A phase 1 study of PARP-inhibitor ABT-767 in advanced solid tumors with BRCA1/2 mutations and high-grade serous ovarian, fallopian tube, or primary peritoneal cancer
Conclusions ABT-767 had an acceptable safety profile up to the established RP2D of 400  mg BID and dose-proportional PK. Patients withBRCA1 or BRCA2 mutation, HRD positivity, and platinum sensitivity were more sensitive to ABT-767. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 8, 2018 Category: Drugs & Pharmacology Source Type: research

The in vitro assessment of dipyridophenazine complexes in H-ras oncogene transformed rat embryo fibroblast 5RP7 cell line
Conclusions These findings show that dpzz and its complexes can be studied as novel alternative chemotherapeutics in cancer treatment. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 8, 2018 Category: Drugs & Pharmacology Source Type: research

Repurposing of the CDK inhibitor PHA-767491 as a NRF2 inhibitor drug candidate for cancer therapy via redox modulation
SummaryOxidative stress and cellular response mechanisms such as NRF2-mediated antioxidant responses play differential roles in healthy and diseased cells. Constant generation and elimination of high levels of reactive oxygen species is a hallmark of many cancer cell types; this phenomenon is not observed during steady state of healthy cells. Manipulation of NRF2 transcriptional activity and the cellular redox homeostasis therefore has potential to be therapeutically exploitable for cancer therapy by preferentially targeting cancer cells for induction of oxidative stress. We found that the NRF2 inhibitor brusatol triggered...
Source: Investigational New Drugs - January 3, 2018 Category: Drugs & Pharmacology Source Type: research

A phase IIa study of HA-irinotecan, formulation of hyaluronic acid and irinotecan targeting CD44 in extensive-stage small cell lung cancer
SummaryPreclinical studies in small cell lung cancer (SCLC) have shown that hyaluronic acid (HA) can be effectively used to deliver chemotherapy and selectively decrease CD44 expressing (stem cell-like) tumour cells. The current study aimed to replicate these findings and obtain data on safety and activity of HA-irinotecan (HA-IR). Eligible patients with extensive stage SCLC were consented. A safety cohort (n = 5) was treated with HA-IR and Carboplatin (C). Subsequently, the patients were randomised 1:1 to receive experimental (HA-IR + C) or standard (IR + C) treatment, to a maximu...
Source: Investigational New Drugs - December 26, 2017 Category: Drugs & Pharmacology Source Type: research

Development of a dietary formulation of the SHetA2 chemoprevention drug for mice
SummaryDevelopment of cancer chemoprevention compounds requires enhanced consideration for toxicity and route of administration because the target population is healthy. The small molecule drug, SHetA2 (NSC 726189), exhibited in vivo chemoprevention activity and lack of toxicity when administered by oral gavage. Our objective was to determine if a dietary formulation of SHetA2 could achieve effective tissue drug levels without toxicity. C57bl/6  J mice were monitored on modified American Institute of Nutrition (AIN)76A diet mixed with SHetA2 in a 3:1 ratio with Kolliphor HS15, a self-emulsifying drug delivery system (...
Source: Investigational New Drugs - December 22, 2017 Category: Drugs & Pharmacology Source Type: research

A randomized phase 2 study of a HSP27 targeting antisense, apatorsen with prednisone versus prednisone alone, in patients with metastatic castration resistant prostate cancer
Conclusions Apatorsen  + prednisone did not change the proportion of CRPC patients without disease progression at 12 weeks compared to prednisone but was associated with significant PSA declines. Further evaluation of Hsp27 targeting in prostate cancer is warranted. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 18, 2017 Category: Drugs & Pharmacology Source Type: research

