Identification of cellular and molecular factors determining the response of cancer cells to six ergot alkaloids
In conclusion, the cytotoxicity of ergot alkaloids is not involved in classical mechanisms of drug resistance opening the possibility to bypass resistance and to treat otherwise drug-resistant and refractory tumors. The modes of action are multifactorial, which is a typical feature of many natural compounds. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 24, 2014 Category: Drugs & Pharmacology Source Type: research

BYL719, a selective inhibitor of phosphoinositide 3-Kinase α, enhances the effect of selumetinib (AZD6244, ARRY-142886) in KRAS-mutant non-small cell lung cancer
Conclusion Taken together, these data suggest that combination treatment with selumetinib and BYL719 is a promising therapeutic approach to overcoming resistance to MEK inhibitors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 24, 2014 Category: Drugs & Pharmacology Source Type: research

Phase I dose-escalation study evaluating safety, tolerability and pharmacokinetics of MEDI-573, a dual IGF-I/II neutralizing antibody, in Japanese patients with advanced solid tumours
Conclusions MEDI-573 is well tolerated at the doses investigated. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 24, 2014 Category: Drugs & Pharmacology Source Type: research

Preclinical combination therapy of the investigational drug NAMI-A + with doxorubicin for mammary cancer
Conclusions The combined therapy of NAMI-A with doxorubicin synergizes on lung metastasis in a preclinical mouse model. The combination therapy at the maximum tolerated doses of the two drugs is toxic. Hence, this combination is not suitable for clinical studies using maximum tolerated doses. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 23, 2014 Category: Drugs & Pharmacology Source Type: research

Novel benzoxazines as inhibitors of angiogenesis
In this study, we screened eight novel benzoxazine inhibitors of both PI3K isoforms and the related DNA-PK, for their anti-angiogenic effects. Our findings identified the novel benzoxazine (7, 8 (substituted)-2-morpholino-benz (1,3) oxazine: LTUSI122) to be non-toxic at concentrations up to 5 μM, while exhibiting significant inhibition of various aspects of angiogenesis including endothelial proliferation, migration and tube formation. The molecular mechanisms were examined using an angiogenesis array, revealing inhibition of several proliferative and migratory angiogenic factors, including VEGFR, MMP, IL-8, uPAR a...
Source: Investigational New Drugs - October 23, 2014 Category: Drugs & Pharmacology Source Type: research

A phase Ib study of linsitinib (OSI-906), a dual inhibitor of IGF-1R and IR tyrosine kinase, in combination with everolimus as treatment for patients with refractory metastatic colorectal cancer
Conclusions The MTD of OSI-906 and everolimus was 50 mg BID and 5 mg QD, respectively. No indications of clinical activity were observed in refractory mCRC patients. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 22, 2014 Category: Drugs & Pharmacology Source Type: research

A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer
Conclusions Combination trastuzumab, lapatinib, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with advanced malignancy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 18, 2014 Category: Drugs & Pharmacology Source Type: research

A multicenter phase 1 study of γ -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors
Conclusions The recommended phase 2 dose is capecitabine 1,000 mg/m2 orally twice daily on days 1 through 14 with RO4929097 20 mg orally once daily on days 1–3, 8–10 and 15–17 with a 21 day cycle. Clinical benefit was observed in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. Plasma concentrations of RO4929097 were above those needed for Notch inhibition. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 16, 2014 Category: Drugs & Pharmacology Source Type: research

A phase II trial of bevacizumab plus temsirolimus in patients with advanced hepatocellular carcinoma
Conclusion This first-line HCC trial evaluating the BEV/TEM doublet reports an ORR of 19 % and OS of 14 months which is favorable but requires further study at a more optimized dose and schedule. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 16, 2014 Category: Drugs & Pharmacology Source Type: research

Phase 1 trial of tivantinib in combination with sorafenib in adult patients with advanced solid tumors
Conclusions The combination treatment could be administered at full standard single-agent doses in all patients except those with HCC, where tivantinib was lowered to 240 mg BID. Preliminary evidence of anticancer activity was observed in patients with RCC, HCC, and melanoma, including patients refractory to sorafenib and/or other anti-VEGF pathway therapies. The combination treatment has therapeutic potential in treating a variety of solid tumors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - October 8, 2014 Category: Drugs & Pharmacology Source Type: research

