Effectiveness and safety of eribulin in Japanese patients with HER2-negative, advanced breast cancer: a 2-year post-marketing observational study in a real-world setting
Conclusions The effectiveness and safety results of eribulin as the first- or second-line treatment were favorable. Thus, these suggest eribulin may be a first-line treatment candidate for patients with HER2-negative advanced breast cancer in Japan. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 15, 2020 Category: Drugs & Pharmacology Source Type: research

Acknowledgement of Reviewers 2019
(Source: Investigational New Drugs)
Source: Investigational New Drugs - January 14, 2020 Category: Drugs & Pharmacology Source Type: research

Efficacy of different dosing schedules of capecitabine for metastatic breast cancer: a single-institution experience
Conclusions Our single institution experience showed that alternate dosing of capecitabine (biweekly, 28-day  cycle) may be a reasonable alternative to standard 21-day cycle with similar efficacy and fewer dose reductions. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 13, 2020 Category: Drugs & Pharmacology Source Type: research

Phase I dose-escalation study of the safety, tolerability, and pharmacokinetics of aflibercept in combination with S-1 in Japanese patients with advanced solid malignancies
Conclusions The tolerability and safety of aflibercept 2  mg/kg in combination with S-1 was confirmed in Japanese patients with advanced solid tumors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 5, 2020 Category: Drugs & Pharmacology Source Type: research

Patient selection for a developmental therapeutics program using whole genome and Transcriptome analysis
Discussion When compared to single-gene DNA-based data alone, WGTA led to a 3-fold increase in treatment matching. In a setting where there is a high level of uncertainty around both the investigational agents and the biomarkers, more data are needed to fully evaluate the impact of routine use of WGTA. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 5, 2020 Category: Drugs & Pharmacology Source Type: research

NCI 6896: a phase I trial of vorinostat (SAHA) and isotretinoin (13-cis retinoic acid) in the treatment of patients with advanced renal cell carcinoma
SummaryPreclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumor sensitivity to retinoids and have synergistic anti-tumor activity when combined. We performed a Phase I clinical trial to evaluate the safety and preliminary efficacy of combining the oral HDAC inhibitor vorinostat and isotretinoin in patients with advanced renal cell carcinoma (RCC). Vorinostat was administered at 300  mg orally twice daily in combination with escalating doses of isotretinoin for 3 consecutive days per week. A standard 3 + 3 dose escalation design was used. Dose limiting toxicities (DLT) were...
Source: Investigational New Drugs - January 2, 2020 Category: Drugs & Pharmacology Source Type: research

A phase 2 clinical trial of the heat shock protein 90 (HSP 90) inhibitor ganetespib in patients with refractory advanced esophagogastric cancer
In this study 26 eligible patients mainly: male 77%, median age 64 years were enrolled. The most common drug-related adverse events were diarrhea (77%), fatigue (65%), elevated ALKP (42%), and elevated AST (38%). The most common grade 3/4 AEs included: leucopenia (12%), fatigue (12%), diarrhea (8%), and el evated ALKP (8%). The ORR of 4% reflects the single patient of 26 who had a complete response and stayed on treatment for more than seventy (70) months. Median PFS and OS was 61 days (2.0 months), 94 days (3.1 months) respectively. Ganetespib showed manageable toxicity. While the study was termi ...
Source: Investigational New Drugs - January 1, 2020 Category: Drugs & Pharmacology Source Type: research

Discovery of a novel and highly selective CDK9 kinase inhibitor (JSH-009) with potent antitumor efficacy in preclinical acute myeloid leukemia models
SummaryAcute myeloid leukemia (AML) is reported to be vulnerable to transcription disruption due to transcriptional addiction. Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, has attracted extensive attention as a drug target. Although several inhibitors, such as alvocidib and dinaciclib, have shown potent therapeutic effects in clinical trials on AML, the lack of high selectivity for CDK9 and other CDKs has limited their optimal clinical efficacy. Therefore, developing highly selective CDK9 inhibitors is still imperative for the efficacy and safety profile in treating AML. Here, we report a n...
Source: Investigational New Drugs - December 22, 2019 Category: Drugs & Pharmacology Source Type: research