Everolimus induced mood changes in breast cancer patients: a case-control study
SummaryIntroduction The PI3K/Akt/mTOR pathway plays a critical role in cancer cell growth, proliferation and angiogenesis, but also in brain homeostasis and the pathophysiology of mood disorders. The impact of the mTOR inhibitor everolimus on the mood of breast cancer patients is unknown.Materials and methods Consecutive, post-menopausal metastatic breast cancer patients receiving hormone therapy +/ − everolimus were prospectively followed-up using the Beck Depression Inventory (BDI) and the MADRS (Montgomery and Asberg Depression Rating Scale) questionnaires.Results Post hoc tests comparing everolimus  +&thin...
Source: Investigational New Drugs - December 18, 2017 Category: Drugs & Pharmacology Source Type: research

Comparison of published and unpublished phase I clinical cancer trials: an analysis of the CliniclTrials.gov database
SummaryIntroduction The role of phase I cancer trials is constantly evolving and they are increasingly being used in ‘go/no’ decisions in drug development. As a result, there is a growing need to ensure trials are published when completed. There are limited data on the publication rate and the factors associated with publication in phase I trials.Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching publications published prior to April 1, 2017. Logistic regression was used to identify factors associated with unpubl...
Source: Investigational New Drugs - December 13, 2017 Category: Drugs & Pharmacology Source Type: research

Phase 1 and pharmacokinetic study of LY3007113, a p38 MAPK inhibitor, in patients with advanced cancer
Conclusions The recommended phase 2 dosage of LY3007113 was 30  mg Q12H. Three patients continued treatment after the first radiographic assessment, and the BED was not achieved. Further clinical development of this compound is not planned as toxicity precluded achieving a biologically effective dose. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 1, 2017 Category: Drugs & Pharmacology Source Type: research

Prognostic Implication of Inflammation-based Prognostic Scores in Patients with Intrahepatic Cholangiocarcinoma Treated with First-line Gemcitabine plus Cisplatin
Conclusion The current study suggests that mGPS might be the relevant prognostic index that could stratify the survival outcomes of patients with unresectable or metastatic iCCA who received first-line GemCis. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 1, 2017 Category: Drugs & Pharmacology Source Type: research

The sirtuin 1/2 inhibitor tenovin-1 induces a nonlinear apoptosis-inducing factor-dependent cell death in a p53 null Ewing ’s sarcoma cell line
In conclusion, our results provide new insights into tenovin-1’s mode of action by demonstrating that it can induce different pathways of cell death. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 18, 2017 Category: Drugs & Pharmacology Source Type: research

ATP-binding cassette transporters limit the brain penetration of Wee1 inhibitors
Conclusion The brain penetration of these Wee1 inhibitors is severely limited by ABC transporters, which may compromise their clinical efficacy against intracranial neoplasms such as DIPG and GBM. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 17, 2017 Category: Drugs & Pharmacology Source Type: research

LFM-A13, a potent inhibitor of polo-like kinase, inhibits breast carcinogenesis by suppressing proliferation activity and inducing apoptosis in breast tumors of mice
SummaryThe goals of the present study were to define the anticancer activity of LFM-A13 ( α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)-propenamide), a potent inhibitor of Polo-like kinase (PLK), in a mouse mammary cancer model induced by 7,12-dimethylbenz(a)anthracene (DMBA)in vivo and explore its anticancer mechanism(s). We also examined whether the inhibition of PLK by LFM-A13 would improve the efficiency of paclitaxel in breast cancer growthin vivo. To do this, female BALB/c mice received 1  mg of DMBA once a week for 6 weeks with oral gavage. LFM-A13 (50 mg/kg body weight) was adminis...
Source: Investigational New Drugs - November 15, 2017 Category: Drugs & Pharmacology Source Type: research

Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer
SummaryBackground Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC).Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25  mg/m2 on days 1 and 8 and cisplatin 30  mg/m2 on days 2 to 4) for up to six cycle...
Source: Investigational New Drugs - November 14, 2017 Category: Drugs & Pharmacology Source Type: research

A phase 2 study of ontuxizumab, a monoclonal antibody targeting endosialin, in metastatic melanoma
Conclusions Ontuxizumab at both doses was well tolerated. The 24-week PFS value was 11.4% among all ontuxizumab-treated patients. The overall response rate was 3.1% at the 4  mg/kg dose, with clinical benefit achieved in 42.4% of response evaluable patients. Efficacy of single-agent ontuxizumab at these doses in melanoma was low. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 11, 2017 Category: Drugs & Pharmacology Source Type: research

