Sunitinib - induced sudden hearing loss
(Source: Investigational New Drugs)
Source: Investigational New Drugs - July 30, 2016 Category: Drugs & Pharmacology Source Type: research

Molecular and cellular effects of a novel hydroxamate-based HDAC inhibitor – belinostat – in glioblastoma cell lines: a preliminary report
Summary Histone deacetylase (HDAC) inhibitors are now intensively investigated as potential cytostatic agents in many malignancies. Here, we provide novel information concerning the influence of belinostat (Bel), a hydroxamate-based pan-HDAC inhibitor, on glioblastoma LN-229 and LN-18 cells. We found that LN-229 cells stimulated with 2  μmol/L of Bel for 48 h resulted in 70 % apoptosis, while equivalent treatment of LN-18 cells resulted in only 28 % apoptosis. In LN-229 cells this effect was followed by up-regulation of pro-apoptotic genes including Puma , Bim , Chop and p21 . In treated LN-18 cell...
Source: Investigational New Drugs - July 29, 2016 Category: Drugs & Pharmacology Source Type: research

The renal effects of ALK inhibitors
Summary Anaplastic lymphoma kinase 1 (ALK-1) is a member of the insulin receptor tyrosine kinase family. In clinical practice, three small molecule inhibitors of ALK-1 are used, namely crizotinib, ceritinib and alectinib. Several more agents are in active pre-clinical and clinical studies. Crizotinib is approved for the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC). According to the package insert and published literature, treatment with crizotinib appears to be associated with kidney failure as well as an increased risk for the development and progression of renal cysts. In addition, this agent is...
Source: Investigational New Drugs - July 29, 2016 Category: Drugs & Pharmacology Source Type: research

A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors
Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 23, 2016 Category: Drugs & Pharmacology Source Type: research

AZD9291 overcomes T790  M-mediated resistance through degradation of EGFR L858R/T790M in non-small cell lung cancer cells
Summary The discovery of activating mutations of epidermal growth factor receptor (EGFR) has resulted in the development of more effective treatments for non-small cell lung cancer (NSCLC). Although first-generation EGFR tyrosine kinase inhibitors (EGFR TKIs) provide significant clinical benefit, acquired resistance often occurs, most commonly ( & gt;50  %) via a T790 M resistance mutation. Although AZD9291 is selective for both T790 M and activating EGFR mutations over wild-type EGFR, it is highly active when T790 M is present, especially EGFR L858R/T790M , and modestly active when T790  M is...
Source: Investigational New Drugs - July 22, 2016 Category: Drugs & Pharmacology Source Type: research

Continuation maintenance therapy with S-1 in chemotherapy-na ïve patients with advanced squamous cell lung cancer
Conclusion S-1 maintenance therapy might be a feasible treatment option in patients with squamous cell lung cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 22, 2016 Category: Drugs & Pharmacology Source Type: research

A phase I trial of cabozantinib and gemcitabine in advanced pancreatic cancer
Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 21, 2016 Category: Drugs & Pharmacology Source Type: research

A phase I dose-escalation study of LY2875358, a bivalent MET antibody, given as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies
Conclusions LY2875358 at doses up to 2000 mg demonstrated a favorable safety and tolerability profile as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 16, 2016 Category: Drugs & Pharmacology Source Type: research

A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors
Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAFV600E mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 16, 2016 Category: Drugs & Pharmacology Source Type: research

A phase I trial of the aurora kinase inhibitor , ENMD-2076, in patients with relapsed or refractory acute myeloid leukemia or chronic myelomonocytic leukemia
Summary ENMD-2076 is a novel, orally-active molecule that inhibits Aurora A kinase, as well as c-Kit, FLT3 and VEGFR2. A phase I study was conducted to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and toxicities of ENMD-2076 in patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). Patients received escalating doses of ENMD-2076 administered orally daily [225 mg (n = 7), 375 mg (n = 6), 325 mg (n = 9), or 275 mg (n = 5)]. Twenty-seven patients were treated (26 AML; 1 CMML-2). The most common n...
Source: Investigational New Drugs - July 12, 2016 Category: Drugs & Pharmacology Source Type: research

Phase I dose-finding study of monotherapy with atezolizumab, an engineered immunoglobulin monoclonal antibody targeting PD-L1, in Japanese patients with advanced solid tumors
Conclusions Atezolizumab was well tolerated in Japanese patients at doses up to 20 mg/kg q3w. The safety profile and Cycle 1 serum atezolizumab concentrations were similar to those previously observed in non-Japanese patients. These data support the participation of Japanese patients in ongoing pivotal global studies of atezolizumab. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 1, 2016 Category: Drugs & Pharmacology Source Type: research

Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer
Conclusions There was no significant clinical activity of LY2603618 and pemetrexed combination therapy in patients with advanced NSCLC. The results were comparable with historical pemetrexed single-agent data, with similar safety and PK profiles being observed. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 27, 2016 Category: Drugs & Pharmacology Source Type: research

Intravenous and intraperitoneal paclitaxel with S-1 for treatment of refractory pancreatic cancer with malignant ascites
Conclusion Combination chemotherapy consisting of intravenous and intraperitoneal PTX with S-1 showed acceptable toxicity and favorable efficacy in pancreatic cancer patients with malignant ascites. (Clinical trial registration number: UMIN000005306) (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 23, 2016 Category: Drugs & Pharmacology Source Type: research

Involvement of AMP-activated protein kinase in mediating pyrrolo-1,5-benzoxazepine–induced apoptosis in neuroblastoma cells
This study provides new insights into understanding the molecular and cellular mechanisms involved in PBOX-induced cell death in neuroblastoma and further supports their future use as novel anti-cancer agents for the treatment of neuroblastoma. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 22, 2016 Category: Drugs & Pharmacology Source Type: research

Phase I trial of dacomitinib, a pan-human epidermal growth factor receptor (HER) inhibitor, with concurrent radiotherapy and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (XDC-001)
Conclusions The triple combination has a tolerable side effect profile and dose levels 15 mg and 30 mg were cleared safely. The addition of dacomitinib did not preclude delivery of standard chemoradiotherapy. Studies testing the addition of other HER-targeted therapies to platinum-based concurrent chemo-radiotherapy in LA-SCCHN have failed to demonstrate improved patient outcomes and have reported trends towards excessive toxicities. These results generated uncertainty regarding the future of these agents in combination with chemo-radiation for the treatment of LA-SCCHN, which ultimately led to the early terminat...
Source: Investigational New Drugs - June 11, 2016 Category: Drugs & Pharmacology Source Type: research

Continuation maintenance therapy with S-1 in chemotherapy-naïve patients with advanced squamous cell lung cancer
Conclusion S-1 maintenance therapy might be a feasible treatment option in patients with squamous cell lung cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - June 9, 2016 Category: Drugs & Pharmacology Source Type: research

Intravitreal vascular endothelial growth factor (VEGF) inhibitor injection in unrecognised early pregnancy
Summary The use of intravitreal vascular endothelial growth factor (VEGF) inhibitor medications has widened considerably to include indications affecting females of reproductive age. Our patient was inadvertently exposed to bevacizumab within the first trimester when placental growth and fetal organogenesis take place and patient suffered pregnancy loss. There is insufficient information to suggest that such use is safe, nor is there definitive evidence to suggest that it causes harm. We advise that ophthalmologists discuss pregnancy with women of childbearing age undergoing intraocular anti-VEGF injections and in...
Source: Investigational New Drugs - June 2, 2016 Category: Drugs & Pharmacology Source Type: research

A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer
Conclusion: Although met with a favorable toxicity profile, the addition of AT-101 to docetaxel in R/M HNSCC does not appear to demonstrate evidence of efficacy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 26, 2016 Category: Drugs & Pharmacology Source Type: research

Prediction of response to everolimus in neuroendocrine tumors: evaluation of clinical, biological and histological factors
Summary Objectives Several targeted therapies are available for metastatic neuroendocrine tumours (NETs) but no predictive factor of response to these treatments has been identified yet. Our aim was to identify and evaluate clinical, biological, histological and functional markers of response to everolimus. Methods We retrospectively reviewed 53 patients with NETs treated with everolimus (68 % in clinical trials). Clinical, biological and histological data were analyzed. The functional marker p-p70S6K, a main effector of the mTOR pathway, was studied by immunohistochemistry in 43 cases. Prognos...
Source: Investigational New Drugs - May 26, 2016 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics and excretion of 14 C-omacetaxine in patients with advanced solid tumors
Summary Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to ≥ 2 tyrosine kinase inhibitor treatments. This phase I study assessed the disposition, elimination, and safety of 14C-omacetaxine in patients with solid tumors. Methods The study comprised a 7-days pharmacokinetic assessment followed by a treatment period of ≤ six 28-days cycles. A single subcutaneous dose of 1.25 mg/m2 14C-omacetaxine was administered to six patients. Blood, urine, and feces were collected through 168&...
Source: Investigational New Drugs - May 25, 2016 Category: Drugs & Pharmacology Source Type: research

