Pharmaceutical good manufacturing practice: Leuplin ® production in Japan identifies major international shortcomings
SummaryIn Japan, the production of Leuplin®, a key drug for the treatment of prostate cancer and breast cancer, was temporarily suspended in 2020 by the manufacturer. The incident illustrated several significant failings, namely the lack of uniformity in international GMP (Good Manufacturing Practice) regulations, the lack of mechanisms to resolve disputes between PIC/S (Pharmaceutical Inspection Co-operation Scheme) member countries, and the importance of maintaining a stable supply of safe GMP-compliant essential medicines. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 9, 2021 Category: Drugs & Pharmacology Source Type: research

Association of XRCC3 rs1799794 polymorphism with survival of glioblastoma multiforme patients treated with combined radio-chemotherapy
This study reports the results of a monocentric prospective analysis conducted with the aim of evaluating the impact of XRCC1rs25487, XRCC3rs861539, XRCC3rs1799794, RAD51rs1801320 and GSTP-1rs1695 single nucleotide polymorphisms (SNP) on patients with high-grade glioma treated with concomitant radio-chemotherapy. From October 2010 to August 2019, a total of 75 patients aged ≥18 years, with histological diagnosis of high-grade glioma, isocitrate dehydrogenase (IDH) 1/2 wild type and treated with radio-chemotherapy and sequential chemotherapy with temozolomide (TMZ) were prospectively recruited. The local ethic commi...
Source: Investigational New Drugs - February 8, 2021 Category: Drugs & Pharmacology Source Type: research

Phase 2 study of bevacizumab plus carboplatin/nab-paclitaxel followed by bevacizumab plus nab ‐paclitaxel for non‐squamous non‐small cell lung cancer with malignant pleural effusion
Conclusion  The combination of Bev plus CBDCA/nab-PTX, a novel combination, might have efficacy with acceptable toxicities in chemotherapy-na ïve non-SQ NSCLC patients with MPE.Trial Registration University Hospital Medical Information Network in Japan (UMIN) Clinical Trials Registry (No. UMIN000013329) registered on 4th March 2014. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 5, 2021 Category: Drugs & Pharmacology Source Type: research

Autophagy promotes oncolysis of an adenovirus expressing apoptin in human bladder cancer models
This study suggests that Ad-VT can induce selective autophagic antitumor activities in bladder cancer through the AMPK-Raptor-mTOR pathway, which can be further improved by rapamycin. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 3, 2021 Category: Drugs & Pharmacology Source Type: research

Hydroxyethylcellulose as a methotrexate carrier in anticancer therapy
In conclusion, cellulose, which is a non-biodegradable chain glucose polymer, can be successfully used as a drug carrier, which opens up new research perspectives. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 1, 2021 Category: Drugs & Pharmacology Source Type: research

Subcellular distribution and mechanism of action of AL906, a novel and potent EGFR inhibitor rationally designed to be green fluorescent
SummaryTo enhance the potency of EGFR inhibitors, we developed a novel  strategy that seeks to conjugate EGFR to a bioactive moiety leading to a molecule termed “combi-molecule”. In order to mimic the penetration of this type of molecules, based upon previously reported structure activity relationship studies, we designed a new molecule containing a quinazoline mo iety tethered to a p-nitrobenzoxadiazole (NBD) moiety [molecular weight (MW) 700]. Despite its size, AL906 growth inhibitory activity was superior to that of the clinical drug gefitinib. Furthermore, AL906 retained significant EGFR inhibitory act...
Source: Investigational New Drugs - February 1, 2021 Category: Drugs & Pharmacology Source Type: research

Anti-transcriptional intermediary factor 1- γ antibody-positive dermatomyositis induced by nivolumab for lung adenocarcinoma: A case report
In conclusion, our case demonstrates that the development of dermatomyositis was causally related to immune activation by nivolumab. Given the potential exacerbation of autoimmune paraneoplastic disorders in cancer patients receiving immunotherapy, clinicians should be aware of early manifestations of systemic irAEs that require prompt diagnosis and intervention. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 1, 2021 Category: Drugs & Pharmacology Source Type: research

