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Evaluating imbalances of adverse events during biosimilar development.

Biosimilars are designed to be highly similar to approved or licensed (reference) biologics and are evaluated based on the totality of evidence from extensive analytical, nonclinical and clinical studies. As part of the stepwise approach recommended by regulatory agencies, the first step in the clinical evaluation of biosimilarity is to conduct a pharmacokinetics similarity study in which the potential biosimilar is compared with the reference product. In the context of biosimilar development, a pharmacokinetics similarity study is not necessarily designed for a comparative assessment of safety. Development of PF-05280014, a potential biosimilar to trastuzumab, illustrates how a numerical imbalance in an adverse event in a small pharmacokinetics study can raise questions on safety that may require additional clinical trials.

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Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition.

The PI3K pathway is hyperactivated in many cancers, including 70 % of breast cancers. Pan- and isoform-specific inhibitors of the PI3K pathway are currently being evaluated in clinical trials. However, the clinical responses to PI3K inhibitors when used as single agents are not as efficient as expected.
In order to anticipate potential molecular mechanisms of resistance to the p110α isoform-selective inhibitor BYL719, we developed resistant breast cancer cell lines, assessed the concomitant changes in cellular signaling pathways using unbiased phosphotyrosine proteomics and characterized the mechanism of resistance using pharmacological inhibitors.
We found an increase in IGF1R, IRS1/IRS2 and p85 phosphorylation in the resistant lines. Co-immunoprecipitation experiments identified an IGF1R/IRS/p85/p110β complex that causes the activation of AKT/mTOR/S6K and stifles the effects of BYL719. Pharmacological inhibition of members of this complex reduced mTOR/S6K activation and restored sensitivity to BYL719.
Our study demonstrates that the IGF1R/p110β/AKT/mTOR axis confers resistance to BYL719 in PIK3CA mutant breast cancers. This provides a rationale for the combined targeting of p110α with IGF1R or p110β in patients with breast tumors harboring PIK3CA mutations.

Phase I Study of Lapatinib and Pemetrexed in the Second-Line Treatment of Advanced or Metastatic Non-Small-Cell Lung Cancer With Assessment of Circulating Cell Free Thymidylate Synthase RNA as a Potential Biomarker.

Lapatinib is a dual tyrosine kinase inhibitor that targets epidermal growth factor receptor and HER2. We report on a dose-escalation study of lapatinib combined with pemetrexed in second-line treatment to evaluate the safety and efficacy in advanced or metastatic non-small-cell lung cancer (NSCLC) and an exploratory study in which circulating cell-free thymidylate synthase ribonucleic acid (cfTSmRNA) was measured in all patients and compared with clinical benefit.
Eligible patients had stage IIIB or IV NSCLC after 1 previous line of chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 to 2. Three dose levels (DLs) of lapatinib (daily)/pemetrexed (every 21 days) were evaluated: DL0, 1250 mg/400 mg; DL1, 1250 mg/500 mg; and DL2, 1500 mg/500 mg, respectively. The primary outcome was identification of the optimal treatment regimen.
Eighteen patients were treated (DL0: n = 4; DL1: n = 8; DL2: n = 6). The most common adverse events (any grade) were diarrhea (61%), rash (44%), nausea (33%), anemia, and fatigue (both 28%). DL1 was determined as optimal after 3 dose-limiting toxicities (DLTs) during the first cycle of DL2 (Grade 3 diarrhea and mucositis, Grade 4 lymphocytopenia); no other DLTs were observed. Partial response was detected in 4 patients. cfTSmRNA was at the limit of detection and was not measurable in all patients. Nonsignificant trends were observed, suggesting that higher levels of cfTSmRNA are associated with poorer outcome. Confirmatory studies are required.
Lapatinib and pemetrexed was well tolerated, and data suggest a similar response rate to pemetrexed monotherapy.
Copyright © 2015 Elsevier Inc. All rights reserved.

Antibiotic susceptibility in Streptococcus pneumoniae, Haemophilus influenzae and Streptococcus pyogenes in Pakistan: a review of results from the Survey of Antibiotic Resistance (SOAR) 2002-15.