Evaluation of the potential effect of dacomitinib, an EGFR tyrosine kinase inhibitor, on ECG parameters in patients with advanced non-small cell lung cancer
SummaryPurpose The study evaluated the potential effect of dacomitinib, a small molecule epidermal growth factor receptor (EGFR) inhibitor, on the electrocardiogram (ECG) parameters in adult patients with advanced non-small cell lung cancer enrolled in a multicenter, open-label, phase 2 study.Methods Patients received dacomitinib for six doses of 45  mg every 12 h in a 7-day lead-in cycle (cycle 0), then 60 mg every 12 h for six doses in a 14-day cycle (cycle 1). Clock time-matched triplicate ECGs were performed at 0, 2, 4, 6, 8 and 10 h on day 1 (baseline) and day 4 of cycle 0, and prior to d...
Source: Investigational New Drugs - December 18, 2019 Category: Drugs & Pharmacology Source Type: research

Design, synthesis and cytotoxicity of the antitumor agent 1-azabicycles for chemoresistant glioblastoma cells
SummaryTwelve multi-functional pyrrolizidinones, indolizidinones and pyrroliazepinones were prepared from formal aza-[3  + 2] and aza-[3 + 3] cycloadditions of five- to seven-membered heterocyclic enaminones as diverse ambident electrophiles. The antitumor activity of these alkaloid-like compounds was investigated through an initial screening performed on human glioblastoma multiform (GBM) cell lines (GL-15, U251), on murine glioma cells line (C6) and on normal glial cells. Of the compounds tested, the new pyrrolo[1,2a]azepinone, [ethyl (3-oxo-1,2-diphenyl-6,7,8,9-tetrahydro-3H-pyrrolo[1,2a]azep...
Source: Investigational New Drugs - December 13, 2019 Category: Drugs & Pharmacology Source Type: research

Sorafenib may enhance antitumour efficacy in hepatocellular carcinoma patients by modulating the proportions and functions of natural killer cells
This study showed that sorafenib could affect the proportions and functions of peripheral CD56brightCD16− and CD56dimCD16+ NK cells, which was associated with the outcomes including OS of HCC patients. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 12, 2019 Category: Drugs & Pharmacology Source Type: research

Risk factors for cancer-associated thrombosis in patients undergoing treatment with immune checkpoint inhibitors
SummaryPurpose Anticancer agents are known to increase cancer-associated thrombosis (CAT) onset. CAT onset rate is reported to be 1.92% in cisplatin-based therapy, 6.1% in paclitaxel plus ramucirumab combination therapy, and 11.9% in bevacizumab monotherapy. Because immune checkpoint inhibitors (ICIs) cause a sudden increase in T cell number, an association between administration of these drugs and increase in CAT incidence is likely. However, the extent to which ICI administration affects CAT incidence remains unclear. Further, risk factors for CAT incidence have not yet been identified. The present study investigated CAT...
Source: Investigational New Drugs - December 9, 2019 Category: Drugs & Pharmacology Source Type: research

W941, a new PI3K inhibitor, exhibits preferable anti-proliferative activities against nonsmall cell lung cancer with autophagy inhibitors
SummaryThe PI3K pathway is aberrantly activated in many cancers and plays a critical role in tumour cell proliferation and survival, making it a rational therapeutic target. In the present study, the effects and the underlying mechanism of a new PI3K inhibitor, W941, were investigated in non-small-cell lung cancer (NSCLC). The results of this study showed that W941 inhibited the growth of A549 and Hcc827 cells with IC50 values of 0.12 and 0.23  μM, respectively, and that W941 markedly inhibited the growth of A549 xenograft tumours in a nude mouse model without decreasing body weight. Western blotting assays showed ...
Source: Investigational New Drugs - December 9, 2019 Category: Drugs & Pharmacology Source Type: research

