bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting PIK3CA mutant breast cancer with the combination of PIK3CA-specific inhibitor, BYL719, and IGF1-R antibody, ganitumab.
Authors: Cao Z, Alexander , Pinzon-Ortiz Maria , Chen Yan , Li Xiaoyan , Beltran Pedro J. , Gansert Jennifer L. , Peters Malte , Schlegel Robert , Schumacher Karl Maria , Huang Alan 
Published: March 2020

e13525 Background: PI3K/AKT signaling is a critical growth and survival pathway in many human cancers. PI3Ks are lipid kinases that are important in controlling signaling pathways involved in cell proliferation, motility, cell death and cell invasion. The α isoform of PI3K (PIK3CA) is linked upstream mainly to receptor tyrosine kinases and is commonly mutated in various solid tumor types. The existing scientific evidence strongly supports the concept of targeting PIK3CA in human cancers, especially those harboring PIK3CA mutations. Sustained PIK3CA inhibition may lead to aberrant RTK signaling to attenuate PIK3CA inhibition. IGF1R is a RTK commonly expressed in human neoplasia. Its signaling has been implicated in tumor cell survival. Additionally, IGF1R/IRS signaling has been shown to be a feedback pathway to down-modulate mTOR inhibition by RAD001 in cancer cells. We reason that the efficacy of PIK3CA inhibition would be enhanced if PIK3CA inhibitor is combined with a targeted agent against a key RTK in pAKT signaling. Methods: We set out to examine whether PIK3CA inhibition would also trigger IGF1-R/IRS signaling. In addition, we explored the combination of PIK3CA-specific inhibitor, BYL719, and a fully human antibody against IGF1-R, ganitumab, preclinically against a PIK3CA mutant breast cancer model, MCF7. Results: Our data indicate that IGF1-R/IRS signaling is activated upon PIK3CA inhibition. BYL719 exhibited concentration-dependent tumor growth inhibition in vitro. Ganitumab alone had modest inhibitory activity. The combination of BYL719 and ganitumab inhibited MCF7 growth synergistically in vitro. This combination was further tested in an MCF7 xenograft in mice. BYL719 monotherapy resulted in tumor stasis. Ganitumab alone had marginal growth inhibition. The combination of BYL719 and ganitumab led to tumor regression. Conclusions: Our data suggest that the combination of BYL719 and ganitumab would act synergistically to inhibit PIK3CA mutant breast cancer cells by blocking two inter-connected pathways. The combination of BYL719 and ganitumab has now entered into clinical trial (NCT01708161). It represents a promising approach against PI3KCA mutant breast cancers.
Preclinical and clinical data for tbo-filgrastim: A short-acting filgrastim.
Authors: Buchner Anton , Mueller Udo W. , Bias Peter , Engert Andreas 
Published: March 2020

e13555 Background: Tbo-filgrastim is a G-CSF approved in the US as a biologic under the BLA 351(a) pathway, for reducing duration of severe neutropenia (DSN) in patients with non-myeloid malignancies receiving chemotherapy (CTx) associated with a clinically significant incidence of febrile neutropenia (FN). Here, we summarize data from the development program (16 preclinical studies; 2 Phase I and 3 Phase III clinical studies). Methods: Preclinical: The PK, safety pharmacology, PD, and toxicology of tbo-filgrastim vs reference filgrastim were investigated in 3 in vitro studies and 13 animal model studies. Clinical: The PK/PD of tbo-filgrastim and filgrastim were compared in 2 Phase I studies in 200 healthy volunteers. The safety and efficacy of tbo-filgrastim were compared with filgrastim in 3 Phase III studies in 677 patients receiving CTx for breast cancer (BC), lung cancer (LC) and non-Hodgkin lymphoma (NHL). The BC study, in which DSN was the primary parameter, was placebo controlled. Results: Preclinical: Binding affinity to the human G-CSF receptor and growth-promoting activity were comparable between tbo-filgrastim and filgrastim in vitro. In vivo, no relevant differences were seen between tbo-filgrastim and reference filgrastim in PK, PD, safety, or tolerability in animal models. Clinical and laboratory findings, gross pathology and histopathology in animal models were similar to filgrastim. Clinical: tbo-Filgrastim was safe, effective, and comparable to filgrastim in the prevention of FN. DSN, absolute neutrophil count (ANC) nadir, and time to ANC recovery were comparable. The incidence of FN was low (mean of 12.1%, 15.0%, and 11.1% in Cycle 1 of the BC, LC, and NHL studies, respectively), with no significant differences between agents. In the BC study, in Cycle 1, DSN was 1.1 vs 3.9 days for tbo-filgrastim and placebo, respectively. The efficacy of tbo-filgrastim was independent of the myelotoxic potential of CTx. Immunogenicity and incidence of binding and neutralizing antibodies were low and comparable. Conclusions: The safety profiles of tbo-filgrastim and filgrastim were similar and characteristic of filgrastims. Tbo-filgrastim was superior to placebo and equivalent to filgrastim in reducing DSN after myelotoxic CTx. Clinical trial information: 2004-001452-36, 2004-001450-84, 2004-001449-13.
