Bosutinib is a recently approved ABL inhibitor. In spite of the well-documented effectiveness of BCR-ABL inhibitors in treating chronic myeloid leukemia, development of resistance is a continuous clinical challenge. Transporters that facilitate drug uptake and efflux have been proposed as one potential source of resistance to tyrosine kinase inhibitor treatment. Our aim was to determine which carriers are responsible for bosutinib transport.
K562S cells overexpressing the drug transporters ABCB1, ABCG2, and SLC22A1 were generated, characterized and used in proliferation assay and intracellular uptake and retention assay (IUR). In vivo experiments were performed in nude mice injected with K562S, K562DOX cells (overexpressing ABCB1), and K562DOX silenced for ABCB1 (K562DOX/sh P-GP).
The IUR assay using C-14 bosutinib showed that only ABCB1 was responsible for active bosutinib transport. K562DOX cells showed the lowest intracellular level of bosutinib, while K562DOX cells treated with the ABCB1 inhibitor verapamil showed intracellular bosutinib levels comparable with parental K562S. Proliferation assays demonstrated that K562DOX are resistant to bosutinib treatment while verapamil is able to restore the sensitivity to the drug. Nude mice injected with K562DOX and treated with bosutinib showed very limited response and quickly relapsed after stopping treatment while K562S as well as K562DOX/sh P-GP remained tumor-free.
Our data suggest that the analysis of ABCB1 expression levels might help determine treatment options for patients exhibiting resistance to bosutinib.

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On March 24, 2016 SRI International announced a new collaborative project between scientists at SRI International and physician-researchers from Stanford Cancer Institute that will support development of novel drugs for treatment of triple-negative breast cancer (Press release, SRI International, MAR 25, 2016, View Source [SID:1234510020]).

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Close to 20 percent of breast cancers are triple-negative, a type of tumor that lacks the three most common receptors that fuel most breast cancer growth. These tumors are unresponsive to hormone therapy or drugs targeting these receptors.

The research collaboration will explore the use of a preclinical drug known as sudemycin D6 that targets a "molecular machine" called the spliceosome. The spliceosome is critical to the basic biological transformation of DNA to RNA to proteins.

It "edits" raw RNA transcribed from DNA, cutting and piecing together stretches of code to form the instructions for creating various functional proteins, much as a film editor crafts a finished movie from raw footage. If this biological editor complex is defective, proteins that ultimately result from its actions can be dysfunctional and lead to various forms of cancer, including triple-negative breast cancer.

The research team will be led by Thomas R. Webb, Ph.D., director of Medicinal Chemistry at SRI Biosciences, a division of SRI International, and George Sledge, M.D., professor and chief of the Division of Oncology at Stanford University Medical Center.

"As both a medicinal chemist and cancer survivor, I know that new treatments are desperately needed for cancer," said Webb.

"It is my greatest hope that we can combine the unique strengths of SRI Biosciences and the Stanford Cancer Institute to make long-lasting impact in the treatment of triple-negative breast cancer, where unfortunately there are currently few effective therapeutic options. The strategy may also work for a range of other cancers, including lymphoma, melanoma, and certain brain and colon cancers."

"Stanford and SRI both have unique strengths, and together we can create something wonderful for patients with cancer: new treatments that are more effective and less toxic," said Dr. Sledge.

Webb’s research group designed sudemycin D6 to neutralize the SF3B1 protein of the spliceosome with enhanced activity and duration of action as well as less toxicity than previous spliceosome targeting agents. The team has also developed a marker tumor cell line that fluorescently glows when treated with sudemycin D6. This advance enables real-time monitoring of the drug’s activity, which will support translation to the clinical setting.

The SRI Biosciences and Stanford Cancer Institute collaboration is the first step in determining whether sudemycin D6 may be effective against triple-negative breast cancer. As part of the research, tumor samples from anonymous patients will be analyzed at the molecular level and examined in mouse models.

