Phase II trial of continuous treatment with sunitinib in patients with high-risk (BCG-refractory) non-muscle invasive bladder cancer
Conclusions In NMIBC refractory to BCG, treatment with sunitinib was safe but not associated with improved clinical outcomes. The immune effects of sunitinib deserve further investigation. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 24, 2019 Category: Drugs & Pharmacology Source Type: research

A multicenter, prospective phase II trial of gemcitabine plus axitinib in patients with renal cell carcinoma with a predominant sarcomatoid component
Conclusion GX showed promising efficacy in patients with SRCC. GX could be considered as a treatment option for patients with SRCC and should be confirmed in larger clinical trials. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 24, 2019 Category: Drugs & Pharmacology Source Type: research

A phase I dose-reduction study of apatinib combined with pemetrexed and carboplatin in untreated EGFR and ALK negative stage IV non-squamous NSCLC
Conclusion In patients with advanced non-squamous NSCLC, the feasible dose of apatinib given with standard-dose pemetrexed and carboplatin was 500  mg/day schedule 2/1. The schedule was generally well tolerated and demonstrated promising clinical benefit in NSCLC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 24, 2019 Category: Drugs & Pharmacology Source Type: research

Cotargeting the JAK/STAT signaling pathway and histone deacetylase by ruxolitinib and vorinostat elicits synergistic effects against myeloproliferative neoplasms
SummaryThe majority of patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) harbor a gain of function mutation V617F in Janus kinase (JAK) 2. Although JAK2 inhibitors such as ruxolitinib have been shown to be clinically efficacious, the hematological toxicity and eventual drug resistance limit its use as monotherapy. Other gene mutations or dysregulation correlated with the disease phenotype and prognosis have been found to contribute to the complexity and heterogeneity of MPNs, giving rise to an increasing demand for combination therapies. Here, we combine ruxolitinib and the histone deacetylase inhibit...
Source: Investigational New Drugs - June 22, 2019 Category: Drugs & Pharmacology Source Type: research

Anticancer evaluation of a novel dithiocarbamate hybrid as the tubulin polymerization inhibitor
SummaryNovel quinoline-dithiocarbamate hybrids were synthesized and designed by the molecular hybridization strategy. All these derivatives were evaluated for their antiproliferative activity against three selected cancer cell lines (MGC-803, HepG-2 and PC-3). Among them, compound10c displayed the best antiproliferative activity against PC-3 cells with an IC50 value of 0.43  μM. Celluar mechanisms investigated that compound10c could inhibit the migration against PC-3 cells by regulation the expression levels of E-cadherin and N-cadherin. Compound10c induced morphological changes of PC-3 cells and regulated apoptosi...
Source: Investigational New Drugs - June 10, 2019 Category: Drugs & Pharmacology Source Type: research

Negative impact of malignant effusion on osimertinib treatment for non-small cell lung cancer harboring EGFR mutation
Summary3rd-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, have reasonable efficacy in non –small-cell lung cancers (NSCLC) withEGFR mutations. However, the efficacy of osimertinib in NSCLC patients with fluids, such as pleural, pericardial and abdominal effusions, is unclear. We evaluated the efficacy of osimertinib in this specific setting. NSCLC patients harboringEGFR T790  M mutations who experienced progressive disease after first EGFR-TKI treatment and started osimertinib treatment between April 2016 and August 2018 were retrospectively screened. I...
Source: Investigational New Drugs - June 10, 2019 Category: Drugs & Pharmacology Source Type: research

The influence of the coadministration of the p-glycoprotein modulator elacridar on the pharmacokinetics of lapatinib and its distribution in the brain and cerebrospinal fluid
Conclusion This study showed that elacridar influenced the pharmacokinetics of lapatinib. The inhibition of ABCB1 and ABCG2 transporters by elacridar substantially enhanced the penetration of lapatinib into the CSF and BT. The blocking of protein transporters could become indispensable in the treatment of patients with breast cancer and brain metastases. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 8, 2019 Category: Drugs & Pharmacology Source Type: research