4EGI-1 represses cap-dependent translation and regulates genome-wide translation in malignant pleural mesothelioma
SummaryDeregulation of cap-dependent translation has been implicated in the malignant transformation of numerous human tissues. 4EGI-1, a novel small-molecule inhibitor of cap-dependent translation, disrupts formation of the eukaryotic initiation factor 4F (eIF4F) complex. The effects of 4EGI-1-mediated inhibition of translation initiation in malignant pleural mesothelioma (MPM) were examined. 4EGI-1 preferentially inhibited cell viability and induced apoptosis in MPM cells compared to normal mesothelial (LP9) cells. This effect was associated with hypophosphorylation of 4E –binding protein 1 (4E–BP1) and decre...
Source: Investigational New Drugs - November 8, 2017 Category: Drugs & Pharmacology Source Type: research

Contribution of reactive oxygen species to the anticancer activity of aminoalkanol derivatives of xanthone
In this study, we investigated the role of ROS in the anticancer mechanism of new aminoalkanol derivatives of xanthone. Most xanthones used in the study displayed significant pro-oxidant effects similar to those of gambogic acid, one of the most active anticancer xanthones. The pro-oxidant activity of our xanthones was shown both directly (by determination of ROS induction, effects on the levels of intracellular antioxidants, and expression of antioxidant enzymes) and indirectly by demonstrating that the overexpression of manganese superoxide dismutase decreases ROS-mediated cell senescence. We also observed that mitochond...
Source: Investigational New Drugs - November 8, 2017 Category: Drugs & Pharmacology Source Type: research

Cyclodextrin polymers as nanocarriers for sorafenib
SummaryPolymeric nanoparticles based on cyclodextrins are currently undergoing clinical trials as new promising nanotherapeutics. In light of this interest, we investigated cyclodextrin cross-linked polymers with different lengths as carriers for the poorly water-soluble drug sorafenib. Both polymers significantly enhanced sorafenib solubility, with shorter polymers showing the most effective solubilizing effect. Inclusion complexes between sorafenib and the investigated polymers exhibited an antiproliferative effect in tumor cells similar to that of free sorafenib. Polymer/Sorafenib complexes also showed lower in vivo tis...
Source: Investigational New Drugs - November 8, 2017 Category: Drugs & Pharmacology Source Type: research

Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma
Conclusions GNP can be safely given to chemotherapy na ïve PDAC patients. Efficacy appears to be slightly improved over previously reported results for standard weekly × 3 every 28 day gemcitabine and nab-paclitaxel dosing. CNI change may be prognostic for OS. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 8, 2017 Category: Drugs & Pharmacology Source Type: research

Combination treatment with docetaxel and histone deacetylase inhibitors downregulates androgen receptor signaling in castration-resistant prostate cancer
Conclusions The results suggested that docetaxel, in combination with HDACIs, suppressed the expression and nuclear translocation of AR-FL and AR-Vs and showed synergistic anti-proliferative effect in CRPC cells. This combination therapy may be useful for the treatment of patients with CRPC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 7, 2017 Category: Drugs & Pharmacology Source Type: research

Phase1 study of cisplatin plus pemetrexed with erlotinib and bevacizumab for chemotherapy-na ïve advanced non-squamous non-small cell lung cancer with EGFR mutations
Conclusions This quartet chemotherapy regimen was tolerable and effective in our patient population (UMIN000012536). (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 4, 2017 Category: Drugs & Pharmacology Source Type: research

Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors
Conclusion This daily subcutaneous regimen of bortezomib showed a dose dependent plasma exposure, evidence of target inhibition and preliminary signs of clinical activity. However, cumulative neurological toxicity of this dose-dense daily regimen might preclude its further clinical development. (Source: Investigational New Drugs)
Source: Investigational New Drugs - November 2, 2017 Category: Drugs & Pharmacology Source Type: research