[HuArgI (co)-PEG5000]-induced arginine deprivation leads to autophagy dependent cell death in pancreatic cancer cells
In this study, we examined the sensitivity of pancreatic cancer cells to [HuArgI (Co)-PEG5000]-induced arginine deprivation as well as the mechanisms underlying deprivation-induced cell death. [HuArgI (Co)-PEG5000]-induced arginine deprivation was cytotoxic to all cell lines tested with IC50 values in the pM range at 72  h post-treatment. Three of the five cell lines were rescued by the addition of excess L-citrulline and expressed ASS1, indicating partial arginine auxotrophy. The remaining two cell lines, on the other hand, were not rescued by the addition of L-citrulline and did not express ASS1, indicating comp let...
Source: Investigational New Drugs - December 9, 2019 Category: Drugs & Pharmacology Source Type: research

Microarray expression profiles and bioinformatics analysis of mRNAs, lncRNAs, and circRNAs in the secondary temozolomide-resistant glioblastoma
AbstractTemozolomide is a first line anti-tumor drug used for the treatment of patients with Glioblastoma multiforme (GBM). However, the drug resistance to temozolomide limits its clinical application. Therefore, novel strategies to overcome chemoresistance are desperately needed for improved treatment of human GBM. Here, we simultaneously detected, for the first time, the expression profiles of mRNAs, lncRNAs, and circRNAs in three pairs of secondary temozolomide-resistant glioblastoma (STRG) and matched primary glioblastoma tissues by microarrays. Using these data, we discovered a total of 92 mRNA, 299 lncRNAs and 53 cir...
Source: Investigational New Drugs - December 9, 2019 Category: Drugs & Pharmacology Source Type: research

Phase I study of TAS-115, a novel oral multi-kinase inhibitor, in patients with advanced solid tumors
SummaryTAS-115 is a novel MET, VEGFR, FMS and PDGFR inhibitor, developed to improve the continuity of drug administration with a relatively short half-life. We assessed its tolerability, safety, pharmacokinetics, efficacy, and pharmacodynamics in patients with solid tumors. This open-label, dose-escalation phase I study of TAS-115 consisted of three parts: part 1 (TAS-115 was administered orally once daily [SID]); part 2 and an expansion part (SID in a 5  days on/2 days off [5-on/2-off] schedule for 21 days per cycle). In part 1 (200–800 mg SID administered to 21 patients), systemic exposure after...
Source: Investigational New Drugs - December 9, 2019 Category: Drugs & Pharmacology Source Type: research

Combination of a novel microtubule inhibitor MBRI-001 and gemcitabine synergistically induces cell apoptosis by increasing DNA damage in pancreatic cancer cell lines
In this study, we aimed to investigate the anti-tumor effects of MBRI-001 in combination with GEM in BxPC-3 and MIA PaCa-2 human PC cell lines. In vitro and in vivo results indicate that MBRI-001 showed synergistic activity with GEM. GEM induced apoptosis by increasing DNA damage (phosphorylated core histone protein H2AX (γ-H2AX)), MBRI-001 activated mitochondrial-apopto tic pathway (cleaved poly-ADP ribose polymerase (PARP)). Thus, the combination of the two intensified both apoptosis and DNA damage and showed significantly superior anti-tumor activity compared to each agent alone. The adoption of combination of MBR...
Source: Investigational New Drugs - December 3, 2019 Category: Drugs & Pharmacology Source Type: research

Early depth of tumor shrinkage and treatment outcomes in non-small cell lung cancer treated using Nivolumab
SummaryBackground It would be useful to have criteria for predicting long-term treatment responses to immune checkpoint inhibitors (ICIs). Maximum depth of response correlates with treatment outcomes among patients receiving programmed death protein 1 axis inhibitors for non-small cell lung cancer (NSCLC). We investigated associations between early depth of response and survival outcomes among patients receiving nivolumab for NSCLC.Methods Using records from prospective observational cohorts, we identified 83 previously treated advanced patients with NSCLC who received nivolumab during 2016 –2017. Thirty-one patients...
Source: Investigational New Drugs - November 14, 2019 Category: Drugs & Pharmacology Source Type: research