CKT0353, a novel microtubule targeting agent, overcomes paclitaxel induced resistance in cancer cells
SummaryMicrotubule targeting agents (MTAs) are extensively used in cancer treatment and many have achieved substantial clinical success. In recent years, targeting microtubules to inhibit cell division has become a widespread pharmaceutical approach for treatment of various cancer types. Nevertheless, the development of multidrug resistance (MDR) in cancer remains a major obstacle for successful application of these agents. Herein, we provided the evidence that CKT0353, α-branched α,β-unsaturated ketone, possesses the capacity to successfully evade the MDR phenotype as an MTA. CKT0353 induced G2/M phase ar...
Source: Investigational New Drugs - June 8, 2019 Category: Drugs & Pharmacology Source Type: research

Novel thiosemicarbazones induce high toxicity in estrogen-receptor-positive breast cancer cells (MCF7) and exacerbate cisplatin effectiveness in triple-negative breast (MDA-MB231) and lung adenocarcinoma (A549) cells
SummaryCis-diamminedichloroplatinum(II) (CDDP), known as cisplatin, has been extensively used against breast cancer, which is the most frequent cancer among women, and lung cancer, the leading cancer that causes death worldwide. Novel compounds such as thiazole derivatives have exhibited antiproliferative activity, suggesting they could be useful against cancer treatment. Herein, we synthesized two novel thiosemicarbazones and an aldehyde to combine with CDDP to enhance efficacy against ER-positive breast MCF7 cancer cells, triple-negative/basal-B mammary carcinoma cells (MDA-MB231) and lung adenocarcinoma (A549) human cel...
Source: Investigational New Drugs - June 8, 2019 Category: Drugs & Pharmacology Source Type: research

Activation of IGF-1R pathway and NPM-ALK G1269A mutation confer resistance to crizotinib treatment in NPM-ALK positive lymphoma
SummaryALK-positive anaplastic large cell lymphoma (ALCL) represents a subset of non-Hodgkin ’s lymphoma that is treated with crizotinib, a dual ALK/MET inhibitor. Despite the remarkable initial response, ALCLs eventually develop resistance to crizotinib. ALK inhibitor resistance in tumors is a complex and heterogeneous process with multiple underlying mechanisms, including ALK gene ampli fication, ALK kinase domain mutation, and the activation of various bypass signaling pathways. To overcome resistance, multiple promising next-generation ALK kinase inhibitors and rational combinatorial strategies are being develope...
Source: Investigational New Drugs - June 8, 2019 Category: Drugs & Pharmacology Source Type: research

A phase II study of the orally administered negative enantiomer of gossypol (AT-101), a BH3 mimetic, in patients with advanced adrenal cortical carcinoma
Conclusions AT-101 had no meaningful clinical activity in this study in patients with advanced ACC, but demonstrated feasibility of prospective therapeutic clinical trials in this rare cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 6, 2019 Category: Drugs & Pharmacology Source Type: research

Sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Japan
This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings.Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively.Results Before March 2018, 44...
Source: Investigational New Drugs - June 6, 2019 Category: Drugs & Pharmacology Source Type: research

Effects of chemotherapy on placental development and function using in vitro culture of human primary cytotrophoblasts
Discussion The most commonly used chemotherapeutic drugs are well supported in vitro by syncytiotrophoblasts, except for epirubicin, which was very cytotoxic. Chemotherapy perturbed the expression of genes normally upregulated during placental differentiation and angiogenesis but not the expression of the drug transporters. Further studies looking at the effect of combination therapy and the transporter capacities to reject the drugs will be needed to better define the effects of chemotherapy on placental development and function. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 3, 2019 Category: Drugs & Pharmacology Source Type: research

Pharmacological effects of the simultaneous and sequential combinations of trifluridine/tipiracil (TAS-102) and 5-fluorouracil in fluoropyrimidine-sensitive colon cancer cells
SummaryThe aim of this study was to investigate possible synergistic effects in vitro of trifluridine/tipiracil (TAS-102) and 5-fluoruracil (5-FU) on fluoropyrimidine-sensitive colon cancer cell lines of different mutational status in order to build a rational basis for the future use of this combination therapy in adjuvant settings or as a first-line treatment for metastatic disease. Proliferation assays were performed on HT-29 (B-raf mutated), SW-620 (ras mutated), and Caco-2 (wild type) colon cancer cell lines exposed to 120-h treatments of 5-FU, TAS-102 and their different combination schedules (simultaneous, sequentia...
Source: Investigational New Drugs - June 1, 2019 Category: Drugs & Pharmacology Source Type: research