Systematic analysis reveals a lncRNA-mRNA co-expression network associated with platinum resistance in high-grade serous ovarian cancer
SummaryResistance to platinum-based chemotherapy is the major barrier to treating high-grade serous ovarian cancer (HGS-OvCa). To improve HGS-OvCa patient prognosis, it is critical to identify the underlying mechanisms that promote platinum resistance. The goal of the present study was to identify a lncRNA-mRNA co-expression network and key lncRNAs that predict resistance to platinum-based chemotherapy in ovarian cancer patients. By systematically analyzing the expression profiles of lncRNAs and mRNAs in HGS-OvCa samples from the Cancer Genome Atlas (TCGA), we revealed that lncRNAs play important roles in platinum resistan...
Source: Investigational New Drugs - October 30, 2017 Category: Drugs & Pharmacology Source Type: research

Ganoderic acid, lanostanoid triterpene: a key player in apoptosis
SummaryCancer is a multifactorial disease, causing behavioral and metabolic alterations, leading to uncontrolled cell proliferation with collateral weakening of immune system. Crucial balance between cell proliferation and cell death determines the fate of a cell, which might progress towards survival or apoptosis. Apoptosis is a complex, programmed, and highly regulated process causing dramatic morphological and biochemical perturbations in the cellular machinery.Ganoderma lucidum is a basidiomycetes, polypore mushroom known for its pharmacological properties in cancer. The major bioconstituents inG. lucidum are terpenoid...
Source: Investigational New Drugs - October 28, 2017 Category: Drugs & Pharmacology Source Type: research

Combined treatment with pemetrexed and vinflunine in patients with metastatic urothelial cell carcinoma after prior platinum-containing chemotherapy – results of an exploratory phase I study
SummaryVinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 2...
Source: Investigational New Drugs - October 28, 2017 Category: Drugs & Pharmacology Source Type: research

Radiomics to predict immunotherapy-induced pneumonitis: proof of concept
This study suggests that radiomic features can classify and predict those patients at baseline who will subsequently develop immunotherapy-induced pneumonitis, further enabling risk-stratification that will ultimately lead to better treatment outcomes. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 27, 2017 Category: Drugs & Pharmacology Source Type: research

Posterior reversible encephalopathy syndrome (PRES) induced by pazopanib, a multi-targeting tyrosine kinase inhibitor, in a patient with soft-tissue sarcoma: case report and review of the literature
We describe a case of a 49-year-old woman with retroperitoneal soft-tissue sarcoma who developed PRES during pazopanib administration. Pazopanib at 800  mg/day was administered as her third-line treatment at relapse. After 38 days of pazopanib, she was admitted to our hospital with severe headache, vomiting, and systemic hypertension. The next day, she developed consciousness deterioration and visual disturbance together with exacerbated systemic hypertension. Brain MR images revealed hyper-intense signals on FLAIR sequences in the bilateral occipital lobes and the left thalamus. Intravenous nicardipine injection...
Source: Investigational New Drugs - October 25, 2017 Category: Drugs & Pharmacology Source Type: research

Phase I study of the combination of crizotinib (as a MET inhibitor) and dasatinib (as a c-SRC inhibitor) in patients with advanced cancer
Conclusions The combination of crizotinib and dasatinib is safe to administer but tolerability is limited given the high rate of adverse events. Responses and durable stable disease were limited. Further precision therapy approach using this specific combination may be difficult given the toxicity. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 19, 2017 Category: Drugs & Pharmacology Source Type: research

Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads
Conclusions Published ADC clinical data is limited by non-uniform reporting for toxicity and lack of dosing information, limiting the ability to develop quantitative models relating toxicity to exposure. However, the current analysis suggests that key G3/4 toxicities of ADCs in the clinic are likely off-target and related to payload. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 13, 2017 Category: Drugs & Pharmacology Source Type: research