Phase (Ph) I study of pazopanib (P) in combination with vinorelbine (V) in patients with metastatic non-small cell lung cancer (mNSCLC) and breast cancer (mBC).
Authors: Gentzler Ryan D. , Kaklamani Virginia G. , Worden Rebekah , Zumdahl Therese , Simm Hala D , Rademaker Alfred , Johnson Melissa Lynne , Patel Jyoti D. 
Published: March 2020

e13568 Background: V is an established treatment for mNSCLC and mBC, but combination 2nd line chemotherapy has not shown clear benefit for either disease. The anti-VEGF agent bevacizumab improves response rate and progression free survival (PFS) for mNSCLC and mBC. P is a tyrosine kinase inhibitor targeting the VEGF receptors. We hypothesize that because CYP3A4 is inhibited by P and responsible for metabolism of V, there may be synergy between P + V. This is a ph I study testing the combination of P + V in previously treated pts with mNSCLC and mBC. Methods: Pts with Stage IIIB/IV NSCLC or Stage IV mBC with ≤ 2 (lung) or ≤ 3 (breast) prior chemotherapies, no prior VEGF inhibitors, and PS 0-2 were treated with P + V. The objective was to determine the maximum tolerated dose (MTD) of P + V. Dose escalations followed a standard 3+3 design. After 6 pts, the protocol was amended to add an intermittent dosing cohort (2a) to improve tolerability. Response assessment (RA) occurred q 42 days (d) while on study. Pts had weekly toxicity assessments, and PK data was collected on d 1-2 of the first 2 cycles. Results: Eight pts (7 mNSCLC, 1 mBC) were enrolled in 3 of 9 planned cohorts. Pts received a median of 2 cycles. All pts experienced at least 1 grade (gr) 3/4 toxicity. Six dose-limiting toxicities occurred in 4 pts in cohort 2/2a. Five severe adverse events were reported in 4 pts and included thrombocytopenia, neutropenia, abdominal (abd) pain, pneumonia, and hepatotoxicity. Gr 3/4 toxicities were: neutropenia (6), fatigue (2), thrombocytopenia (1), hyperbilirubinemia (1), transaminitis (1), hypertension (1), abd pain (1), and pneumonia (1). 1 pt refused treatment after 1 cycle and had no RA. 5 of 8 pts expired due to progressive disease. No partial responses were noted. Median PFS was 66 d (95% CI 35 to 384 d). Conclusions: Combination of P + V in pre-treated mNSCLC and mBC results in high rates of gr 3/4 toxicities at all dose levels. The trial was suspended due to significant drug-drug interactions before the MTD could be determined. No further study of P in combination with V is warranted in either pt population. Clinical trial information: NCT01060514. [Table: see text]
Orally administrative melk (maternal embryonic leucine zipper kinase)-targeting small molecule inhibitor suppresses the growth of various types of human cancer.