Phase II study of avelumab in multiple relapsed/refractory germ cell cancer
This study aimed to determine the efficacy and safety of avelumab, a PD-L1 inhibitor, in patients with GCTs.Methods In this phase 2 study, patients with multiple relapsed and/or refractory GCTs were treated with avelumab at a dose of 10  mg/kg administered biweekly until progression or unacceptable toxicity. The primary endpoint was 12-week progression-free survival (PFS). Fifteen evaluable patients had to be enrolled in the first cohort, and if
Source: Investigational New Drugs - June 1, 2019 Category: Drugs & Pharmacology Source Type: research

Increasing complexity in oncology phase I clinical trials
SummaryClinical trials in oncology have become increasingly complex because of incorporation of predictive biomarkers and patient selection based on molecular profiling of tumors. We have examined the change in procedures and work intensity in phase 1 oncology trials over the years with several parameters used as surrogates of complexity. Categories that were included as events were clinical evaluations, pharmacokinetic (PK) laboratory tests, non-PK laboratory tests, specific molecular or histological characteristics, questionnaires and subjective assessments, routine clinical and physical examinations, imaging, invasive p...
Source: Investigational New Drugs - May 28, 2019 Category: Drugs & Pharmacology Source Type: research

Induction of endoplasmic reticulum stress by aminosteroid derivative RM-581 leads to tumor regression in PANC-1 xenograft model
SummaryThe high fatality and morbidity of pancreatic cancer have remained almost unchanged over the last decades and new clinical therapeutic tools are urgently needed. We determined the cytotoxic activity of aminosteroid derivatives RM-133 (androstane) and RM-581 (estrane) in three human pancreatic cancer cell lines (BxPC3, Hs766T and PANC-1). In PANC-1, a similar level of antiproliferative activity was observed for RM-581 and RM-133 (IC50 = 3.9 and 4.3 μM, respectively), but RM-581 provided a higher selectivity index (SI = 12.8) for cancer cells over normal pancreatic cells than RM-133...
Source: Investigational New Drugs - May 28, 2019 Category: Drugs & Pharmacology Source Type: research

Combination treatment of cancer cells with pan-Akt and pan-mTOR inhibitors: effects on cell cycle distribution, p-Akt expression level and radiolabelled-choline incorporation
Conclusions Pan-mTOR and pan-Akt inhibition may be highly effective in cancer treatment and measuring changes in choline uptake could be useful in detecting efficacious drug combinations. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 28, 2019 Category: Drugs & Pharmacology Source Type: research

Clinical outcomes of patients with G1/G2 neuroendocrine tumors arising from foregut or hindgut treated with somatostatin analogs: a retrospective study
SummaryNeuroendocrine tumors (NET) are rare tumors for which somatostatin analogs (SSA) are used not only for symptom control due to a functioning tumor, but also for the disease control of unresectable NET. The efficacy of SSA for midgut NET has been verified by previous studies, but insufficient evidence exists for SSA treatment of NET in the foregut and hindgut (F/H-NET). The aim of this retrospective study was to evaluate the efficacy of SSA for unresectable F/H-NET. Patients with unresectable F/H-NET treated with SSA between February 2011 and August 2017 at our hospital were retrospectively reviewed. Parameters of eff...
Source: Investigational New Drugs - May 28, 2019 Category: Drugs & Pharmacology Source Type: research

HER-targeted tyrosine kinase inhibitors enhance response to trastuzumab and pertuzumab in HER2-positive breast cancer
This study evaluated the anti-proliferative effects of adding anti-HER2 tyrosine kinase inhibitors (TKIs) to trastuzumab and pertuzumab in HER2-positive breast cancer cells. Afatinib was tested alone and in combination with trastuzumab in HER2-positive breast cancer cell lines. TKIs (lapatinib, neratinib, afatinib) combined with trastuzumab and/or pertuzumab were tested in 3 cell lines, with/without amphiregulin and heregulin-1 β. Seven of 11 HER2-positive cell lines tested were sensitive to afatinib (IC50 
Source: Investigational New Drugs - May 28, 2019 Category: Drugs & Pharmacology Source Type: research