Gastrointestinal perforation related to lenvatinib, an anti-angiogenic inhibitor that targets multiple receptor tyrosine kinases, in a patient with metastatic thyroid cancer
SummaryLenvatinib, a novel potent multikinase inhibitor, was approved for the treatment of radioiodine-refractory differentiated thyroid cancer based on results from phase III trial (SELECT study). Thyroid cancer is a diverse disease that includes anaplastic thyroid cancer (ATC), which the most aggressive form of the disease, although it accounts for
Source: Investigational New Drugs - October 11, 2017 Category: Drugs & Pharmacology Source Type: research

Dual Src and EGFR inhibition in combination with gemcitabine in advanced pancreatic cancer: phase I results
SummaryPancreatic adenocarcinoma remains a major therapeutic challenge, as the poor (
Source: Investigational New Drugs - October 9, 2017 Category: Drugs & Pharmacology Source Type: research

Hersintuzumab: A novel humanized anti-HER2 monoclonal antibody induces potent tumor growth inhibition
SummaryHumanized monoclonal antibodies (mAbs) against HER2 including trastuzumab and pertuzumab are widely used to treat HER2 overexpressing metastatic breast cancers. These two mAbs recognize distinct epitopes on HER2 and their combination induces a more potent blockade of HER2 signaling than trastuzumab alone. Recently, we have reported characterization of a new chimeric mAb (c-1T0) which binds to an epitope different from that recognized by trastuzumab and significantly inhibits proliferation of HER2 overexpressing tumor cells. Here, we describe humanization of this mAb by grafting all six complementarity determining re...
Source: Investigational New Drugs - October 6, 2017 Category: Drugs & Pharmacology Source Type: research

Phase I study of the combination of quinacrine and erlotinib in patients with locally advanced or metastatic non small cell lung cancer
Conclusion Combination of quinacrine and erlotinib was well tolerated but showed limited efficacy in advanced NSCLC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 2, 2017 Category: Drugs & Pharmacology Source Type: research

Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors
Conclusions Erdafitinib was well tolerated in Japanese patients with advanced or refractory solid tumors.Trial Registration: NCT01962532. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 30, 2017 Category: Drugs & Pharmacology Source Type: research

The kinesin Eg5 inhibitor K858 induces apoptosis and reverses the malignant invasive phenotype in human glioblastoma cells
SummaryGlioblastoma multiforme is the most common primary malignant brain tumor and its current chemotherapeutic options are limited to temozolomide. Recently, some synthetic compounds acting as inhibitors of kinesin spindle protein Eg5 have shown pronounced antitumor activity. Our group has recently demonstrated that one of these kinesin Eg5 inhibitors, named K858, exerted important antiproliferative and apoptotic effects on breast cancer cells. Since glioblastoma cells usually express high levels of kinesin Eg5, we tested the effect of K858 on two human glioblastoma cell lines (U-251 and U-87) and found that K858 inhibit...
Source: Investigational New Drugs - September 30, 2017 Category: Drugs & Pharmacology Source Type: research

Association of Glutathione S-Transferase P-1 (GSTP-1) rs1695 polymorphism with overall survival in glioblastoma patients treated with combined radio-chemotherapy
SummaryGlioblastoma (GBM) is the most frequent malignant primary brain tumor in adults and, despite recent advances, the prognosis for this cancer remains dismal. The aims of this study were to test the influence ofXRCC1 rs25487,XRCC3 rs861539, XRCC3 rs1799794,RAD51 rs1801320 andGSTP-1 rs1695 single nucleotide polymorphisms on progression free survival (PFS) and overall survival (OS) in GBM patients treated with radiotherapy (RT) and temozolomide (TMZ). Fifty GBM patients treated with upfront radio-chemotherapy (RT 60  Gy/30 sessions; TMZ 75 mg/m2 during RT and 200  mg/m2 days 1 → 5 every...
Source: Investigational New Drugs - September 30, 2017 Category: Drugs & Pharmacology Source Type: research