Authors: Chung Suyoun , Suzuki Hanae , Miyamoto Takashi , Takamatsu Naofumi , Tatsuguchi Ayako , Ueda Koji , Kijima Kyoko , Matsuo Yo , Nakamura Yusuke 
Published: March 2020

e13569 Background: We previously reported MELK (maternal embryonic leucine zipper kinase) as a novel therapeutic target for breast cancer. MELK was also highly upregulated in multiple types of cancer including prostate, pancreas and lung cancers, and plays indispensable roles in cancer cell survival, particularly in the maintenance of tumor-initiating cells. In this study, we attempted to identify novel substrates of MELK and develop the small-molecule MELK inhibitor. Methods: To elucidate the MELK signaling pathway in breast cancer cells, we screened MELK substrates by 2D-PAGE and mass spectrometric analysis, and characterized two of them for their roles in mammary carcinogenesis. Furthermore, we conducted a high-throughput screening of a compound library followed by structure-activity relationship studies. We investigated the growth suppressive effect of a MELK inhibitor OTSSP167 using xenograft models in mice and a mammosphere-formation assay. Results: We identified two novel MELK substrates, DBNL and PSMA1, which plays critical roles in invasiveness of cancer cells and maintenance of mammary tumor-initiating cells. We successfully obtained a highly potent MELK inhibitor OTSSP167 with IC50 of 0.41 nM. OTSSP167 inhibited the phosphorylation of these two substrates by MELK as well as mammosphere formation of breast cancer cells, and exhibited strong tumor-growth suppressive effects on xenografts of human breast, lung, prostate, and pancreas cancer cell lines in mice by both intravenous and oral administration. Conclusions: Orally administrative MELK inhibitor OTSSP167 is a promising compound to treat various types of human cancer. This compound can inhibit the phosphorylation of MELK substrates and also suppresses the formation of cancer stem cells in breast cancer cells, providing a novel strategy to cure cancer.
Multicentric survey on dose reduction in cancer drug therapy: Detection and measurement of critical phenomena as potential indicators of suspected adverse reactions.
Authors: Tenti Elena , Casadei Gardini Andrea , Amadori Dino , Fiacchi Paola , Stancari Alessandra , Zanardi Alessandra , Cherubini Chiara , Sferra Stella , Sara Simonetta , Rondoni Cristina , Maugeri Antonio , Restuccia Silvia , Gallani Maria Laura , Palazzini Simonetta , Bianchini Erika , Menozzi Silvia , Musi Eleonora , Minguzzi Martina 
Published: March 2020

e13579 Background: The antineoplastics are considered drugs with a high number of side effects. Paradoxically, in the National Network of Pharmacovigilance the number of reported adverse reactions of these medicine is proportionally lower than that of normal drugs. In the field of pharmacovigilance programs promoted by the Region Emilia Romagna and funded by AIFA (Italian Medicines Agency) a project of multicenter surveillance of cancer drugs and their effect has been developed aimed at improving patient safety. The project joined 7 centers: IRCCS IRST (Coordinating Center) and the Hospitals of Ravenna, Parma, R. Emilia, Bologna, Ferrara and Rimini. Methods: All centers except one used the management software Log80 and therefore shared a database of information of analogous structure (the data presented come from the database of medication prescription). The survey included patients that started therapy in 2011 and reduced it in the same year. It was analyzed dose reduction from 10% to 50% during the first 90 days of therapy (dose reduction was counted from the actual administred dose to patient). The first 90 days of therapy have been considered as a significant time frame to intercept critical phenomena. Results: Out of a total of 12,389 patients, 1,320 have reduced the dose in the firts 3 mounth of treatment (10.7%). The drugs that have mostly resulted in a reduction of dose were Paclitaxel and Oxaliplatin (with a reduction of respectively 17.4% and 17.3% in term of number of patients ), Docetaxel (14.8%), Carboplatin (15%), Fluorouracil (10.7%) and among oral medications Capecitabine (6.9%). Conclusions: This survey has shown that patients treated with chemotherapy have had a dose reduction lower than compared to published studies. With regards to these reduction it must be highlighted that approximately 20% of patients have reduced by 30% the dose within three months of therapy. The dose reduction may underlie suspected adverse reactions; in this perspective, further investigations could show if the patients had severe adverse drug reactions.