The imidazoline compound RX871024 promotes insulinoma cell death independent of AMP-activated protein kinase inhibition
Summary We have previously shown that the insulinotropic imidazoline compound RX871024 induces death of insulinoma MIN6 cells, an effect involving stimulation of c-Jun N-terminal kinase (JNK) and caspase 3. It has also been reported that AMP-activated protein kinase (AMPK) activates JNK and induces β-cell death. Here we show that RX871024, but not another insulinotropic imidazoline compound (BL11282), suppressed AMPK activity in MIN6 cells. The inhibitory effect of RX871024 on AMPK was supported by the observation that the imidazoline induced lipid droplet formation in the cytoplasm of MIN6 cells. This reflec...
Source: Investigational New Drugs - May 25, 2016 Category: Drugs & Pharmacology Source Type: research

In vitro and in vivo antineoplastic and immunological effects of pterocarpanquinone LQB-118
In this report we describe its antineoplastic effect in vivo and assess its toxicity toward the immune system. Treated mice presented no changes in weight of primary and secondary organs of the immune system nor their cellular composition. Immunophenotyping showed that treatment increased CD4+ thymocytes and proportionally reduced the CD4+CD8+ subpopulation in the thymus. No significant changes were observed in T CD8+ peripheral lymphocytes nor was the activation of fresh T cells affected after treatment. LQB-118 induced apoptosis in murine tumor cells in vitro, being synergistic with the autophagy promoter rapamycin. Furt...
Source: Investigational New Drugs - May 18, 2016 Category: Drugs & Pharmacology Source Type: research

The aurora kinase inhibitor VX-680 shows anti-cancer effects in primary metastatic cells and the SW13 cell line
Abstract New therapeutic targets are needed to fight cancer. Aurora kinases (AK) were recently identified as vital key regulators of cell mitosis and have consequently been investigated as therapeutic targets in preclinical and clinical studies. Aurora kinase inhibitors (AKI) have been studied in many cancer types, but their potential capacity to limit or delay metastases has rarely been considered, and never in adrenal tissue. Given the lack of an effective pharmacological therapy for adrenal metastasis and adrenocortical carcinoma, we assessed AKI (VX-680, SNS314, ZM447439) in 2 cell lines (H295R and SW13 cells)...
Source: Investigational New Drugs - May 14, 2016 Category: Drugs & Pharmacology Source Type: research

Phase II trial of weekly Docetaxel, Zoledronic acid, and Celecoxib for castration-resistant prostate cancer
Conclusion The combination of Docetaxel, Celecoxib, and Zoledronic acid failed to improve OS or to offer an acceptable biologic response. We do not believe that there is compelling evidence to include either Celecoxib or Zoledronic acid in further phase II/III trials. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 10, 2016 Category: Drugs & Pharmacology Source Type: research

Peloruside A, a microtubule-stabilizing agent, induces aneuploidy in ovarian cancer cells
Summary To ensure proper chromosome segregation, mitosis is tightly regulated by the spindle assembly checkpoint (SAC). Low concentrations of microtubule-stabilizing agents can induce aneuploid populations of cells in the absence of G2/M block, suggesting pertubation of the spindle checkpoint. We investigated the effects of peloruside A, a microtubule-stabilizing agent, on expression levels of several key cell cycle proteins, MAD2, BUBR1, p55CDC and cyclin B1. Synchronized 1A9 ovarian carcinoma cells were allowed to progress through the cell cycle in the presence or absence of peloruside A. Co-immunoprecipitation ...
Source: Investigational New Drugs - May 7, 2016 Category: Drugs & Pharmacology Source Type: research

Phase 1 study on S-1 and oxaliplatin therapy as an adjuvant after hepatectomy for colorectal liver metastases
Conclusion In a patient undergoing hepatectomy for CLM, 80 mg/m2 of S-1 and 130 mg/m2 of oxaliplatin are recommended as adjuvant therapy. A further study is required to confirm the efficacy and safety of this regimen on a larger scale. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 7, 2016 Category: Drugs & Pharmacology Source Type: research