Treatment-related serious adverse events and fatal adverse events with regorafenib in cancer patients: a meta-analysis of phase 3 randomized controlled trials
SummaryRegorafenib (Stivarga) is an oral small-molecule multikinase inhibitor commonly used against a variety of cancers. We performed a meta-analysis of all phase 3 randomized controlled trials (RCTs) of regorafenib to quantify the increased risk of SAEs and FAEs. We carried out a systematic search of electronic databases for studies published from inception to February 2017 without any restrictions. Eligibility criteria included phase 3 RCTs of tumors comparing regorafenib, alone or in combination with non-targeted chemotherapy (regorafenib arm) versus placebo or non-targeted chemotherapy (control arm). Data on SAEs and ...
Source: Investigational New Drugs - September 22, 2017 Category: Drugs & Pharmacology Source Type: research

Metformin as a repurposed therapy in advanced non-small cell lung cancer (NSCLC): results of a phase II trial
Conclusion Adding metformin to chemotherapy for advanced NSCLC was safe but did not significantly improve clinical outcomes compared to historical phase III controls. These results are limited by the small sample size; larger trials are needed. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 22, 2017 Category: Drugs & Pharmacology Source Type: research

A phase I study to assess the mass balance, excretion, and pharmacokinetics of [ 14 C]-ixazomib, an oral proteasome inhibitor, in patients with advanced solid tumors
SummaryThis two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1  mg oral solution dose of [14C]-ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled ixazomib (4  mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to asses...
Source: Investigational New Drugs - September 21, 2017 Category: Drugs & Pharmacology Source Type: research

Mechanisms of cancer cell killing by sea cucumber-derived compounds
SummaryThe aim of cancer therapy is to specifically eradicate tumor cells while causing minimal damage to normal tissues and minimal side-effects. Because of this, the use of natural substances with low toxicity is a good option. Sea cucumbers are one of many potential marine animals that contain valuable nutrients and medicinal properties. The medicinal value of sea cucumbers is attributed to the presence of bioactive agents with promising biological and pharmacological properties that include cytotoxic activity, induction of apoptosis, cell cycle arrest, inhibition of tumor growth, anti-metastatic and anti-angiogenic pro...
Source: Investigational New Drugs - September 18, 2017 Category: Drugs & Pharmacology Source Type: research

Novel inhibitors of lysine (K)-specific Demethylase 4A with anticancer activity
SummaryLysine (K)-specific demethylase 4A (KDM4A) is a histone demethylase that removes methyl residues from trimethylated or dimethylated histone 3 at lysines 9 and 36. Overexpression of KDM4A is found in various cancer types. To identify KDM4A inhibitors with anti-tumor functions, screening with an in vitro KDM4A enzyme activity assay was carried out. The benzylidenehydrazine analogue LDD2269 was selected, with an IC50 of 6.56  μM of KDM4A enzyme inhibition, and the binding mode was investigated using in silico molecular docking. Demethylation inhibition by LDD2269 was confirmed with a cell-based assay using anti...
Source: Investigational New Drugs - September 14, 2017 Category: Drugs & Pharmacology Source Type: research

Comparison of reporting phase I trial results in ClinicalTrials.gov and matched publications
SummaryBackground Data on completeness of reporting of phase I cancer clinical trials in publications are lacking.Methods TheClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching primary publications published prior to November 1, 2016. Reporting in primary publications was compared with theClinicalTrials.gov database using a 28-point score (2=complete; 1=partial; 0=no reporting) for 14 items related to study design, outcome measures and safety profile. Inconsistencies between primary publications andClinicalTrials.gov were recorded. Linea...
Source: Investigational New Drugs - September 14, 2017 Category: Drugs & Pharmacology Source Type: research

Characteristics of patients with sorafenib-treated advanced hepatocellular carcinoma eligible for second-line treatment
Conclusion Regorafenib candidate patients after sorafenib failure are limited, and generally fewer than those who are candidates for second-line treatment. A lower Child –Pugh score and a better ECOG-PS were predictors of eligibility for second-line therapy and regorafenib treatment in sorafenib-treated patients with advanced HCC patients. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 11, 2017 Category: Drugs & Pharmacology Source Type: research