Acute tubulointerstitial nephritis induced by the tyrosine kinase inhibitor vandetanib
We describe the first report case associated with vandetanib, a tyrosine kinase inhibitor indicated for the treatment of aggressive and symptomatic medullary thyroid cancer (CMT) in patients with locally advanced or metastatic non-resectable disease. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 1, 2021 Category: Drugs & Pharmacology Source Type: research

Correction to: Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma
The article Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 1, 2021 Category: Drugs & Pharmacology Source Type: research

RETRACTED ARTICLE: A novel small-molecule inhibitor suppresses colon cancer metastasis through inhibition of metastasis-associated in colon cancer-1 transcription
(Source: Investigational New Drugs)
Source: Investigational New Drugs - February 1, 2021 Category: Drugs & Pharmacology Source Type: research

A phase 1b trial of the CXCR4 inhibitor mavorixafor and nivolumab in advanced renal cell carcinoma patients with no prior response to nivolumab monotherapy
Conclusions The CXCR4 inhibition mediated by mavorixafor, in combination with PD-1 blockade to enhance antitumor immune responses in patients unresponsive to checkpoint inhibitor monotherapy, is worthy of further study. Mavorixafor and nivolumab combination therapy in patients with advanced ccRCC demonstrated potential antitumor activity and a manageable safety profile.Trial registration: ClinicalTrials.gov identifier: NCT02923531. Date of registration: October 04, 2016. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 28, 2021 Category: Drugs & Pharmacology Source Type: research

Effects of rifampicin on the pharmacokinetics of alflutinib, a selective third-generation EGFR kinase inhibitor, and its metabolite AST5902 in healthy volunteers
Conclusions As a strong CYP3A4 inducer, rifampicin exerted significant effects on the pharmacokinetics of alflutinib and the total active ingredients (alflutinib and AST5902). The results suggested that concomitant strong CYP3A4 inducers should be avoided during alflutinib treatment. This trial was registered athttp://www.chinadrugtrials.org.cn. The registration No. is CTR20191562, and the date of registration is 2019-09-12. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 27, 2021 Category: Drugs & Pharmacology Source Type: research

System Xc − : a key regulatory target of ferroptosis in cancer
SummaryFerroptosis is a type of oxidative stress-dependent regulated necrosis characterized by excessive lipid peroxide accumulation. This novel cell death modality has been implicated in preventing cancer progression. Cancer cells tend to modulate their redox state to prevent excessive peroxidation, eventually facilitating tumor growth. System Xc− (a cystine/glutamate antiporter system) is a promising target in cancer cells for ferroptosis induction. The overexpression of system Xc−, especially its core subunit xCT, has been reported in several tumors, and these high expression levels were closely related to c...
Source: Investigational New Drugs - January 27, 2021 Category: Drugs & Pharmacology Source Type: research

Screening and identification of potential biomarkers and therapeutic drugs in melanoma via integrated bioinformatics analysis
In this study, a comprehensive bioinformatics analysis was used to clarify the hub genes and potential drugs. Download the GSE3189, GSE22301, and GSE35388 microarray datasets from the Gene Expression Omnibus (GEO), which contains a total of 33 normal samples and 67 melanoma samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) approach analyze DEGs based on the DAVID. Use STRING to construct protein-protein interaction network, and use MCODE and cytoHubba plug-ins in Cytoscape to perform module analysis and identified hub genes. Use Gene Expression Profile Interactive Analysis (GEPIA) to assess the...
Source: Investigational New Drugs - January 26, 2021 Category: Drugs & Pharmacology Source Type: research

A novel ligand of the translationally controlled tumor protein (TCTP) identified by virtual drug screening for cancer differentiation therapy
Discussion ZINC10157406 was identified as potent ligand of TCTP byin silico andin vitro methods. The compound bound to TCTP with a considerably higher affinity compared to artesunate as known TCTP inhibitor. We were able to demonstrate the effect of TCTP blockade at the p53 binding site, i.e. expression of TCTP decreased, whereas p53 expression increased. This effect was accompanied by a dose-dependent decrease of CDK2, CDK4, CDK, cyclin D1 and cyclin D3 causing a G0/G1 cell cycle arrest in MOLT-4, SK-OV-3 and MCF-7 cells. Our findings are supposed to stimulate further research on TCTP-specific small molecules for differen...
Source: Investigational New Drugs - January 25, 2021 Category: Drugs & Pharmacology Source Type: research