Cellular uptake evaluation of pentagamaboronon-0 (PGB-0) for boron neutron capture therapy (BNCT) against breast cancer cells
In conclusion, the sugar formulations of PGB-0 only improved PGB-0 solubility but had no role in its cellular uptake. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 14, 2019 Category: Drugs & Pharmacology Source Type: research

Discovery and anticancer evaluation of a formononetin derivative against gastric cancer SGC7901 cells
Conclusion Derivative10 is an novel antitumor agent with potential for further clinical applications to treat gastric cancer.Graphical abstract (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 14, 2019 Category: Drugs & Pharmacology Source Type: research

A phase 1 dose-escalation study of checkpoint kinase 1 (CHK1) inhibitor prexasertib in combination with p38 mitogen-activated protein kinase (p38 MAPK) inhibitor ralimetinib in patients with advanced or metastatic cancer
Conclusions This study did not achieve its primary objective of establishing an RP2D of combination prexasertib + ralimetinib that could be safely administered to patients with advanced cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 8, 2019 Category: Drugs & Pharmacology Source Type: research

A phase I study of vistusertib (dual mTORC1/2 inhibitor) in patients with previously treated glioblastoma multiforme: a CCTG study
SummaryThe PI3K/AKT/mTOR pathway activation plays a central role in glioblastoma multiforme (GBM) development and progression, and in resistance to anti-cancer therapies. Inhibition of the PI3K pathway has been shown to sensitize cultured glioma cells and tumor xenografts to the effects of temozolomide (TMZ) and radiation. Vistusertib is an oral inhibitor of mTORC1/2 complexes. The primary objective of this Canadian Cancer Trials Group phase I study was to determine the recommended phase II dose (RP2D) of vistusertib in patients with GBM receiving TMZ at first progression following primary treatment. Vistusertib was admini...
Source: Investigational New Drugs - November 8, 2019 Category: Drugs & Pharmacology Source Type: research

The influence of direct-acting antivirals in hepatitis C virus related hepatocellular carcinoma after curative treatment
This study was done to elucidate the influence of direct-acting antiviral (DAA) agents on the recurrence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related HCC (HCV-HCC) after curative therapies. HCV-HCC patients who received curative therapies and obtained a complete response were analyzed. From January 2017 to September 2017, 112 HCV-HCC patients received DAA and obtained a sustained virological response (SVR). From January 2006 to December 2014, another 345 HCV-HCC patients received peg-interferon-based treatment and 118 obtained SVR. From January 2012 to December 2016, 248 HCV-HCC patien...
Source: Investigational New Drugs - November 7, 2019 Category: Drugs & Pharmacology Source Type: research

Anticancer activities of vitamin K3 analogues
SummaryIn a previous study we reported on the synthesis of 1,4-naphthoquinone-sulfides by thiolation of 1,4-naphthohydroquinones with primary aryl and alkyl thiols using laccase as catalyst. These compounds were synthesized as Vitamin K3 analogues. Vitamin K3 (VK3; 2-methyl-1,4-naphthoquinone; menadione) is known to have potent anticancer activity. This investigation reports on the anticancer activity of these VK3 analogues against TK10 renal, UACC62 melanoma, MCF7 breast, HeLa cervical, PC3 prostate and HepG2 liver cancer cell lines to evaluate their cytostatic effects. A 1,4-naphthohydroquinone derivative exhibited poten...
Source: Investigational New Drugs - November 6, 2019 Category: Drugs & Pharmacology Source Type: research