Nathan Collins Ph.D., vice president of Pharmaceutical and Chemical Technologies in SRI Biosciences and Sanjay Malhotra Ph.D., FRSC, associate professor of radiation oncology at Stanford are co-directors of the SRI Biosciences – Stanford Drug Discovery and Development Program that was announced in January 2016 to combine the translational capabilities of both organizations focused on creating a pipeline of innovative cancer drugs for unmet needs in oncology.

According to Malhotra, "The Webb-Sledge collaboration is an excellent example of how translation of a lab discovery into clinic can be expedited though the Stanford-SRI Drug Discovery and Development program. This is a new program, and we hope our wider research community will benefit from our joint efforts."

"Building on our collaborative program we are delighted to be working with the Stanford Cancer Institute to develop therapies for serious unmet needs in the treatment of cancer," added Collins.

Treatment of acute myeloid leukemia (AML) remains difficult owing to the development of treatment resistance, which might be overcome through antagonists of inhibitors of apoptosis proteins (IAPs).
The present multicenter, open-label, dose-escalation study aimed to evaluate the tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of Debio1143 (formerly AT-406), a new IAP antagonist, when given along with a standard "7 plus 3 regimen" of daunorubicin and cytarabine to poor-risk patients with AML during the induction cycle. Consecutive patient cohorts received once-daily 100, 200, 300, or 400 mg of oral Debio1143 on treatment days 1 to 5. Blood samples were collected regularly until hematologic recovery or response was documented. Bone marrow samples were collected on days 0, 14, and 29 and PK and PD samples on days 1, 3, 5, 8, and 10 and 1, 2, and 8, respectively.
Of the 29 enrolled patients, 23 completed the study. The most common adverse events of any grade deemed related to treatment were nausea (31% of patients), diarrhea (14%), and febrile neutropenia (14%). Exposure exceeded dose proportionality, without accumulation over 5 days. Inhibition of cellular IAP1 was detectable in the CD34/CD117(+) cells and blasts. A total of 11 patients (38%) achieved complete remission, most in the 100-mg dose cohort. Of these, 6 (56%) developed a relapse within the study period. The patients with a response more frequently showed plasma increases of tumor necrosis factor-α and interleukin-8 after the first dose of Debio1143.
Debio1143 ≤ 400 mg/d showed good tolerability in combination with daunorubicin and cytarabine. Additional studies in subsets of patients with AML are warranted.
Copyright © 2015 Elsevier Inc. All rights reserved.

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Engineered nanoparticles (eNPs) for biological and biomedical applications are produced from functionalised nanoparticles (NPs) after undergoing multiple handling steps, giving rise to an inevitable loss of NPs. Herein we present a practical method to quantify nanoparticles (NPs) number per volume in an aqueous suspension using standard spectrophotometers and minute amounts of the suspensions (up to 1 μL). This method allows, for the first time, to analyse cellular uptake by reporting NPs number added per cell, as opposed to current methods which are related to solid content (w/V) of NPs. In analogy to the parameter used in viral infective assays (multiplicity of infection), we propose to name this novel parameter as multiplicity of nanofection.

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For regulatory purposes, in a trial comparing two active treatments, a hypothesis such as noninferiority or superiority must be prespecified even when there is little known about how they compare against each other or when the objective is simply to identify the best. In this paper, we extend an alternative classification methodology, the classification approach of Qu et al (Statistics in Medicine, 30:3488-3495), to compare two active treatments when outcomes are binary and time-to-event variables. This method based on estimation approach instead of hypothesis testing can be useful when little prior information is available on which treatment has better efficacy. The entire decision space is divided into eight distinct possible outcomes based on predefined lower and upper non-inferiority margins, and the conclusion will be drawn according to the location of the confidence interval for relative risk or hazard ratio (or its logarithm transformation). We demonstrate theoretically that this method controls the misclassification rate at the specified level. We also illustrate the method by simulations and using data from a Phase 3 first-line nonsmall cell lung cancer study.

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