Acknowledgement of Reviewers 2020
(Source: Investigational New Drugs)
Source: Investigational New Drugs - January 25, 2021 Category: Drugs & Pharmacology Source Type: research

Comparative incidence of immune-related adverse events and hyperprogressive disease in patients with non-small cell lung cancer receiving immune checkpoint inhibitors with and without chemotherapy
AbstractImmune-related adverse events (irAEs) and hyperprogressive disease (HPD) are serious problems arising in the early period of monotherapy (MT) with programmed cell death protein 1 (PD-1) and programmed cell death ligand1 (PD-L1) inhibitors. However, the frequency and clinical features of these problems in patients receiving combination therapy (CT) with cytotoxic chemotherapy in addition to these agents remain unclear. We retrospectively screened patients with pathologically confirmed advanced or recurrent non-small cell lung cancer (NSCLC) who had received PD-1/PD-L1 inhibitors at Kurume University Hospital between...
Source: Investigational New Drugs - January 22, 2021 Category: Drugs & Pharmacology Source Type: research

Aurora kinase A inhibitor, LY3295668 erbumine: a phase 1 monotherapy safety study in patients with locally advanced or metastatic solid tumors
Conclusions MTD of LY3295668 was 25 mg BID. LY3295668 had a manageable toxicity profile and demonstrated activity in some patients with locally advanced or metastatic solid tumors.Trial registration ClinicalTrials.gov, NCT03092934. Registered March 22, 2017.https://clinicaltrials.gov/ct2/show/NCT03092934. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 22, 2021 Category: Drugs & Pharmacology Source Type: research

AD80, a multikinase inhibitor, exhibits antineoplastic effects in acute leukemia cellular models targeting the PI3K/STMN1 axis
This study identified structural GDP366 analogs and the cellular and molecular mechanisms underlying their suppressive effects on acute leukemia cellular models.STMN1 mRNA levels were higher in AML and ALL patients, independent of risk stratification (allp 
Source: Investigational New Drugs - January 21, 2021 Category: Drugs & Pharmacology Source Type: research

Advances in anti-BRAF therapies for lung cancer
SummaryNon-small cell lung cancer (NSCLC) is one of the most frequent causes of mortality in the western world. v-raf murine sarcoma viral oncogene homolog B (BRAF) is a member of the Raf kinase family and plays a critical role in cellular growth, proliferation, and differentiation through the mitogen-activated protein kinase pathway. The incidence of BRAF mutations in NSCLC is low, accounting for 0 –3% of all cases of lung cancer. Given the results obtained in metastatic melanoma, several studies have reported the efficacy of anti-BRAF therapies in NSCLC treatment. In this review, we describe changes in the landscap...
Source: Investigational New Drugs - January 21, 2021 Category: Drugs & Pharmacology Source Type: research

Downregulation of breast cancer resistance protein by long-term fractionated radiotherapy sensitizes lung adenocarcinoma to SN-38
In conclusion, these results presented important data on the sensitivity changes of lung ad enocarcinoma cells to chemotherapeutic drugs after acquiring radioresistance and suggested that irinotecan (the prodrug of SN-38) might be a promising drug candidate for lung adenocarcinoma patients with acquired radioresistance. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 21, 2021 Category: Drugs & Pharmacology Source Type: research

Toxicokinetics of the tumour cell mitochondrial toxin, PENAO, in rodents
SummaryPENAO (4-(N-(S-penicillaminylacetyl)amino)phenylarsonous acid) is a second-generation peptide arsenical that inactivates mitochondria in proliferating tumour cells by covalently reacting with mitochondrial inner-membrane adenine nucleotide transferase. The toxicokinetics of PENAO has been investigated in Sprague-Dawley rats to inform route of administration and dosing for human clinical trials. PENAO was well tolerated at 3.3  mg/kg daily intravenous injections but associated with significant toxicity at 10 mg/kg, primarily in the males. The major target organ for toxic effects was the kidney, with changes...
Source: Investigational New Drugs - January 19, 2021 Category: Drugs & Pharmacology Source Type: research

Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors
Conclusions: Entrectinib is well absorbed, with linear PK that is suitable for once-daily dosing, and can be taken with or without food. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 18, 2021 Category: Drugs & Pharmacology Source Type: research

Gut microbiota homeostasis restoration may become a novel therapy for breast cancer
SummaryBreast cancer is the most diagnosed cancer in women. It significantly impairs a patient ’s physical and mental health. Gut microbiota comprise the bacteria residing in a host’s gastrointestinal tract. Through studies over the last decade, we now know that alterations in the composition of the gut microbiome are associated with protection against colonization by pathogens and other diseases, such as diabetes and cancer. This review focuses on how gut microbiota can affect breast cancer development through estrogen activity and discusses the types of bacteria that may be involved in the onset and the progr...
Source: Investigational New Drugs - January 17, 2021 Category: Drugs & Pharmacology Source Type: research

Effectiveness of cetuximab as preemptive postsurgical therapy for oral squamous cell carcinoma patients with major risk: a single ‐center retrospective cohort study
SummaryA retrospective cohort study was performed to investigate the effectiveness of preemptive postsurgical therapy with cetuximab for patients with a major risk of recurrence or metastasis after clinical complete resection of primary oral squamous cell carcinoma (OSCC). The study period was from 2007 to 2019 for patients treated at the Department of Oral and Maxillofacial Surgery, Dokkyo Medical University School of Medicine. OSCC patients with major risk (n  = 88) in the follow-up period were divided into groups with no postsurgical treatment (NP group), with standard postsurgical treatment (SP group), an...
Source: Investigational New Drugs - January 15, 2021 Category: Drugs & Pharmacology Source Type: research

Immunotherapy-induced pneumonitis in non-small cell lung cancer patients: current concern in treatment with immune-check-point inhibitors
In this study, we investigated the clinical and CT features of IIP in non-small cell lung cancer (NSCLC) patients treated with ICI.Methods CT images and clinical data of 98 NSCLC patients in our hospital were retrospectively analyzed after ICI therapy, and the incidence, onset time, CT findings, grade, treatment and prognosis of IIP were recorded.Results Nineteen patients developed IIP, which occurred 42 ∼210 days after ICI therapy, and the median time was 97 days. The CT findings for IIP showed multifocal ground-glass opacity (GGO) in 5 cases, patchy shadows in 6 cases, mixed distribution of patchy and strip-like shad...
Source: Investigational New Drugs - January 11, 2021 Category: Drugs & Pharmacology Source Type: research

A rat toxicological study of intra-arterial injection of Tirapazamine, a hypoxia-activating Cancer therapeutic agent, followed by hepatic artery ligation
Conclusion TPZ by IA injection followed by embolization is tolerated up to 7  mg/kg. This finding supports the strategy of administering an IA injection of TPZ followed by trans-arterial embolization to the liver. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 11, 2021 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic effects of proton pump inhibitors on the novel PARP inhibitor fluzoparib: a single-arm, fixed-sequence trial in male healthy volunteers
Conclusions The proton pump inhibitor omeprazole did not have a significant influence on the PK behavior of fluzoparib, and its safety profile was good upon co-administration with omeprazole. (NCT04108676, 30 September 2019) (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 9, 2021 Category: Drugs & Pharmacology Source Type: research

The clinical efficacy and safety of single-agent pembrolizumab in patients with recurrent granulosa cell tumors of the ovary: a case series from a phase II basket trial
Conclusions Although our results do not support the routine use of pembrolizumab monotherapy in unselected GCT patients, some patients with adult-type GCT may derive a clinical benefit, with a low risk of toxicity. Future studies should investigate the role of immunotherapy and predictors of clinical benefit in this patient population. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 7, 2021 Category: Drugs & Pharmacology Source Type: research

Selective targeting of the androgen receptor-DNA binding domain by the novel antiandrogen SBF-1 and inhibition of the growth of prostate cancer cells
SummaryProstate cancers are reliant on androgens for growth and survival. Clinicians and researchers are looking for potent treatments for the resistant forms of prostate cancer; however, a handful of small molecules used in the treatment of castration-resistant prostate cancer have not shown potent effects owing to the mutations in the AR (Androgen Receptor). We used SBF-1, a well-characterized antitumor agent with potent cytotoxic effects against different kinds of cancers and investigated its effect on human prostate cancer. SBF-1 substantially inhibited the proliferation, induced apoptosis, and caused cell cycle arrest...
Source: Investigational New Drugs - January 7, 2021 Category: Drugs & Pharmacology Source Type: research