Differential effects of selenium (Se) on normal and malignant cells treated with chemotherapy (CT) and radiation (RT).
Authors: Jameson Michael B. , Lobb Richard J , Jacobson Gregory M , Cursons Ray T 
Published: March 2020

e13583 Background: Preclinical work has demonstrated that Se compounds potentiate anticancer effects of CT and RT while reducing normal tissue toxicities. The molecular basis for the therapeutic selectivity has yet to be fully elucidated but includes modulation of intracellular glutathione (GSH) concentrations, endoplasmic reticulum (ER) stress responses, DNA repair, induction of apoptosis and cellular resistance to CT and RT. Our aim was to evaluate the dose-response relationship of the Se compound methylseleninic acid (MSA) on molecular pathways involved in the response of normal and malignant cells to CT and RT. Methods: Peripheral blood mononuclear cells (PBMC) obtained from healthy blood donors and malignant THP-1 human monocytic leukaemia cells were exposed in vitro to MSA 2.5, 5 or 15 µM in varying combinations with MSA, RT, cisplatin (Pt), doxorubicin (Dox) and cytosine arabinoside (Ara-C). GSH concentration was measured by ELISA, DNA damage and repair by COMET assay, cell viability by MTT assay and ER stress response protein expression by western blotting. Results: MSA was selectively toxic to THP-1 cells and induced a protective increase in GSH in PBMC but a decrease in high concentrations within THP-1 cells. DNA damage induced by Ara-C or Dox in the COMET assay was significantly reduced by MSA in PBMC but increased in THP-1 cells. Cell death after 2 Gy RT was increased by all doses of MSA in THP-1 cells but only by the highest dose in PBMC. The cytotoxicity of Dox and Ara-C at sublethal doses was significantly enhanced by MSA in THP-1 cells and to a lesser extent in PBMC, but MSA increased cell death from Pt only in THP-1 cells. MSA induced a protective ER stress response in PBMC exposed to Ara-C but an apoptotic response in THP-1 cells. Conclusions: MSA at clinically-relevant concentrations had a differential effect on cell survival and death responses to RT and CT with relative protection of PBMC and enhanced death of THP-1 cells. Several mechanisms mediated this therapeutic selectivity and the dose-dependence of the Se effect varied between malignant and normal cells. These assays could potentially be used in clinical trials to evaluate pharmacodynamic markers of Se effects in conjunction with CT and/or RT.
Comparison of pharmacokinetics of S-1 between the initial and reduced dose in patients with locally advanced head and neck cancer.
Authors: Yamazaki Tomoko , Ishiki Hiroto , Yajima Yoko , Kobayashi Takehiko , Enokida Tomohiro , Zenda Sadamoto , Arahira Satoko , Kawashima Mitsuhiko , Tahara Makoto 
Published: March 2020

e13586 Background: S-1 is an oral fluoropyrimidine that combines tegafur (FT) with two modulators, gimeracil (CDHP) and oteracil potassium (Oxo). CDHP augments 5-FU activity by inhibiting dihydropyrimidine dehydrogenase (DPD). As 50% of CDHP is excreted in the urine, renal dysfunction may directly affect the inhibitory effect on DPD and lead to increased 5-FU concentrations, and dose modification is recommended if renal dysfunction occurs (M.Tahara et. al; Cancer Science, 2011). However, the method of dose modification has not been established. We compared the pharmacokinetics of S-1 between the initial and reduced dose in patients with locally advanced head and neck cancer. Methods: This was a prospective study at a single institution. Eligibility required histologically or cytologically confirmed carcinoma of the head and neck with unresectable locally advanced disease. Chemotherapy consisted of administration of S-1 twice daily on days 1-14 at 60 mg/m2/day, and cisplatin at 20 mg/m2/day on days 8-11, repeated twice at a 5-week interval. Single daily radiation of 70 Gy in 35 fractions was given concurrently startingon day 1. Two additional cycles of chemotherapy wereplanned after the completion of CRT. S-1 dose was reduced to 40 or 30 mg/m2/day in accordance with adverse events. Peripheral blood samples were drawn before and at 1, 2, 4, 8, and 10 hours on day 7 in the first cycle and in the cycle with dose reduction. Primary endpoint was the change in 5-FU AUCss0-10 between the initial and reduced S-1 dose. Results: Eight patients were enrolled between July 2010 and July 2011, and 30 cycles of chemotherapy were administered. Four pts required S-1 dose reduction due to mucosal infection (n=2), febrile neutropenia (n=1), or renal dysfunction (n=1). PK parameters are compared below. Conclusions: AUCss0-10 for 5FU with a reduced dose of S-1 was significantly lower than with the initial dose.Further investigation with more patients is warranted. [Table: see text]
Effect of obatoclax (GX15-070) on cell survival, apoptosis, and prosurvival autophagy in head and neck squamous cell carcinoma (HNSCC).