Improved in vivo antitumor effect of a daunorubicin - GnRH-III bioconjugate modified by apoptosis inducing agent butyric acid on colorectal carcinoma bearing mice
Summary Compared to classical chemotherapy, peptide-based drug targeting is a promising therapeutic approach for cancer, which can provide increased selectivity and decreased side effects to anticancer drugs. Among various homing devices, gonadotropin-releasing hormone-III (GnRH-III) peptide represents a suitable targeting moiety, in particular in the treatment of hormone independent tumors that highly express GnRH receptors (e.g. colon carcinoma). We have previously shown that GnRH-III[4Lys(Ac),8Lys(Dau = Aoa)] bioconjugate, in which daunorubicin was attached via oxime linkage to the 8Lys of a GnRH-III ...
Source: Investigational New Drugs - May 5, 2016 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic drug interactions of the selective androgen receptor modulator GTx-024(Enobosarm) with itraconazole, rifampin, probenecid, celecoxib and rosuvastatin
Summary GTx-024 (also known as enobosarm) is a first in class selective androgen receptor modulator being developed for diverse indications in oncology. Preclinical studies of GTx-024 supported the evaluation of several potential drug-drug interactions in a clinical setting. A series of open-label Phase I GTx-024 drug-drug interaction studies were designed to interrogate potential interactions with CYP3A4 inhibitor (itraconazole), a CYP3A4 inducer (rifampin), a pan-UGT inhibitor (probenecid), a CYP2C9 substrate (celecoxib) and a BCRP substrate (rosuvastatin). The plasma pharmacokinetics of GTx-024, its major metab...
Source: Investigational New Drugs - April 22, 2016 Category: Drugs & Pharmacology Source Type: research

CD20-targeting in B-cell malignancies: novel prospects for antibodies and combination therapies
Abstract Expression of CD20 antigen by the most of transformed B cells is believed to be the driving force for targeting this molecule by using anti-CD20 monoclonal antibodies. While it is true that most lymphoma/leukemia patients can be cured, these regimens are limited by the emergence of treatment resistance. Based on these observations, development of anti-CD20 monoclonal antibodies and combination therapies have been recently proposed, in particular with the aim to optimize the cytotoxic activity. Here we outline a range of new experimental agents concerning the CD20 positive B-cell tumors which provide high ...
Source: Investigational New Drugs - April 13, 2016 Category: Drugs & Pharmacology Source Type: research

A Phase I study of olaparib and irinotecan in patients with colorectal cancer: Canadian Cancer Trials Group IND 187
Conclusions Olaparib can be combined with irinotecan if administered intermittently. Both olaparib and irinotecan required significant dose reductions. The lack of anti-tumor efficacy observed in this trial makes this combination of little interest for further clinical development. Trial Registration ID NCT00535353. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 13, 2016 Category: Drugs & Pharmacology Source Type: research

A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma
Conclusions Pevonedistat was generally well tolerated at the MTD. Anticipated pharmacodynamic effects of NAE inhibition were observed with single-agent pevonedistat in peripheral blood and tumor tissue. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 8, 2016 Category: Drugs & Pharmacology Source Type: research

AZD9291 overcomes T790 M-mediated resistance through degradation of EGFR L858R/T790M in non-small cell lung cancer cells
Summary The discovery of activating mutations of epidermal growth factor receptor (EGFR) has resulted in the development of more effective treatments for non-small cell lung cancer (NSCLC). Although first-generation EGFR tyrosine kinase inhibitors (EGFR TKIs) provide significant clinical benefit, acquired resistance often occurs, most commonly (>50 %) via a T790 M resistance mutation. Although AZD9291 is selective for both T790 M and activating EGFR mutations over wild-type EGFR, it is highly active when T790 M is present, especially EGFRL858R/T790M, and modestly active when T790 M is a...
Source: Investigational New Drugs - April 5, 2016 Category: Drugs & Pharmacology Source Type: research

A phase I, dose escalation, pharmacodynamic, pharmacokinetic, and food-effect study of α 2 integrin inhibitor E7820 in patients with advanced solid tumors
Conclusions:Food had no effect on E7820 exposure. A dose of 50 mg BID was considered the MTD. Treatment with E7820 is safe and tolerable with 2/3 of patients (66.7 %) at MTD having SD as their best response. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 2, 2016 Category: Drugs & Pharmacology Source Type: research

Exposure–safety–efficacy analysis of single-agent ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma: dose selection for a phase 3 maintenance study
Summary Background Ixazomib is the first oral, small molecule proteasome inhibitor to reach phase 3 trials. The current analysis characterized the exposure-safety and exposure-efficacy relationships of ixazomib in patients with relapsed/refractory multiple myeloma (MM) with a purpose of recommending an approach to ixazomib dosing for maintenance therapy. Methods Logistic regression was used to investigate relationships between ixazomib plasma exposure (area under the curve/day; derived from individual apparent clearance values from a published population pharmacokinetic analysis) and safety/efficacy...
Source: Investigational New Drugs - April 2, 2016 Category: Drugs & Pharmacology Source Type: research