The flavonoid luteolin suppresses infantile hemangioma by targeting FZD6 in the Wnt pathway
AbstractInfantile hemangioma is the most common vascular tumor of childhood. It is characterized by clinical expansion of endothelial cells and promoted by angiogenic factors. Luteolin is a flavonoid compound that carries anti-cancer and anti-angiogenesis properties. The study aimed to investigate the effect of luteolin in treating infantile hemangioma. We first tested the effect of luteolin on cell proliferative potential and VEGFA expression in hemangioma-derived stem cells (HemSCs). We then examined the efficacy of systemic application of luteolin in a murine hemangioma model. We then identified the downstream factor re...
Source: Investigational New Drugs - January 7, 2021 Category: Drugs & Pharmacology Source Type: research

Efficacy and safety of modified FOLFIRINOX as salvage therapy for patients with refractory advanced biliary tract cancer: a retrospective study
Conclusion Treatment with mFOLFIRINOX has promising efficacy and favorable tolerance as salvage therapy in patients with refractory advanced BCT. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 7, 2021 Category: Drugs & Pharmacology Source Type: research

Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRAS G12R -mutant pancreatic ductal adenocarcinoma
Conclusion This study in heavily pre-treated pancreatic adenocarcinoma patients suggests alternative strategies beyond single agent MEK inhibition are required for this unique, molecular subset of pancreatic cancer patients. The trial was registered on February 2nd, 2017 under identifier NCT03040986 withClinicalTrials.gov. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 6, 2021 Category: Drugs & Pharmacology Source Type: research

The E3 ligase HUWE1 mediates TGFBR2 ubiquitination and promotes gastric cancer cell proliferation, migration, and invasion
This study aimed to investigate whether HUWE1 plays a role in GC development in vitro by mediating transforming growth factor-β receptor 2 (TGFBR2) ubiquitination and degradation. HUWE1 was overexpressed in SGCA-7901 GC cells and silenced in MGC-803 GC cells. Then, GC cell proliferation, migration, and invasion were evaluated by MTT assay and Transwell migration and invasion assay, respectively. The regulatory effect and mechanism of HUWE1 on TGFBR2 expression were assessed by qRT-PCR, western blot, and ubiquitination assay. HUWE1 mR NA and protein levels were higher in human GC tissues than in matched noncancerous ga...
Source: Investigational New Drugs - January 6, 2021 Category: Drugs & Pharmacology Source Type: research

Nephrotoxicity in patients with solid tumors treated with anti-PD-1/PD-L1 monoclonal antibodies: a systematic review and meta-analysis
Conclusions Anti-PD-1/PD-L1 mAbs can significantly increase nephrotoxicity in patients with solid tumors, especially when combined with chemotherapy. During the application of these drugs, we should remain aware of nephrotoxicity for better efficacy.Trial registration number and date of registration Not applicable. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 6, 2021 Category: Drugs & Pharmacology Source Type: research

Phase II study of the histone deacetylase inhibitor vorinostat (Suberoylanilide Hydroxamic Acid; SAHA) in recurrent or metastatic transitional cell carcinoma of the urothelium – an NCI-CTEP sponsored: California Cancer Consortium trial, NCI 6879
Conclusions: Vorinostat on this dose-schedule had limited efficacy and significant toxicity resulting in a unfavorable risk:benefit ratio in patients with mUC. NCT00363883. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 6, 2021 Category: Drugs & Pharmacology Source Type: research