To investigate changes in the antibiotic susceptibility of Streptococcus pneumoniae, Haemophilus influenzae and Streptococcus pyogenes from the Survey of Antibiotic Resistance (SOAR) in community-acquired respiratory tract infections (CA-RTIs) between 2002 and 2015 in Pakistan.
This is a review based on previously published studies from 2002-03, 2004-06 and 2007-09 and also new data from 2014-15. Susceptibility was determined by Etest() or disc diffusion according to CLSI and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints.
A total of 706 isolates from CA-RTIs comprising 381 S. pneumoniae, 230 H. influenzae and 95 S. pyogenes were collected between 2002 and 2015 and tested against a range of antibiotics. Antibiotic resistance in S. pneumoniae rose steeply from 2002 to 2009, with isolates non-susceptible to penicillin and macrolides increasing from 10% to 34.1% and from 13%-14% to 29.7%, respectively. Susceptibility to amoxicillin/clavulanic acid (and by inference amoxicillin) remained between 99.4% and 100% from 2002 to 2015. Over the years, the prevalence of susceptibility to cefuroxime was 98%-100% among S. pneumoniae. Resistance in S. pneumoniae to some older antibiotics between 2007 and 2009 was high (86.8% for trimethoprim/sulfamethoxazole and 57.2% for tetracycline). Between 2002 and 2015, ampicillin resistance (β-lactamase-positive strains) among H. influenzae has remained low (between 2.6% and 3.2%) and almost unchanged over the years (H. influenzae was not tested during 2004-06). For S. pyogenes isolates, macrolide resistance reached 22%; however, susceptibility to penicillin, amoxicillin/clavulanic acid and cefuroxime remained stable at 100%.
In S. pneumoniae from Pakistan, there has been a clear reduction in susceptibility to key antibiotics since 2002, but not to amoxicillin/clavulanic acid (amoxicillin) or cefuroxime. However, susceptibility in H. influenzae has remained stable. Local antibiotic susceptibility/resistance data are essential to support informed prescribing for CA-RTIs and other infections.
© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected].

Reductive carboxylation supports redox homeostasis during anchorage-independent growth.

Cells receive growth and survival stimuli through their attachment to an extracellular matrix (ECM). Overcoming the addiction to ECM-induced signals is required for anchorage-independent growth, a property of most malignant cells. Detachment from ECM is associated with enhanced production of reactive oxygen species (ROS) owing to altered glucose metabolism. Here we identify an unconventional pathway that supports redox homeostasis and growth during adaptation to anchorage independence. We observed that detachment from monolayer culture and growth as anchorage-independent tumour spheroids was accompanied by changes in both glucose and glutamine metabolism. Specifically, oxidation of both nutrients was suppressed in spheroids, whereas reductive formation of citrate from glutamine was enhanced. Reductive glutamine metabolism was highly dependent on cytosolic isocitrate dehydrogenase-1 (IDH1), because the activity was suppressed in cells homozygous null for IDH1 or treated with an IDH1 inhibitor. This activity occurred in absence of hypoxia, a well-known inducer of reductive metabolism. Rather, IDH1 mitigated mitochondrial ROS in spheroids, and suppressing IDH1 reduced spheroid growth through a mechanism requiring mitochondrial ROS. Isotope tracing revealed that in spheroids, isocitrate/citrate produced reductively in the cytosol could enter the mitochondria and participate in oxidative metabolism, including oxidation by IDH2. This generates NADPH in the mitochondria, enabling cells to mitigate mitochondrial ROS and maximize growth. Neither IDH1 nor IDH2 was necessary for monolayer growth, but deleting either one enhanced mitochondrial ROS and reduced spheroid size, as did deletion of the mitochondrial citrate transporter protein. Together, the data indicate that adaptation to anchorage independence requires a fundamental change in citrate metabolism, initiated by IDH1-dependent reductive carboxylation and culminating in suppression of mitochondrial ROS.