Authors: Yazbeck Victor Y. , Li Changyou , Johnson Daniel E 
Published: March 2020

e13587 Background: Approximately 500,000 new cases of head and neck cancer are diagnosed annually worldwide, with 300,000 deaths per year. Patients with recurrent and metastatic disease have a dismal prognosis with a median survival of less than one year. Current standard of care involves a platinum-based regimen for patients with good performance status, but is usually difficult to tolerate. Novel therapeutic approaches are in great need for this patient population. The antiapoptotic BCL-2 family proteins, including BCL-2, BCL-XL, and MCL-1 are involved in oncogenesis and chemoresistance and are overexpressed in HNSCC. Obatoclax is a pan-BCL2 inhibitor capable of inhibiting MCL-1, in addition to BCL-2 and BCL-XL. Methods: We determined the activity of obatoclax in 4 well-characterized HNSCC cell lines (UMSCC-1, Cal-33, 1483, UMSCC-22A). Cell viability was determined by MTT assay and apoptosis by Annexin-V binding, FACS analysis, and immunoblotting. Autophagy was assessed by immunofluorescence and immunoblotting. Results: All 4 HNSCC cell lines were highly sensitive to single-agent obatoclax with IC50’s ranging from 50-200 nM. Obatoclax induced apoptosis in all cell lines as evidenced by increased Annexin-V binding at 48 hours in a dose-dependent manner from less than 10% in vehicle treated cells to 30-60% in cells treated with obatoclax. Processing/activation of caspase-3 and cleavage of PARP protein was also observed. In addition, obatoclax induced prosurvival autophagy in all cell lines and the addition of the autophagy inhibitor chloroquine enhanced obatoclax cytotoxicity. In vivo studies of obatoclax using human HNSCC xenograft tumors is currently underway. Conclusions: This preclinical study suggests that obatoclax might have therapeutic value in HNSCC, as a single agent or in combination with an autophagy inhibitor.
Infusion-related reactions (IRR) during NGR-hTNF therapy as potential predictors of clinical outcome.