AN-7, a butyric acid prodrug, sensitizes cutaneous T-cell lymphoma cell lines to doxorubicin via inhibition of DNA double strand breaks repair
This study aimed to elucidate the mechanism underlying the effect of AN-7 on Dox-induced double-strand DNA breaks (DSBs) in CTCL, MyLa and Hut78 cell lines. The following markers/assays were employed: comet assay; western blot of γH2AX and p-KAP1; immunofluorescence of γH2AX nuclear foci; Western blot of repair protein; quantification of DSBs-repair through homologous recombination. DSB induction by Dox was evidenced by an increase in DSB markers, and DSBs-repair, by their subsequent decrease. The addition of AN-7 slightly increased Dox induction of DSBs in MyLa cells with no effect in Hut78 cells. AN-7 inhibit...
Source: Investigational New Drugs - September 8, 2017 Category: Drugs & Pharmacology Source Type: research

Safety, tolerability, and pharmacokinetic profile of dabrafenib in Japanese patients with BRAF V600 mutation-positive solid tumors: a phase 1 study
Conclusions Dabrafenib was well tolerated and rapidly absorbed administered as single- or multiple dose. Comparable safety and pharmacokinetic profiles were observed compared with non-Japanese patients. Dabrafenib has promising clinical activity in Japanese patients withBRAF mutated malignant melanoma. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 7, 2017 Category: Drugs & Pharmacology Source Type: research

Crucial microRNAs and genes in metformin ’s anti-pancreatic cancer effect explored by microRNA-mRNA integrated analysis
SummaryDespite great improvements in surgical procedures and chemotherapy, pancreatic cancer remains one of the most aggressive and fatal human malignancies, with a low 5-year survival rate. Therefore, novel therapeutic strategies for the prevention and treatment of pancreatic cancer are urgently needed. The present study aimed to investigate the mechanisms by which metformin exerts its anticancer effects on the microRNA-mRNA interactions in human pancreatic cancer. Microarray and systematic analyses revealed that the anti-pancreatic cancer effects of metformin were correlated with 3 up-regulated microRNAs and 4 of their t...
Source: Investigational New Drugs - September 5, 2017 Category: Drugs & Pharmacology Source Type: research

Phase I dose escalation and pharmacokinetic study on the nanoparticle formulation of polymeric micellar paclitaxel for injection in patients with advanced solid malignancies
Conclusions PM-paclitaxel showed high MTD without additional toxicity, and exhibited desirable antitumor activity. The recommended dose of PM paclitaxel for phase II study is 300  mg/m2. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 4, 2017 Category: Drugs & Pharmacology Source Type: research

Phase II basket trial of perifosine monotherapy for recurrent gynecologic cancer with or without PIK3CA mutations
Conclusions Perifosine monotherapy showed good tolerability but expected efficacy was not achieved. Modest efficacy was demonstrated in ovarian cancer patients withPIK3CA mutations and endometrial cancer patients withPIK3CA wild-type; no difference was observed betweenPIK3CA wild-type and mutant in cervical cancer. Absence of PTEN expression may be predictive of clinical efficacy with perifosine monotherapy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 2, 2017 Category: Drugs & Pharmacology Source Type: research

Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies
Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib. (Source: Investigational New Drugs)
Source: Investigational New Drugs - August 30, 2017 Category: Drugs & Pharmacology Source Type: research

Vinblastine and antihelmintic mebendazole potentiate temozolomide in resistant gliomas
SummaryGlioblastoma (GBM) is a very aggressive tumor that has not had substantial therapeutic improvement since the introduction of temozolomide (TMZ) in combination with radiotherapy. Combining TMZ with other chemotherapeutic agents is a strategy that could be further explored for GBM. To search for molecular predictors of TMZ resistance, the TCGA (The Cancer Genome Atlas) database was utilized to assess the impact of specific genes on TMZ response. Patients whose tumors expressed low levels of FGFR3 and AKT2 responded poorly to TMZ. Combination treatment of vinblastine (VBL) plus mebendazole (MBZ) with TMZ was more effec...
Source: Investigational New Drugs - August 29, 2017 Category: Drugs & Pharmacology Source Type: research