Phase I study of the indoleamine 2,3-dioxygenase 1 inhibitor navoximod (GDC-0919) as monotherapy and in combination with the PD-L1 inhibitor atezolizumab in Japanese patients with advanced solid tumours
This study investigated the safety, tolerability and pharmacokinetics of navoximod alone and in combination with atezolizumab in Japanese patients with advanced solid tumours. This was a phase I, open-label, dose-escalation study. Patients received monotherapy with navoximod 400  mg, 600 mg or 1000 mg orally twice daily (BID) in Stage 1 and navoximod 200 mg, 400 mg, 600 mg or 1000 mg orally BID plus atezolizumab 1200 mg intravenously every 21 days in Stage 2. Objectives included safety, tolerability, efficacy and pharmacokinetic outcomes.Overall, 20 patients were e nrolled (Stag...
Source: Investigational New Drugs - May 24, 2019 Category: Drugs & Pharmacology Source Type: research

Entrectinib resistance mechanisms in ROS1 -rearranged non-small cell lung cancer
SummaryEntrectinib is a pan-tyrosine-kinase inhibitor that targets oncogenic rearrangements inNTRK,ROS1 andALK. The combined results of two clinical trials demonstrated the efficacy of entrectinib inROS1-rearranged NSCLC. Because the development of drug resistance is inevitable, it would be helpful to determine the mechanisms of entrectinib resistance in aROS1-rearranged tumor model so that future therapeutic strategies can be developed. Here, we characterized the molecular basis of resistance in entrectinib-resistantROS1-rearranged HCC78 cells (HCC78ER cells). These cells were analyzed by next-generation sequencing and ge...
Source: Investigational New Drugs - May 24, 2019 Category: Drugs & Pharmacology Source Type: research

Reduced expression of annexin A1 promotes gemcitabine and 5-fluorouracil drug resistance of human pancreatic cancer
SummaryIntrinsic chemoresistance is the main reason for the failure of human pancreatic ductal adenocarcinoma (PDAC) therapy. To identify the candidate protein, we compared the protein expression profiling of PDAC cells and its distinct surviving cells following primary treatment with gemcitabine (GEM) and 5-fluorouracil (5-FU) by two-dimensional electrophoresis combined with liquid chromatography –mass spectrometry or mass spectrometry. A total of 20 differentially expressed proteins were identified, and annexin A1 (ANXA1) was analyzed for further validation. The functional validation showed that the downregulation ...
Source: Investigational New Drugs - May 23, 2019 Category: Drugs & Pharmacology Source Type: research

Assessment of the cytotoxic effects of aporphine prototypes on head and neck cancer cells
Conclusion Our results revealed that APO, C1, and A5 exhibit cytotoxic effects in HNSCC cells. The mechanisms of action appear to be partly via the generation of DNA damages and apoptosis induction through Caspase-3 pathway activation. This study provides preclinical data that suggest a potential therapeutic role for APO, C1, and A5 against head and neck cancer cells. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 17, 2019 Category: Drugs & Pharmacology Source Type: research

Cardamonin, a natural chalcone, reduces 5-fluorouracil resistance of gastric cancer cells through targeting Wnt/ β-catenin signal pathway
Conclusions Overall, this study revealed that cotreatment of cardamonin and 5-FU could strongly potentiate the antitumor activity of 5-FU, and put forth cardamonin as a rational therapeutic strategy for drug-resistant GC treatment. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 17, 2019 Category: Drugs & Pharmacology Source Type: research

Preclinical activity and a pilot phase I study of pacritinib, an oral JAK2/FLT3 inhibitor, and chemotherapy in FLT3 -ITD-positve AML
In conclusion, pacritinib, an inhibitor ofFLT3-ITD and resistant-conferring TKD mutations, was well tolerated and demonstrated preliminary anti-leukemic activity in combination with chemotherapy in patients withFLT3 mutations. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 17, 2019 Category: Drugs & Pharmacology Source Type: research