Metabolite profiling of the multiple tyrosine kinase inhibitor lenvatinib: a cross-species comparison
The objective of the current study was to further elucidate the metabolic pathways of lenvatinib in humans and to compare these results to the metabolism in rats and monkeys. To this end, we used plasma, urine and feces collected in a human mass balance study after a single 24 mg (100 μCi) oral dose of 14C-lenvatinib. Metabolites of 14C-lenvatinib were identified using liquid chromatography (high resolution) mass spectrometry with off-line radioactivity detection. Close to 50 lenvatinib-related compounds were detected. In humans, unchanged lenvatinib accounted for 97 % of the radioactivity in plasma, and ...
Source: Investigational New Drugs - March 28, 2016 Category: Drugs & Pharmacology Source Type: research

Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors
Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 22, 2016 Category: Drugs & Pharmacology Source Type: research

Randomized phase II trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer
Conclusion The addition of veliparib to cyclophosphamide, at the dose and schedule evaluated, did not improve the response rate over cyclophosphamide treatment alone in patients with heavily pre-treated triple-negative breast cancer. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 21, 2016 Category: Drugs & Pharmacology Source Type: research

The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells
Summary Inhibitors of kinesin spindle protein Eg5 are characterized by pronounced antitumor activity. Our group has recently synthesized and screened a library of 1,3,4-thiadiazoline analogues with the pharmacophoric structure of K858, an Eg5 inhibitor. We herein report the effects of K858 on four different breast cancer cell lines: MCF7 (luminal A), BT474 (luminal B), SKBR3 (HER2 like) and MDA-MB231 (basal like). We demonstrated that K858 displayed anti-proliferative activity on every analyzed breast cancer cell line by inducing apoptosis. However, at the same time, we showed that K858 up-regulated survivin, an a...
Source: Investigational New Drugs - March 19, 2016 Category: Drugs & Pharmacology Source Type: research

A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers
Conclusions ASG-5ME treatment was generally well tolerated with limited evidence of antitumor activity. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 18, 2016 Category: Drugs & Pharmacology Source Type: research

Molecular mode of action of NKP-1339 – a clinically investigated ruthenium-based drug – involves ER- and ROS-related effects in colon carcinoma cell lines
Abstract Sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339) is a clinically investigated ruthenium-based metal complex, which shows promising results in solid tumors, such as non-small cell lung cancer, colorectal carcinoma, and most distinctively in gastrointestinal neuroendocrine tumors. In previous studies, fast binding to albumin as well as transferrin could be shown. The enhanced permeability and retention (EPR) effect, which is diversely being exploited for tumor targeting, could therefore be applicable for NKP-1339. Here we studied the serum dependence of its biological activity in variou...
Source: Investigational New Drugs - March 18, 2016 Category: Drugs & Pharmacology Source Type: research

Peptide aptamer identified by molecular docking targeting translationally controlled tumor protein in leukemia cells
Summary Bioinformatics screening and molecular docking analyses were utilized to select high affinity peptides targeting translationally controlled tumor protein (TCTP). Selected peptide aptamers were tested towards cancer cell lines with different levels of TCTP expression. One peptide (WGQWPYHC) revealed specific cytotoxicity according to the TCTP expression in tumor cells without affecting normal cells. Western blot analysis showed peptide-induced down-regulation of TCTP as primary target as well as of cell-cycle related downstream proteins (CDK2, CDK6, Cyclin D3) in MOLT-4 leukemia cells. “WGQWPYHC&rdquo...
Source: Investigational New Drugs - March 14, 2016 Category: Drugs & Pharmacology Source Type: research

Microtubule-stabilizing properties of the avocado-derived toxins (+)-( R )-persin and (+)-( R )-tetrahydropersin in cancer cells and activity of related synthetic analogs
Summary The avocado toxin (+)-R-persin (persin) is active at low micromolar concentrations against breast cancer cells and synergizes with the estrogen receptor modulator 4-hydroxytamoxifen. Previous studies in the estrogen receptor-positive breast cancer cell line MCF-7 indicate that persin acts as a microtubule-stabilizing agent. In the present study, we further characterize the properties of persin and several new synthetic analogues in human ovarian cancer cells. Persin and tetrahydropersin cause G2M cell cycle arrest and increase intracellular microtubule polymerization. One analog (4-nitrophenyl)-deshydroxyp...
Source: Investigational New Drugs - March 12, 2016 Category: Drugs & Pharmacology Source Type: research