Epigallocatechin-3-gallate mouthwash protects mucosa from radiation-induced mucositis in head and neck cancer patients: a prospective, non-randomised, phase 1 trial
SummaryRadiation-induced oral mucositis has a dismal outcome with limited treatment options. We conducted a phase I study to evaluate the safety and preliminary efficacy of epigallocatechin-3-gallate (EGCG) mouthwash when given along with radiation in head and neck cancer. Patients with pathologically confirmed head and neck cancer were eligible for this study. EGCG mouthwash was administered at the assigned dosage level (starting at 440  μmol/L, three times a day) in a standard 3 + 3 dose escalation design. Mucosal toxicity, patient satisfaction, and mucositis-related pain (MTP) were assessed weekly....
Source: Investigational New Drugs - November 6, 2019 Category: Drugs & Pharmacology Source Type: research

7-Chloroquinoline-1,2,3-triazoyl carboxamides induce cell cycle arrest and apoptosis in human bladder carcinoma cells
In conclusion, QTCA-1 and QTCA-4 are promising candidates for inducing cytotoxicity, cell cycle arrest, and apoptosis in human bladder cancer cells. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 5, 2019 Category: Drugs & Pharmacology Source Type: research

Phase I study of continuous olaparib capsule dosing in combination with carboplatin and/or paclitaxel (Part 1)
Conclusions Olaparib in combination with carboplatin and/or paclitaxel resulted in increased hematologic toxicities, making it challenging to establish a dosing regimen that could be tolerated for multiple cycles without dose modifications. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 29, 2019 Category: Drugs & Pharmacology Source Type: research

Phase I study of the mTOR inhibitor everolimus in combination with the histone deacetylase inhibitor panobinostat in patients with advanced clear cell renal cell carcinoma
Conclusion A safe and tolerable dosing regimen was established for combination everolimus/panobinostat therapy with myelosuppression as the major DLT. This therapeutic pairing did not appear to improve clinical outcomes in our group of patients with advanced ccRCC. There was differential expression of miR-605 that correlated with treatment response. Clinical trial information: NCT01582009. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 24, 2019 Category: Drugs & Pharmacology Source Type: research

Naked antisense double-stranded DNA oligonucleotide efficiently suppresses BCR-ABL positive leukemic cells
In conclusion, ADO technology is an attractive method for therapeutic application. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 23, 2019 Category: Drugs & Pharmacology Source Type: research

Veliparib in ovarian cancer: a new synthetically lethal therapeutic approach
SummaryEpithelial ovarian cancer (EOC) accounts for nearly 90% of all ovarian malignancies. The standard therapeutic strategy includes cytoreductive surgery and neo (adjuvant) platinum-based chemotherapy. Relapse of advanced high grade serous ovarian cancer (HGSOC) is related to the development of drug resistance. A defective DNA damage response is a defining hallmark of HGSOC. Poly (ADP-ribose) polymerase (PARP) inhibitors exploit this deficiency through synthetic lethality and have emerged as promising anticancer therapies, especially in breast cancer gene (BRCA1 orBRCA2) mutation carriers. Apart from inducing synthetic ...
Source: Investigational New Drugs - October 23, 2019 Category: Drugs & Pharmacology Source Type: research

Clinical efficacy and safety of apatinib combined with S-1 in advanced esophageal squamous cell carcinoma
Conclusion The combination therapy of apatinib plus S-1 was effective and well tolerated in the treatment of advanced ESCC patients after first-line chemotherapy failure. The combination therapy has the potential to be a potent therapeutic option for advanced ESCC patients after first-line chemotherapy failure. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 23, 2019 Category: Drugs & Pharmacology Source Type: research

Prolonged response to 177 Lu-DOTATATE therapy of a bone marrow infiltration in a refractory thymic neuro endocrine tumor
This report highlights that PRRT could be an effective therapeutic option for advanced bone metastatic disease tNET, with the significant benefit of alleviation of bone pain and radiologic response, without severe or irreversible haematotoxicity. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 23, 2019 Category: Drugs & Pharmacology Source Type: research