Authors: Rossoni Gilda , Gregorc Vanesa , Bulotta Alessandra , Viganò Maria Grazia , Todisco Gabriele , Lambiase Antonio , Bordignon Claudio 
Published: March 2020

e13593 Background: NGR-hTNF, a selective antivascular agent, transiently modulates the systemic release of cytokines/chemokines. Intravenous infusion of NGR-hTNF is distinguished by an early on-target effect, IRR, which mostly consists of short-lived grade 1/2 chills. Methods: Incidence, predictors of development and relationships of IRR with treatment outcome were assessed in a pooled analysis of individual patient data from 5 phase II trials with NGR-hTNF. Global data set comprised 205 previously treated patients (pts) who had received NGR-hTNF 0.8 µg/m2 every 3 weeks (q3w) or weekly (q1w) alone in mesothelioma, colon and liver cancers or in combination with doxorubicin in small cell lung and ovarian cancers. In all trials, response to therapy (RECIST) was measured q6w until progression. Regression models estimated the effect size of IRR on response rate (RR; complete and partial response), disease control rate (DCR; RR plus stable disease) and progression free survival (PFS). Results: 137/205 pts (67%) experienced IRR on treatment, while 68 pts (33%) did not. In the IRR group, 63% of pts had grade 1 and 37% grade 2. By time to onset, 88% of pts developed IRR during first 6 weeks of therapy and 12% later. According to dosing schedule, IRR rates were higher with q1w than with q3w (85% vs 62%; p=.008). Baseline characteristics were (IRR vs non-IRR groups): median age: 66 vs 64; male: 50% vs 56%; PS ≥ 1: 34% vs 35%, range of prior lines: 1-4 vs 1-5. Among baseline characteristics, logistic regression analysis retained only a lower number of prior lines associated with higher IRR rates (OR=1.4; p=.02). Onset of IRR was related to better treatment outcome. RR was 12% in the IRR and 3% in the non-IRR group (OR=4.4; p=.05), while DCR was 50% in pts who had IRR and 34% in pts who did not (OR=2.0; p=.02). In pts with or without IRR, 6-month PFS was 21% vs 7% (HR=0.62; p=.001), respectively. Improvement in PFS time remained significant in a landmark analysis set at the 6-week time point (p=.004). On multivariate analyses adjusted for baseline variables, IRR independently predicted higher odds of tumor response (p=.05) and lower risk of progression or death (p=.009). Conclusions: Onset of IRR on NGR-hTNF treatment may predict subsequent clinical outcome. Clinical trial information: NCT00483080-NCT00483509-NCT00484211-NCT00484276-NCT00484432.
Cetuximab biweekly plus mFOLFOX6 as first-line therapy in patients (pts) with KRAS wild-type (wt) metastatic colorectal cancer (mCRC): An interim analysis of the CEBIFOX trial.
Authors: Kasper Stefan , Meiler Johannes , Knipp Heike , Hoehler Thomas , Reimer Peter , Steinmetz Tilman , Berger Winfried , Linden Gabriele , Ting Saskia , Markus Peter , Paul Andreas , Schuler Martin H. , Trarbach Tanja 
Published: March 2020

e14502 Background: Combination of mFOLFOX6 with weekly cetuximab is a standard first line regimen in pts with KRAS wt mCRC. Weekly application of cetuximab increases the in-hospital time of pts with negative impact on quality of life. This multicentric phase II trial evaluates the efficacy of mFOLFOX6 + biweekly cetuximab as first line therapy in KRAS wt mCRC. Methods: Pts with KRAS wt mCRC who were not candidates for primary metastasectomy received cetuximab (500 mg/m2 every 2 weeks) in combination with mFOLFOX6 (oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, 5-FU 400 mg/m2 bolus and 2,400mg/m2 over 46 h q14d). Primary endpoint was objective response rate (ORR) per RECIST 1.0, secondary endpoints were safety, secondary resection rate, quality of life (QoL), progression-free survival (PFS) and overall survival. Data of a pre-specified interim analysis are presented in which 13 responders were needed in the first 37 pts (Simon stage I). Results: As of Dec 2012, 46 pts were registered. Fourty three pts received ≥1 course of treatment, and 34 pts were evaluable for response. Baseline characteristics of the ITT population and efficacy data are listed in the Table. Median follow-up was 14.6 months. Grade 3/4 adverse events occurred in 39% of pts, including leukocytopenia (11%), gastrointestinal toxicity (11%), and rash (9%). Median PFS was 9.6 months (95% CI: 5.0 to 14.1). QoL data will be presented. Conclusions: This pre-specified interim analysis supports efficacy and safety of biweekly cetuximab given in combination with mFOLFOX6 in pts with mCRC. A high rate of objective responses and secondary hepatic resections was achieved. Based on these results enrolment in CEBIFOX is continued. Clinical trial information: NCT01051167. [Table: see text]