Expression of the PTEN/FOXO3a/PLZF signalling pathway in pancreatic cancer and its significance in tumourigenesis and progression
SummaryPancreatic cancer (PC) is one of the most lethal gastrointestinal malignancies. The PTEN/AKT signalling pathway is closely related to the tumourigenesis and progression of PC. The downstream effectors, FOXO3a, PLZF and VEGF, are reported to be involved in angiogenesis, lymph node metastasis and poor survival in PC. By using tissue microarrays and immunohistochemistry, we found, that PTEN, FOXO3a and PLZF expression was significantly decreased in PC specimens compared with that in chronic pancreatitis (CP) specimens, while VEGF expression was significantly increased. Furthermore, the expression of PTEN was positively...
Source: Investigational New Drugs - May 14, 2019 Category: Drugs & Pharmacology Source Type: research

Zelnorm, an agonist of 5-Hydroxytryptamine 4-receptor, acts as a potential antitumor drug by targeting JAK/STAT3 signaling
SummaryThe Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays central roles in cancer cell growth and survival. Drug repurposing strategies have provided a valuable approach for developing antitumor drugs. Zelnorm (tegaserod maleate) was originally designed as an agonist of 5-hydroxytryptamine 4 receptor (5-HT4R) and approved by the FDA for treating irritable bowel syndrome with constipation (IBS-C). Through the use of a high-throughput drug screening system, Zelnorm was identified as a JAK/STAT3 signaling inhibitor. Moreover, the inhibition of STAT3 phosphorylation by Zel...
Source: Investigational New Drugs - May 14, 2019 Category: Drugs & Pharmacology Source Type: research

Pam 3 CSK 4 , a TLR2 ligand, induces differentiation of glioblastoma stem cells and confers susceptibility to temozolomide
SummaryGlioblastoma multiforme (GBM) is the most aggressive human brain tumor, and GBM stem cells (GSC) may be responsible for its recurrence and therapeutic resistance. Toll-like receptors (TLRs), which recognize multiple ligands (endogenous and pathogen-associated) and trigger the immune response of mature immune cells, are also expressed by hematopoietic stem and progenitor cells, where their activation results in the differentiation of these cells into myeloid cells. Since TLR expression has been recently described in neural cells, including neural stem cells, we studied TLR expression by GSCs and the effect of stimula...
Source: Investigational New Drugs - May 11, 2019 Category: Drugs & Pharmacology Source Type: research

Identification of a 3,3-difluorinated tetrahydropyridinol compound as a novel antitumor agent for hepatocellular carcinoma acting via cell cycle arrest through disturbing CDK7-mediated phosphorylation of Cdc2
SummaryTetrahydropyridinol derivatives were recently reported to exhibit good biological activities, and the incorporation of fluorine into organic molecules may have profound effects on their physical and biological properties. Therefore, we investigated the anticancer activities of six fluorinated tetrahydropyridinol derivatives that we synthesized previously. We found that only one compound, 3,3-difluoro-2,2-dimethyl-1,6-diphenyl-5-tosyl-1,2,3,6-tetrahydropyridin-4-ol, showed significant antiproliferative activity on human hepatocellular carcinoma HepG2 and HMCCLM3 cells (the IC50 values were 21.25 and 29.07  μM...
Source: Investigational New Drugs - May 11, 2019 Category: Drugs & Pharmacology Source Type: research

A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma
Conclusion At 15  mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 7, 2019 Category: Drugs & Pharmacology Source Type: research

Randomized phase II trial of neoadjuvant everolimus in patients with high-risk localized prostate cancer
Conclusions Neoadjuvant everolimus given at 5  mg or 10 mg daily for 8 weeks prior to radical prostatectomy did not impact pathologic responses and surgical outcomes of patients with high-risk prostate cancer.Trial registrationNCT00526591. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 30, 2019 Category: Drugs & Pharmacology Source Type: research