Phase I study of intermittent olaparib capsule or tablet dosing in combination with carboplatin and paclitaxel (part 2)
Conclusions Discontinuous dosing of olaparib resulted in significant myelosuppression leading to dose interruptions and/or delays. Anti-tumor activity was encouraging in patients enriched with BRCA-mutated breast and ovarian cancer. The most appropriate olaparib tablet dose for use in further studies evaluating olaparib in combination with carboplatin and paclitaxel is 50 mg bid (days 1 –5). (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 20, 2019 Category: Drugs & Pharmacology Source Type: research

Phase II study of apatinib, a novel tyrosine kinase inhibitor targeting tumor angiogenesis, as second-line treatment for recurrent or advanced cervical cancer patients
This study was designed to evaluate the efficacy and safety of apatinib, a novel tyrosine kinase inhibitor targeting tumor angiogenesis, as second-line treatment in recurrent or advanced cervical cancer patients. Twenty patients who failed cisplatin/paclitaxel ± bevacizumab treatment received a 4-week cycle of apatinib, with a daily dosage of 500 mg or 250 mg. The follow-up period ranged from 5.9 to 21.3 months (median, 14.0 months). None of the patients achieved a complete response (CR). Nevertheless, a partial response (PR), stable disease (SD) an d progressive disease (PD) were observed i...
Source: Investigational New Drugs - October 20, 2019 Category: Drugs & Pharmacology Source Type: research

Impact of l -carnitine on imatinib-related muscle cramps in patients with gastrointestinal stromal tumor
This study aims to assess the impact ofl-carnitine on relieving cramps in patients with GIST taking imatinib.Materials and methods We reviewed our prospective database for patients with GIST who tookl-carnitine (500-mg tablet, 2 –3 times daily) for muscle cramps in Asan Medical Center. The assessment tool included severity by the numeric rating scale (NRS), frequency, duration of cramps, and questionnaire for the disturbance in basic activities of daily living (ADL), instrumental ADL (iADL), outdoor activity, or sleeping before and afterl-carnitine treatment.Results We examined 42 patients [median age: 60 (range: 17 ...
Source: Investigational New Drugs - October 17, 2019 Category: Drugs & Pharmacology Source Type: research

Discovery and evaluation of Atopaxar hydrobromide, a novel JAK1 and JAK2 inhibitor, selectively induces apoptosis of cancer cells with constitutively activated STAT3
In conclusion, AHB is a potential inhibitor that could be developed as a JAK-STAT pathway drug. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 13, 2019 Category: Drugs & Pharmacology Source Type: research

Mass balance and metabolite profiling of 14 C-guadecitabine in patients with advanced cancer
Conclusion The metabolic and excretory pathways of guadecitabine and its metabolites were successfully characterized after subcutaneous guadecitabine administration in cancer patients. These data support the clinical evaluation of safety and efficacy of the subcutaneous guadecitabine drug product. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 10, 2019 Category: Drugs & Pharmacology Source Type: research

The novel PI3K inhibitor S1 synergizes with sorafenib in non-small cell lung cancer cells involving the Akt-S6 signaling
SummaryNon-small cell lung cancer (NSCLC) has been the major cause of cancer-related deaths worldwide. Targeted therapy has been available as an additive strategy for NSCLC patients, but the inevitable resistance to mono-targeted agents has largely hampered its usage in the clinic. We have previously designed and synthesized a novel small molecule compound S1, 2-methoxy-3-phenylsulfonamino-5-(quinazolin-6-yl) benzamides and demonstrated its inhibition of PI3K and mTOR as well as the anti-tumor potential. In the present study, we have identified that S1 alone or combined with the multi-kinase inhibitor sorafenib can inhibit...
Source: Investigational New Drugs - September 10, 2019 Category: Drugs & Pharmacology Source Type: research

A mediator of phosphorylated Smad2/3, evodiamine, in the reversion of TAF-induced EMT in normal colonic epithelial cells
Conclusion Based on our observations, evodiamine can reverse the TAF-induced EMT-like phenotype in colon epithelial cells, which may be associated with its mediation of phosphorylated Smad2 and Smad3 expression. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 10, 2019 Category: Drugs & Pharmacology Source Type: research