TAS-119, a novel selective Aurora A and TRK inhibitor, exhibits antitumor efficacy in preclinical models with deregulated activation of the Myc, β-Catenin, and TRK pathways
SummaryAurora kinase A, a mitotic kinase that is overexpressed in various cancers, is a promising cancer drug target. Here, we performed preclinical characterization of TAS-119, a novel, orally active, and highly selective inhibitor of Aurora A. TAS-119 showed strong inhibitory effect against Aurora A, with an IC50 value of 1.04  nmol/L. The compound was highly selective for Aurora A compared with 301 other protein kinases, including Aurora kinase B. TAS-119 induced the inhibition of Aurora A and accumulation of mitotic cells in vitro and in vivo. It suppressed the growth of various cancer cell lines harboringMYC fami...
Source: Investigational New Drugs - January 6, 2021 Category: Drugs & Pharmacology Source Type: research

NT157, an IGF1R-IRS1/2 inhibitor, exhibits antineoplastic effects in pre-clinical models of chronic myeloid leukemia
In conclusion, NT157 has antineoplastic effects on BCR-ABL1 leukemogenesis, independent of T315I mutational status. (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 6, 2021 Category: Drugs & Pharmacology Source Type: research

Durvalumab for patients with unresectable stage III non-small cell lung cancer and grade 1 radiation pneumonitis following concurrent chemoradiotherapy: a multicenter prospective cohort study
Conclusion Durvalumab can be a feasible treatment option for patients with stage III NSCLC with baseline Grade 1 RP following CCRT.(Trial registration number: UMIN000036061. The registration period was between March 2019 and December 2019.) (Source: Investigational New Drugs)
Source: Investigational New Drugs - January 6, 2021 Category: Drugs & Pharmacology Source Type: research

Identification of chemoresistance-associated microRNAs and hub genes in breast cancer using bioinformatics analysis
This study attempts to explore the mechanism of chemotherapy resistance from the perspective of miRNA and look for several new targets for developing new dru gs. Three datasets (GSE73736, GSE71142 and GSE6434) from Gene Expression Omnibus (GEO) were used for the bioinformatics analysis. Differentially expressed miRNAs (DE-miRNAs) and differentially expressed genes (DE-genes) were obtained by using R package “limma”. DAVID tool was used to perform gen e ontology annotation analysis (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for the overlapping genes. Protein-protein inter...
Source: Investigational New Drugs - January 4, 2021 Category: Drugs & Pharmacology Source Type: research

Characterization and management of ERK inhibitor associated dermatologic adverse events: analysis from a nonrandomized trial of ulixertinib for advanced cancers
SummaryBackground Ulixertinib is the first-in-class ERK1/2 kinase inhibitor with encouraging clinical activity inBRAF- andNRAS-mutant cancers. Dermatologic adverse events (dAEs) are common with ulixertinib, so management guidelines like those established for epidermal growth factor receptor inhibitor (EGFRi)-associated dAEs are needed.Patients and Methods This was an open-label, multicenter, phase I dose escalation and expansion trial of ulixertinib evaluating data from 135 patients with advanced malignancies enrolled between March 2013 and July 2017. Histopathological features, management, and dAEs in 34 patients are also...
Source: Investigational New Drugs - January 3, 2021 Category: Drugs & Pharmacology Source Type: research

Potent synergistic anti-tumor activity of a novel humanized anti-HER2 antibody hersintuzumab in combination with trastuzumab in xenograft models
In this study, we assessed the in vitro and in vivo anti-tumor activity of this mAb individually and in combination with trastuzumab. Different HER2-overexpressing human cancer cell lines, including SKOV3, NCI-N87 HCC1954 and BT-474 were cultured and binding reactivity of Hersintu zumab to these cell lines was analyzed by flow cytometry. In addition, the inhibitory effect of different concentrations of hersintuzumab, trastuzumab and their combination on tumor cells growth was assessed by XTT assay. For Assessment of tumor growth inhibition in xenograft model, Balb/c athymic n ude mice were subcutaneously injected with NCI-...
Source: Investigational New Drugs - January 3, 2021 Category: Drugs & Pharmacology Source Type: research

BIX-01294, a G9a inhibitor, suppresses cell proliferation by inhibiting autophagic flux in nasopharyngeal carcinoma cells
SummaryG9a, a histone methyltransferase, has been found to be upregulated in a range of tumor tissues, and contributes to tumor growth and metastasis. However, the impact of G9a inhibition as a potential therapeutic target in nasopharyngeal carcinoma (NPC) is unclear. In the present study we aimed to investigate the anti-proliferative effect of G9a inhibition in the NPC cell lines CNE1 and CNE2, and to further elucidate the molecular mechanisms underlying these effects. The expression of G9a in NPC tumor tissues was significantly higher than that in normal nasopharyngeal tissues. The pharmacological inhibition of G9a by BI...
Source: Investigational New Drugs - January 2, 2021 Category: Drugs & Pharmacology Source Type: research