Pharmacology, immunogenicity, and efficacy of a novel pegylated recombinant Erwinia chrysanthemi-derived L-asparaginase
Summary Bacterial L-asparaginase (ASNase), hydrolyzing L-asparagine (Asn), is an indispensable component used in the treatment of acute lymphoblastic leukemia (ALL) and certain lymphoma entities. Native Erwinia chrysanthemi-derived ASNase (n-crisantaspase) has been approved as a second-line drug for treating patients exhibiting allergy syndromes to native and pegylated Escherichia coli-derived ASNase (EC-ASNase). However, it still induces hypersensitivity in at least 17 % of treated patients. In the present study, we investigated the pharmacological activity, immunogenicity and anti-leukemic activity of a ne...
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

Preclinical analyses and phase I evaluation of LY2603618 administered in combination with Pemetrexed and cisplatin in patients with advanced cancer
Summary LY2603618 is an inhibitor of checkpoint kinase 1 (CHK1), an important regulator of the DNA damage checkpoints. Preclinical experiments analyzed NCI-H2122 and NCI-H441 NSCLC cell lines and in vitro/in vivo models treated with pemetrexed and LY2603618 to provide rationale for evaluating this combination in a clinical setting. Combination treatment of LY2603618 with pemetrexed arrested DNA synthesis following initiation of S-phase in cells. Experiments with tumor-bearing mice administered the combination of LY2603618 and pemetrexed demonstrated a significant increase of growth inhibition of NCI-H2122 (H2122)...
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

Novel antitumour indole alkaloid, Jerantinine A, evokes potent G2/M cell cycle arrest targeting microtubules
Summary Natural products play a pivotal role in the treatment of cancer; identification of compounds such as taxanes and the vinca alkaloids were seminal landmarks in natural product drug discovery. Jerantinine A, a novel Aspidosperma alkaloid isolated from plant species Tabernaemontana corymbosa, was previously reported to possess cytotoxic activity against vincristine-resistant nasopharyngeal carcinoma cells and is therefore an ideal candidate for biological investigation. Furthermore, Tabernaemontana corymbosa, has been placed in the endangered list of threatened species by the International Union for Conserva...
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3)
Conclusions ASP9521 is a potent, selective, orally bioavailable AKR1C3 inhibitor. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): a trial of the Eastern Cooperative Oncology Group
Conclusions The combination of doxorubicin and bortezomib was well-tolerated in patients with hepatocellular carcinoma, but the primary endpoint was not met. Exploratory analyses of markers of proteasome inhibition suggest a possible prognostic and predictive role and should be explored further in tumor types for which bortezomib is efficacious. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine
We present the identification and characterization of a potent CDK4/6 inhibitor, LY2835219. LY2835219 inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. In vivo target inhibition studies show LY2835219 is a potent inhibitor of Rb phosphorylation, induces a complete cell cycle arrest and suppresses expression of several Rb-E2F-regulated proteins 24 hours after a single dose. Oral administration of LY2835219 inhibits tumor growth in human tumor xenografts representing different hist...
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

Activity of the polyamine-vectorized anti-cancer drug F14512 against pediatric glioma and neuroblastoma cell lines.
Summary The poor prognosis of children with high-grade glioma (HGG) and high-risk neuroblastoma, despite multidisciplinary therapeutic approaches, demands new treatments for these indications. F14512 is a topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells via the Polyamine Transport System (PTS) and increases topoisomerase II poisoning. Here, F14512 was evaluated in pediatric HGG and neuroblastoma cell lines. PTS activity and specificity were evaluated using a fluorescent spermine-coupled probe. The cytotoxicity of F14512, alone or in combination with ionizing...
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic/Pharmacodynamic modeling of abexinostat-induced thrombocytopenia across different patient populations: application for the determination of the maximum tolerated doses in both lymphoma and solid tumour patients
Conclusions The PKPD model was able to predict thrombocytopenia following abexinostat administration in both patient populations. A model-based approach to determine the recommended dose in phase I trials is preferable due to the imprecision of the 3 + 3 design. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors
Conclusions: The combination of navitoclax 325 mg with gemcitabine 1,000 mg/m2 was generally well tolerated and exhibited a favorable safety profile in patients with advanced solid tumors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

Rituximab for treating CD20+ prostate cancer with generalized lymphadenopathy: a case report and review of the literature
We report a case of advanced prostate cancer presenting with generalized lymphadenopathy that expressed CCR7 and CD20. CCR7 expression in prostate cancer has been previously reported only once; the expression of CD20 has not been reported before. Rituximab therapy was initiated in this case and resulted in a significant biochemical response. This unique metastatic and biochemical pattern may signify a distinct subtype of prostate cancer that may be amenable to treatment with anti-CD20 antibodies. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