A phase 1 study of oral ASP5878, a selective small-molecule inhibitor of fibroblast growth factor receptors 1 –4, as a single dose and multiple doses in patients with solid malignancies
This study investigated safety, tolerability, and antitumor effect of single and multiple oral doses of ASP5878 in patients with solid tumors. This phase 1, open label, first-in-human study comprised dose-escalation and dose-expansion parts. Primary objectives of the dose-escalation part were to identify the dose-limiting toxicity (DLT), maximum tolerated dose, and recommended dose of ASP5878 for the dose-expansion part. Nine dose cohorts of ASP5878 were evaluated (0.5 ─2 mg once daily; 2─40 mg twice daily [BID]). A single dose of ASP5878 was followed by a 2-day pharmacokinetic collection, and then either 28-...
Source: Investigational New Drugs - April 30, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: Sphingadienes show therapeutic efficacy in neuroblastoma in vitro and in vivo by targeting the AKT signaling pathway
The authors would like to note an omission of disclosure in this paper. Author JDS is cofounder, equity-holder, and consultant of GILTRx Therapeutics. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 29, 2019 Category: Drugs & Pharmacology Source Type: research

Anticancer activity, apoptosis and a structure –activity analysis of a series of 1,4-naphthoquinone-2,3-bis-sulfides
SummaryWe have previously reported on the synthesis of 1,4-naphthoquinone-sulfides and in this investigation we report on their anticancer activity against 6 human cancer cell lines to evaluate their cytostatic effects. The 1,4-naphthoquinone-2,3-bis-sulfides were most effective against melanoma (UACC62) (GI50 = 6.5–10 μM) and prostate (PC3) (GI50 = 5.51–8.53 μM) cancer cell lines. They exhibited better cytostatic effects than etoposide (GI50 = 0.56–36.62 μM), parthenolide (GI50 = 3.58–25.97 μM) and VK3 (GI50&thi...
Source: Investigational New Drugs - April 27, 2019 Category: Drugs & Pharmacology Source Type: research

Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors
Conclusions Ivosidenib demonstrated good oral exposure and a long half-life. Robust, persistent plasma 2-HG inhibition was observed in IDH1-mutant cholangiocarcinoma and chondrosarcoma. Ivosidenib 500  mg QD is an appropriate dose irrespective of various intrinsic and extrinsic factors.Trial RegistrationClinicalTrials.gov (NCT02073994). (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 26, 2019 Category: Drugs & Pharmacology Source Type: research

The metronomic all-oral DEVEC is an effective schedule in elderly patients with diffuse large b-cell lymphoma
Conclusion The favourable activity of DEVEC compared to a real-life series and the convenience of an oral administration, may possibly lay the groundwork for a paradigm-shift in the treatment of elderly DLBCL. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 26, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: Eribulin, trastuzumab, and pertuzumab as first-line therapy for patients with HER2-positive metastatic breast cancer: a phase II, multicenter, collaborative, open-label, single-arm clinical trial
The authors would like to note the replacement of Fig.  2b, for which Fig. 2a was placed erringly, with appropriate Fig. 2b. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 25, 2019 Category: Drugs & Pharmacology Source Type: research

Phase I study of the anti-heparin-binding epidermal growth factor-like growth factor antibody U3-1565 with cetuximab in patients with cetuximab- or panitumumab-resistant metastatic colorectal cancer
SummaryKRAS wild-type colorectal cancers initially responsive to anti-endothelial growth factor receptor (EGFR) antibodies [cetuximab (Cetu)/panitumumab (Pani)] develop acquired resistance. Overexpression of EGFR ligands such as heparin-binding EGF-like growth factor (HB-EGF) may be one resistance mechanism. This phase I study of U3-1565, anti-HB-EGF antibody, and Cetu combination therapy enrolled patients withKRAS wild-type metastatic colorectal cancer who had received two ≤ regimens with fluoropyrimidine, oxaliplatin, irinotecan, and Cetu/Pani and had disease progression on Cetu/Pani. Recommended dose (RD) was determi...
Source: Investigational New Drugs - April 24, 2019 Category: Drugs & Pharmacology Source Type: research

Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors
Conclusions Cobimetinib and pictilisib combination therapy in patients with solid tumors had limited tolerability and efficacy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 24, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma
The authors would like to note an error in Figures  1 and 2 of this paper. The graph in Figure 1 incorrectly reflected the overall survival (OS), when it should have displayed the progression-free survival (PFS). The caption and median PFS values were correct. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 24, 2019 Category: Drugs & Pharmacology Source Type: research