Drug repurposing using transcriptome sequencing and virtual drug screening in a patient with glioblastoma
Conclusions In conclusion, we identified novel small molecules via a drug repurposing approach that could be effectively used for personalized glioblastoma therapy especially for patients carrying BRAF47-438del and PIK3R1-G376R mutations. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 12, 2020 Category: Drugs & Pharmacology Source Type: research

Simvastatin treatment varies the radiation response of human breast cells in 2D or 3D culture
Conclusion The present study suggests that SVA may have potential for radiosensitization. Therefore, it is important to further investigate the role of SVA in relation to the extent of radiosensitization and how it could be used to positively influence the therapy of breast cancer or other entities. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 11, 2020 Category: Drugs & Pharmacology Source Type: research

Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma
Conclusion This drug repositioning screening approach has identified that F-araA could be therapeutically active against MPM cells, in addition to other tumour types, by inhibiting STAT1 expression and nucleic acids synthesis. Further experiments are required to fully investigate this. (Source: Investigational New Drugs)
Source: Investigational New Drugs - December 9, 2020 Category: Drugs & Pharmacology Source Type: research

Ubiquitin-specific protease 7 is a druggable target that is essential for pancreatic cancer growth and chemoresistance
SummaryPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, and most patients die within one year after diagnosis. This cancer is resistant to almost all current therapies, so there is an urgent need to identify novel druggable targets. Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that functions in carcinogenesis, but its role in PDAC is unknown. Our experiments indicated that several subtypes of PDAC cells are sensitive to USP7 inhibition. In particular, pharmaceutical inhibition of USP7 by the small molecule P22077 attenuated PDAC cell growth and induced cell deathin vitro andin vivo. Ph...
Source: Investigational New Drugs - October 21, 2020 Category: Drugs & Pharmacology Source Type: research

Translational approach from preclinical to clinical: comparison of dose finding methods of a new Bcl2 inhibitor using PK-PD modeling and interspecies extrapolation
SummaryThe attrition rate of anticancer drugs during the clinical development remains very high. Interspecies extrapolation of anticancer drug pharmacodynamics (PD) could help to bridge the gap between preclinical and clinical settings and to improve drug development. Indeed, when combined with a physiologically-based-pharmacokinetics (PBPK) approach, PD interspecies extrapolation could be a powerful tool for predicting drug behavior in clinical trials. The present study aimed to explore this field for anticipating the clinical efficacy of a new Bcl-2 inhibitor, S 55746, for which dose ranging studies in xenografted mice a...
Source: Investigational New Drugs - October 21, 2020 Category: Drugs & Pharmacology Source Type: research

ABCG2 C421A polymorphisms affect exposure of the epidermal growth factor receptor inhibitor gefitinib
AbstractATP-binding castle protein G2 (ABCG2) is thought to inhibit the activities of certain gefitinib transporters, thereby affecting drug pharmacokinetics. The C421A polymorphism affects the function and expression of ABCG2 on the cell membrane. Previous studies have shown that proton-pump inhibitors (PPIs) inhibit gefitinib absorption, as well as the function of ABCG2. We evaluated the plasma concentrations of gefitinib in patients with and without the ABCG2 C421A polymorphism, who were or were not taking PPIs. In total, 61 patients with advanced epidermal-growth-factor-positive non-small-cell lung cancer were enrolled...
Source: Investigational New Drugs - October 21, 2020 Category: Drugs & Pharmacology Source Type: research

Real-world assessment of afatinib for patients with EGFR -positive non-small cell lung cancer
Conclusions Afatinib is effective for patients with NSCLC harboring commonEGFR mutations irrespective of their clinicopathological backgrounds. A direct comparison of afatinib and osimertinib in treatment-na ïve patients is warranted to determine the optimal standard of care. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 21, 2020 Category: Drugs & Pharmacology Source Type: research