The drug lag and associated factors for orphan anticancer drugs in Japan compared to the United States
SummaryThe approval of orphan anticancer drugs in Japan has increased to meet high social demand. Drug lag, namely the approval lag of new drugs, is recognized as a social issue in Japan. We investigated the approval lag and its components, submission lag and review-time lag, between Japan and the United States (US) to reveal whether an approval lag still exists, and to identify potential factors that may contribute to reducing the approval lag. Anticancer drugs approved in Japan between April 2004 and November 2017 were investigated using publicly available information. Results showed that the median approval lag of orpha...
Source: Investigational New Drugs - September 10, 2019 Category: Drugs & Pharmacology Source Type: research

A new series of acetohydroxamates shows in vitro and in vivo anticancer activity against melanoma
SummaryCancer treatment is challenging, mainly due to high levels of drug toxicity and the resistance of tumours to chemotherapy. Hydroxamic acid derivatives have recently aroused attention due to their potential to treat malignancies. In the present study, we sought to investigate the anticancer effects of a new series of synthetic acetohydroxamates. The in vitro cytotoxic and antiproliferative effects of 11 synthetic acetohydroxamates were evaluated against the melanoma cell line A375. Apoptosis, cell cycle, and autophagy assays were employed to elucidate the cell death pathways induced by the compounds. The in vivo phar...
Source: Investigational New Drugs - September 5, 2019 Category: Drugs & Pharmacology Source Type: research

Osimertinib in a patient with non-small cell lung cancer and renal failure undergoing hemodialysis: a case report
SummaryOsimertinib is a key drug for cancer patients withEGFR mutations. However, there is little information about its safety in cancer patients who require hemodialysis (HD) for chronic renal failure, despite notable increases in their numbers. Herein, we examined osimertinib safety in such a patient via pharmacokinetics analysis. A 66-year-old man was diagnosed with relapsed stage IV non-small cell lung cancer with anEGFR mutation in exon 21 (L858R) 2  years after stereotactic body radiotherapy. He was undergoing HD three times a week owing to worsening diabetic nephropathy. We administered osimertinib (80 mg/...
Source: Investigational New Drugs - September 4, 2019 Category: Drugs & Pharmacology Source Type: research

Radiosensitizing effects of trabectedin on human A549 lung cancer cells and HT-29 colon cancer cells
Conclusion The results of this study underline the antitumor activity of trabectedin at low nanomolar concentrations. We demonstrated that trabectedin enhanced radiation response in human lung (A549) cancer cells and colon (HT-29) cancer cells. Further studies are necessary to examine trabectedin as a potential candidate for future applications in radiotherapy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 2, 2019 Category: Drugs & Pharmacology Source Type: research

A Phase 1 study of BAL101553, a novel tumor checkpoint controller targeting microtubules, administered as 48-h infusion in adult patients with advanced solid tumors
Conclusions Continuous 48-h IV BAL101553 infusion achieved higher exposure of the BAL27862 active metabolite than a 2-h infusion at the RP2D and did not cause vascular toxicity. Clinicaltrials.gov registration: NCT02895360. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 29, 2019 Category: Drugs & Pharmacology Source Type: research

The tumor suppressor NDRG2 cooperates with an mTORC1 inhibitor to suppress the Warburg effect in renal cell carcinoma
In this study, we found that the mTORC1 pathway was hyperactive in RCC. Immunohistochemistry and western blot analysis showed that phosphorylation of the mTORC1 substrate 4EBP1 at threonine 37/46 increased in RCC tissues compared with that in normal renal tissues. It was also found that mTORC1 inhibitor everolimus suppressed glucose consumption, lactate production, and multiple catalytic enzymes involved in glycolysis in 786-O and ACHN cells, but the accumulation of HIF1 α induced by CoCl2 blocked the inhibitory effect of everolimus on aerobic glycolysis. Interestingly, western blot and metabolite analysis showed tha...
Source: Investigational New Drugs - August 27, 2019 Category: Drugs & Pharmacology Source Type: research

