoposide (CE); mFOLFOX6 + bevacizumab (FB); capecitabine + trastuzumab (CT); sorafenib (S). All arms started with R1507 dose lower than the recommended single agent dose (level -1). If tolerable, R1507 dose was escalated in subsequent cohorts of pts. Accrual to each regimen was dependent on the number of pts developing a DLT at dose level -1. The study used a 3 + 3 + 6 and a 3 + 9 design. Results: N=104 pts enrolled into regimens 1 to 6: 6% new diagnosis, 93% non-recent diagnosis, and 1% not classified. N=18 withdrew for safety [1 death, 17 AEs]. N=80 withdrew for non-safety reasons [n=61 PD, n=17 refused further treatment, n=1 insufficient response, n=1 ‘other’]. A total of 1337 AEs were reported: any grade, across regimens and doses were nausea, diarrhea, and vomiting. N=123 had grade ≥3 AEs (n=28 dose level -1; n=95 dose level 1) in 60 pts that were myelosuppression, fatigue and mucosal inflammation. ORR (partial response [PR] plus stable disease) of evaluable pts across 6 regimens was 36% with 5 PRs: regimens PB (non-small cell lung cancer, nasopharyngeal cancer), CE (melanoma), FB (colon cancer) and S (gastrointestinal stromal tumor: GIST). The GIST pt (>4 prior therapies) had a PR for 3 years. Three pts (breast cancer, melanoma, adenoid cystic carcinoma) were on study for >1 year. 71% pts had SD ≥ 4 months. Conclusions: R1507 added to 6 standard chemotherapy regimens was well tolerated with no significant safety issues. Trial was terminated early due to discontinued development of R1507. Clinical trial information: NCT00811993.
Trabectedin to induce mitochondrial membrane potential dissipation and reactive oxygen species generation in breast cancer cells.
Authors: Atmaca Harika , Bozkurt Emir , Cakar Burcu , Surmeli Zeki Gokhan , Uzunoglu Selim , Uslu Ruchan , Karaca Burcak 
Published: March 2020

e13580 Background: Trabectedin (Yondelis; ET-743) is a tetrahydroisoquinoline alkaloid that was originally derived from the marine tunicate Ecteinascidia turbinata and is currently prepared synthetically. It ıs currently used for the treatment of soft tissue sarcomas. It has been shown that Trabectedin provides the production of superoxides near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis, however the apoptotic mechanisms of Trabectedin is still very limited. The objective of this study is to investigate the underlying mechanisms of apoptosis Trabectedin in two human breast cancer cell lines (MDA-MB-231 and MDA-MB-453) and one human immortalized non-transformed breast epithelial cell line (MCF-10A), to see if similar oxidation processes take place in breast cancer. Methods: Cytotoxicity was assessed by XTT cell viability assay. Apoptosis was shown by measuring DNA fragmentation, caspase 3/7 activation. Mitochondrial membrane potential (MMP) was evaluated by TMRE dye. Measurement of reactive oxygen species (ROS) was done by using Glutathione S-Transferase (GST) Assay Kit and CM-H2DCFDA dye. Results: Trabectedin induced the cytotoxicity in breast cancer cells in a time and dose dependent manner. Moreover, it increased DNA fragmentation and the MMP dissipation in tested breast cancer cells. The levels of ROS production in parallel with GST enzyme activity were sharply increased by Trabectedin treatment. Conclusions: This is the first study to investigate the role of Trabectedin activity and mechanisms of apoptosis in human breast cancer cells. These preliminary results might show us a way to use Trabectedin alone, or in combination for breast cancer treatment in near future.
A second-generation DNA-binding pyrrole-imidazole polyamide with antitumor activity.
Authors: Nickols Nicholas George , Yang Fei , Li Benjamin C , Szablowski Jerzy O , Wang Chieh-Mei , Dervan Peter Brendan 
Published: March 2020