A phase 2, open-label study of brentuximab vedotin in patients with CD30-expressing solid tumors
Conclusion The safety profile of BV in patients with solid tumors was similar to the known safety profile of BV. In solid tumors, BV had modest activity as a single agent, which was similar to other second-line treatments already available to patients. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 16, 2019 Category: Drugs & Pharmacology Source Type: research

Midkine silencing enhances the anti –prostate cancer stem cell activity of the flavone apigenin: cooperation on signaling pathways regulated by ERK, p38, PTEN, PARP, and NF-κB
In conclusion, MK-regulated events are different between PCSCs, and when combined with apigenin plus MK silencing, docetaxel treatment may be a valuable approach for the eradication of PCSCs. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 16, 2019 Category: Drugs & Pharmacology Source Type: research

A preclinical evaluation of thiostrepton, a natural antibiotic, in nasopharyngeal carcinoma
Conclusion Thiostrepton effectively suppressed NPC cell proliferation, migration, and invasion, likely by several mechanisms. Thiostrepton may be a potential therapeutic agent for treating NPC in the future. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 16, 2019 Category: Drugs & Pharmacology Source Type: research

Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR 2 and miR-34a
SummaryThe pharmacokinetic (PK) and potential effects ofEmodin on liver cancer were systematically evaluated in this study. Both the intragastric administration (i.g.) and hypodermic injection (i.h.) ofEmodin exhibited a strong absorption (absorption rate  human> beagle dog. These PK data provided the basis for the subsequent animal experiments. In liver cancer patient tissues, the expression of vascular endothelial growth factor (VEGF)-induced signaling pathways, including phosphorylated VEGF receptor 2 (VEGFR2), AKT, and ERK1/2,were simultaneously elevated, but miR-34a expression was reduced and negatively corr...
Source: Investigational New Drugs - April 11, 2019 Category: Drugs & Pharmacology Source Type: research

Safety and clinical activity of the Notch inhibitor, crenigacestat (LY3039478), in an open-label phase I trial expansion cohort of advanced or metastatic adenoid cystic carcinoma
Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 6, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: A novel histone deacetylase inhibitor, CG200745, potentiates anticancer effect of docetaxel in prostate cancer via decreasing Mcl-1 and Bcl- XL
The blots of control and docetaxel for caspase-9, caspase-3, caspase-8, Bcl-XL, and tubulin in the Figure 4f were reused from Figure 4 of our previous paper published inJournal of Urology in 2010 (https://doi.org/10.1016/j.juro.2010.07.035). (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 2, 2019 Category: Drugs & Pharmacology Source Type: research

Emodin induced necroptosis in the glioma cell line U251 via the TNF- α/RIP1/RIP3 pathway
This study aimed to investigate the effects and mechanisms of emodin-induced necroptosis in the glioma cell line U251 by targeting the TNF- α/RIP1/RIP3 signaling pathway. We found that emodin could significantly inhibit U251 cell proliferation, and the viability of U251 cells treated with emodin was reduced in a dose- and time-dependent manner. Flow cytometry assays and Hoechst-PI staining assays showed that emodin induced apoptosis an d necroptosis. Real-time PCR and western blot analysis showed that emodin upregulated the levels of TNF-α, RIP1, RIP3 and MLKL. Furthermore, the RIP1 inhibitor Nec-1 and the RIP3...
Source: Investigational New Drugs - March 28, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: Phase II study of sunitinib in Japanese patients with unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumor
In the original publication of this article, the license subtype should be CC BY and not CC BY-NC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 23, 2019 Category: Drugs & Pharmacology Source Type: research

Discovery of a pyrimidine compound endowed with antitumor activity
SummaryRecently, some synthetic nitrogen-based heterocyclic molecules, such as PJ34, have shown pronounced antitumor activity. Therefore, we designed and synthesized new derivatives characterized by a nitrogen-containing scaffold and evaluated their antiproliferative properties in tumor cells. We herein report the effects of three newly synthesized compounds on cell lines from three different human cancers: triple-negative breast cancer, colon carcinoma and glioblastoma. We found that two of these compounds did not affect proliferation, while the third significantly inhibited replication of the three cell lines. Moreover, ...
Source: Investigational New Drugs - March 21, 2019 Category: Drugs & Pharmacology Source Type: research