Effects of salinomycin and niclosamide on small cell lung cancer and small cell lung cancer circulating tumor cell lines
In conclusion, the SCLC CTCs established from patients with relapsed disease lack a typical CSC phenotype in respect to chemosensitivity to CSC-selective drugs, surface markers, expression of pluripotent stem cell and transcription factors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 23, 2019 Category: Drugs & Pharmacology Source Type: research

Stathmin 1 is highly expressed and associated with survival outcome in malignant adrenocortical tumours
Adrenocortical carcinoma (ACC) is an aggressive endocrine cancer with few molecular predictors of malignancy and survival, especially in paediatric patients. Stathmin 1 (STMN1) regulates microtubule dynamics and has been involved in the malignant phenotype of cancer cells. Recently, it was reported that STMN1 is highly expressed in ACC patients, and STMN1 silencing reduces the clonogenicity and migration of ACC cell lines. However, the prognostic significance of STMN1 and its therapeutic potential remain undefined in ACC. In the present study,STMN1 mRNA levels were significantly higher (p 
Source: Investigational New Drugs - August 21, 2019 Category: Drugs & Pharmacology Source Type: research

Benzothiazole derivative bearing amide moiety induces p53-mediated apoptosis in HPV16 positive cervical cancer cells
SummaryIn our previous study, we screened the anti-cancer properties of 10 benzothiazole derivatives in cervical cancer cell lines. In the present study, we aimed to delineate the mechanism of the apoptotic pathway (whether intrinsic or extrinsic) following the treatment of N-(4-(benzo[d]thiazol-2-yl)phenyl)-5-chloro-2-methoxybenzamide (named as A-07) on cervical cancer cell lines. Cellular stress by reactive oxygen species was measured using DCFDA dye by flowcytometry. Protein expression and localization was checked by immunofluorescence for γH2A.X, TP53, and CASP-3. Expression profiles of BAX and BCL-2 was done by ...
Source: Investigational New Drugs - August 19, 2019 Category: Drugs & Pharmacology Source Type: research

Prospective, randomized, cross-over pilot study of the effects of Rikkunshito, a Japanese traditional herbal medicine, on anorexia and plasma-acylated ghrelin levels in lung cancer patients undergoing cisplatin-based chemotherapy
SummaryPurpose Anorexia induced by cytotoxic chemotherapy on delayed phase is a highly frequent adverse event. We aimed to determine the effects of rikkunshito (RKT) on chemotherapy-induced anorexia (CIA) in patients with lung cancer.Methods This prospective, randomized, cross-over pilot trial included 40 lung cancer patients scheduled to undergo cisplatin-based chemotherapy and randomized to either a group given RKT 7.5  g/day for 14 days (Group A,N = 20) or not (Group B,N = 20), then the treatments were switched. All patients received dexamethasone, palonosetron hydrochloride and apr...
Source: Investigational New Drugs - August 18, 2019 Category: Drugs & Pharmacology Source Type: research

A phase I study of enfortumab vedotin in Japanese patients with locally advanced or metastatic urothelial carcinoma
SummaryLocally advanced or metastatic urothelial cancer is an aggressive form of cancer with high recurrence rates and low survival. Nectin-4 is a cell adhesion molecule commonly expressed in several tumors, including high expression in urothelial cancer. Enfortumab vedotin is an antibody –drug conjugate composed of an anti-Nectin-4 humanized monoclonal antibody linked to the microtubule disrupting agent, monomethyl auristatin E. In this phase I study (NCT03070990), Japanese patients with locally advanced/metastatic urothelial cancer treated with prior chemotherapy, or ineligible f or cisplatin, were randomized 1:1 t...
Source: Investigational New Drugs - August 13, 2019 Category: Drugs & Pharmacology Source Type: research