A phase I study of decitabine with pegylated interferon α-2b in advanced melanoma: impact on DNA methylation and lymphocyte populations
Conclusions The response to this combination regimen was characterized by significant myelosuppression, particularly neutropenia. Although disappointing efficacy and slow accrual led to early closure of the trial, hypomethylation showed pharmacodynamic evidence of a therapeutic effect of decitabine at all dose levels. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

Effects of the combination of TRC105 and bevacizumab on endothelial cell biology
In this report, we evaluated the effects of TRC105 on primary human umbilical vascular endothelial cells (HUVEC) as a single agent and in combination with bevacizumab. As single agents, both TRC105 and bevacizumab efficiently blocked HUVEC tube formation, and the combination of both agents achieved even greater levels of inhibition. We further assessed the effects of each drug on various aspects of HUVEC function. While bevacizumab was observed to inhibit HUVEC viability in nutrient-limited medium, TRC105 had little effect on HUVEC viability, either alone or in combination with bevacizumab. Additionally, both drugs inhibit...
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

In vitro 3D colon tumor penetrability of SRJ09, a new anti-cancer andrographolide analog
In conclusion, SRJ09 successfully penetrated through DLD-1 MCL by diffusion and emerged as a potential candidate to be developed as a clinically viable anti-colon cancer drug. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

The novel kinase inhibitor EMD1214063 is effective against neuroblastoma
Conclusions Treatment of neuroblastoma tumor cells with EMD1214063 inhibits HGF-induced c-Met phosphorylation and results in cell death. EMD1214063 treatment is also effective in reducing tumor growth in vivo. EMD1214063 therefore represents a novel therapeutic agent for neuroblastoma, and further preclinical studies of EMD1214063 are warranted. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer
This study assessed the efficacy and safety of low dose oral PARP inhibitor veliparib (ABT-888) and temozolomide (TMZ) in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) in a single-arm, open-label, pilot study. Patients with mCRPC progressing on at least one docetaxel-based therapy and prostate specific antigen (PSA) ≥ 2 ng/mL were treated with veliparib 40 mg twice daily on days 1–7 and TMZ once daily (150 mg/m2/day cycle 1; if well tolerated then 200 mg/m2/day cycle 2 onwards) on days 1–5 q28 days. Patients received 2 (me...
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

A phase I safety and pharmacokinetic study of ABT-263 in combination with carboplatin/paclitaxel in the treatment of patients with solid tumors
Summary Bcl-2 family proteins are the key regulators of the intrinsic apoptotic pathway, controlling the point-of no-return and setting the threshold to engage the death machinery in response to chemical damage. Bcl-2 proteins have emerged as attractive targets for anti-cancer drug development. Navitoclax is a selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor. Primary endpoints assessed the safety and pharmacokinetic (PK) interactions between navitoclax in combination with carboplatin/paclitaxel or paclitaxel alone in patients with solid tumors The study comprised two arms, one a combination ...
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

Gemcitabine and oxaliplatin chemotherapy for advanced hepatocellular carcinoma after failure of anti-angiogenic therapies
Summary Background Sorafenib is the only systemic treatment that has shown a significant benefit in overall survival (OS) and in progression-free survival (PFS) in advanced hepatocellular carcinoma (HCC) patients. No standard of care currently exists for second-line treatment. The association of Gemcitabine-Oxaliplatine (GEMOX) has shown efficacy in the first-line setting. The aim of this study was to evaluate the efficacy of GEMOX after failure of at least one line of anti-angiogenic (AA) therapy. Patient and methods We performed a multicenter retrospective analysis of advanced HCC patients that rece...
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

Phase I study on the safety, pharmacokinetic profile, and efficacy of the combination of TSU-68, an oral antiangiogenic agent, and S-1 in patients with advanced hepatocellular carcinoma
Conclusion The recommended dose for advanced HCC should be 400 mg/day TSU-68 and 100 mg/day S-1 for 4 weeks followed by 2-week rest. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

Atypical reversible posterior leukoencephalopathy syndrome (RPLS) induced by cediranib in a patient with metastatic rectal cancer
Conclusion RPLS is a rare, but serious, clinicoradiologic syndrome which has been described as an adverse effect of many anti-angiogenic agents and should also be considered in patients on cediranib who present with neurologic symptoms along with vasogenic edema seen on MRI. If RPLS is suspected, cediranib should be discontinued and blood pressure should be aggressively controlled. (Source: Investigational New Drugs)
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research

The use of everolimus to reverse tamoxifen resistance in men with metastatic breast cancer: a case report
(Source: Investigational New Drugs)
Source: Investigational New Drugs - September 25, 2014 Category: Drugs & Pharmacology Source Type: research