e13588 Background: Pyrrole-imidazole polyamides are synthetic minor groove binders with programmable sequence recognition. A polyamide that targets the DNA sequence 5’-WGWWCW-3’ (W=A/T) found in the Androgen Receptor (AR) response element inhibits a subset of AR driven transcripts and is cytotoxic in a number of cancer cell lines including LNCaP (prostate cancer), without evidence of DNA damage. Pharmacokinetic studies show bioavailability after intravenous or subcutaneous injection. This polyamide suppressed growth of LNCaP tumor xenografts in mice. However, escalated dosing resulted in significant weight loss that could deter further development. We now report a second-generation polyamide with decreased systemic toxicity that retains efficacy towards LNCaP xenografts. Methods: We investigated the toxicity of our lead polyamide in normal (C57BL/6)mice by necropsy. We then synthesized a focused library of four polyamides that retain the DNA-recognition sequence of our lead molecule, but with chemical substitutions at non-recognition elements. We treated groups of normal male mice (n=4 each) with escalating doses up to 10 mg/kg and observed them for 10 days or until signs of significant distress, after which mice were necropsied. The least toxic polyamide was then tested for suppression of LNCaP xenograft growth (n=14 per treatment arm: 1 mg/kg polyamide versus saline vehicle alone). Tumors were allowed to grow to 200 mm3 prior to treatment by subcutaneous injection every three days for a cycle of six injections. Tumors were then resected and measured. Results: The primary target organ of toxicity for our lead polyamide was the liver, which demonstrated toxicity at 3 mg/kg and dose-limiting toxicity at less than 10 mg/kg. One polyamide in our library demonstrated no evidence of toxicity by necropsy and serum analysis up to 10 mg/kg. This polyamide also suppressed growth of established LNCaP xenografts (T/C: 51%, p=0.0073) at a dose of 1 mg/kg. The other polyamides demonstrated greater toxicity and were not tested further. Conclusions: We report a second-generation polyamide with minimal systemic toxicity in rodents that retains in vivo antitumor activity in prostate cancer xenografts.
Efficacy and safety of every-2-weeks cetuximab combined with FOLFOX or FOLFIRI as first-line therapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC): An Asia-Pacific nonrandomized phase II study (APEC).
Authors: Cheng Ann-Lii , Cornelio Gerardo H. , Shen Lin , Price Timothy Jay , Yang Tsai-Shen , Chung Ik-Joo , Dai Guanghai , Lin Jen-Kou , Sharma Atul , Yeh Kun-Huei , Ma Brigette , Zaatar Adel , Guan Zhongzhen , Masood Nehal , Srimuninnimit Vichien , Yau Thomas Cheung , Sarholz Barbara , Lim Robert S.C. 
Published: March 2020

e14501 Background: Randomized studies have shown that weekly cetuximab added to first-line FOLFOX or FOLFIRI improves clinical outcome in patients (pts) with KRAS wild-type (wt) mCRC. This Asia-Pacific multicenter study investigated FOLFOX or FOLFIRI + every 2 weeks cetuximab (C) as first-line therapy in pts with KRAS wt mCRC. Methods: Eligible pts received every 2 weeks cetuximab (d1 500 mg/m2 q14d) with, based on investigator’s choice, either FOLFOX (oxaliplatin 100 mg/m2, folinic acid [FA] 200 mg/m2 L-form or 400 mg/m2 racemic, then 5-fluorouracil [5-FU], as a 400 mg/m2 iv bolus and a 2400 mg/m2 infusion over 46 h) or FOLFIRI (irinotecan 180 mg/m2, FA 200 mg/m2 L-form, or 400 mg/m2 racemic, then 5-FU, as a 400 mg/m2 iv bolus and a 2400 mg/m2infusion over 46 h), until disease progression, unacceptable toxicity or consent withdrawal. Primary endpoint was tumor response; assessed radiologically (RECIST 1.0) every 8 weeks. Results: Data cut-off was 86 weeks after the date of last patient included. The ITT/safety population comprised 289 pts; 65.1% received FOLFOX + C and 34.9% FOLFIRI + C. Baseline characteristics were generally well balanced. Leukocyte count >10000/mm3was more frequent (16.5% vs 7.9%) and prior adjuvant treatment less frequent (21.3% vs 46.5%) in pts receiving FOLFOX + C. Response (CR or PR) was observed in 170 (58.8%) pts. The overall R0 resection rate was 10.0%. Survival data are not mature. Cetuximab dose intensity was >80% in 77.7% (FOLFOX + C) and 74.3% (FOLFIRI + C) of pts. Most frequent grade 3/4 adverse events (>10% in either arm) were neutropenia, diarrhea, hypokalemia, neuropathy (FOLFOX + C only) and skin reactions. Conclusions: Efficacy and safety profiles of every 2 weeks cetuximab combined with FOLFOX or FOLFIRI were similar to those reported for either chemotherapy plus weekly cetuximab in pivotal studies. Clinical trial information: NCT00778830. [Table: see text]