Why balls are not put inside the basket? A reflection on testicular cancer clinical trial design
Summary New concepts of trial design are being developed based on biomarkers, namely basket and umbrella trials. Basket trials appear optimally positioned to evaluate new molecular markers for testicular germ cell tumors, a rare heterogeneous disease with relatively few molecular alterations. However, not uncommonly, the “balls” fall outside the “basket”. In this short communication, we discussed the different causes limiting the inclusion of TGCT in basket trials and we proposed a new design for trials suitable for this malignancy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 10, 2016 Category: Drugs & Pharmacology Source Type: research

Phase I study of IMGN901, a CD56-targeting antibody-drug conjugate, in patients with CD56-positive solid tumors
Conclusions The RP2D for IMGN901 of 60 mg/m2 administered for 3 consecutive days every 3 weeks was associated with an acceptable tolerability profile. Objective responses were observed in patients with advanced CD56+ cancers. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 9, 2016 Category: Drugs & Pharmacology Source Type: research

Convection-enhancement delivery of liposomal formulation of oxaliplatin shows less toxicity than oxaliplatin yet maintains a similar median survival time in F98 glioma-bearing rat model
In conclusion, a better tumoral accumulation was achieved when oxaliplatin and Lipoxal™ were injected by CED. The liposomal encapsulation of oxaliplatin reduced its toxic, while maintaining its antitumor potential. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 9, 2016 Category: Drugs & Pharmacology Source Type: research

A first-in-human dose-escalation study of the oral proteasome inhibitor oprozomib in patients with advanced solid tumors
Conclusions While generally low-grade, clinically relevant gastrointestinal toxicities occurred frequently with this oprozomib formulation. Despite dose-dependent increases in pharmacokinetics and pharmacodynamics, single-agent oprozomib had minimal antitumor activity in this patient population with advanced solid tumors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 29, 2016 Category: Drugs & Pharmacology Source Type: research

A multicenter phase 1/2a dose-escalation study of the antioxidant moiety of vitamin E 2,2,5,7,8-pentamethyl-6-chromanol (APC-100) in men with advanced prostate cancer
Conclusions APC-100 is a novel agent with dual mechanism of action functioning both as potent antioxidant as well as antiandrogen. No detectable APC-100 was found in the plasma at dose level 5 (2100 mg) and it was felt that maximal feasibility was nearly reached. APC-100 is being reformulated as a tablet to allow further dose escalation. Once a recommended phase 2 dose is established, future studies in prostate cancer chemoprevention should be conducted. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 29, 2016 Category: Drugs & Pharmacology Source Type: research

Phase II study of amrubicin (SM-5887), a synthetic 9-aminoanthracycline, as first line treatment in patients with metastatic or unresectable soft tissue sarcoma: durable response in myxoid liposarcoma with TLS-CHOP translocation
Conclusions Amrubicin has efficacy comparable to doxorubicin in adult STS, is well tolerated and has no significant cardiac toxicity up to a cumulative dose of 4800 mg /m2. Topoisomerase II inhibition with amrubicin warrants further study as a potential ‘targeted therapy’ for TLS-CHOP-translocated myxoid liposarcoma. Results from this trial favor the use of amrubicin for the treatment of STS. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 20, 2016 Category: Drugs & Pharmacology Source Type: research

A never-smoker lung adenocarcinoma patient with a MET exon 14 mutation (D1028N) and a rapid partial response after crizotinib
We describe a case of clinical activity of crizotinib in a female patient with a lung adenocarcinoma displaying a MET exon 14 donor splice site mutation (D1028N) detected using next generation sequencing. Within 5 weeks of crizotinib therapy, a partial response was observed in this 67 year-old woman. Further clinical trials of crizotinib are needed for non-small cell lung cancer exhibiting MET mutations. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 18, 2016 Category: Drugs & Pharmacology Source Type: research

The novel pyrrolo-1,5-benzoxazepine, PBOX-15, synergistically enhances the apoptotic efficacy of imatinib in gastrointestinal stromal tumours; suggested mechanism of action of PBOX-15
In conclusion, our findings indicate the potential of PBOX-15 to improve the apoptotic response of IM in GIST cells and provide a more effective treatment option for GIST patients. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 17, 2016 Category: Drugs & Pharmacology Source Type: research