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Krop I.,Dana-Farber Cancer Institute | Akcakanat A.,Investigational Cancer Therapeutics anderson Cancer Center | Culotta K.S.,Experimental Therapeutics | Tarco E.,Investigational Cancer Therapeutics anderson Cancer Center | And 8 more authors.
Journal of the National Cancer Institute | Year: 2015

Background: There is preclinical synergism between taxanes and MK-2206. We aim to determine the maximum tolerated dose, safety, and activity of combining MK-2206 and paclitaxel in metastatic cancer. Methods: Patients received weekly doses of paclitaxel at 80mg/m2 on day 1, followed by MK-2206 orally on day 2 escalated at 90mg, 135mg, and 200mg. Treatment continued until progression, excessive toxicity, or patient request. Blood and tissue were collected for pharmacokinetic and pharmacodynamics markers. A cycle consisted of three weeks of therapy. Dose-limiting toxicity (DLT) was defined as unacceptable toxicity during the first cycle. All statistical tests were two-sided. Results: Twenty-two patients were treated, nine in dose escalation and 13 in dose expansion. Median age was 55 years. Median number of cycles was four. Dose escalation was completed with no DLT. CTCAE Grade 3 or higher adverse events were fatigue (n = 2), rash (n = 2), hyperglycemia (n = 1), and neutropenia (n = 7). Four patients in the expansion phase required MK-2206 dose reduction. Phase II recommended dose was established as paclitaxel 80mg/m2 weekly on day 1, and MK-2206 135mg weekly on day 2. Paclitaxel systemic exposure was similar in the presence or absence of MK-2206. Plasma MK-2206 concentrations were similar to data from previous phase I monotherapy. There was a statistically significant decrease in expression of pAKT S473 (P =.01) and pAKT T308 (P =.002) after therapy. PI3K/AKT/mTOR downregulation in tumor tissues and circulating markers did not correlate with tumor response or clinical benefit. There were five objective responses, and nine patients had stable disease. Conclusion: MK-2206 was well tolerated with paclitaxel. Preliminary antitumor activity was documented. © 2015 The Author. Source


Yang H.,TRIUMF Laboratory Particle and Nuclear Physics | Miao Q.,TRIUMF Laboratory Particle and Nuclear Physics | Johnson B.F.,General Electric | Rishel M.J.,General Electric | And 8 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

Oxidative stress has been implicated in a variety of conditions, including cancer, heart failure, diabetes, neurodegeneration and other diseases. A potential biomarker for oxidative stress is the cystine/glutamate transporter, system xC -. l-Aminosuberic acid (l-ASu) has been identified as a system xC - substrate. Here we report a facile method for [11C]N-Me labeling of l-ASu, automation of the radiochemical process, and preliminary PET imaging with EL4 tumor bearing mice. The results demonstrate uptake in the tumor above background, warranting further studies on the use of radiolabeled analogs of l-ASu as a PET imaging agent for system xC -. © 2014 Elsevier Ltd. All rights reserved. Source


Meric-Bernstam F.,Khalifa University | Johnson A.,Khalifa University | Holla V.,Khalifa University | Bailey A.M.,Khalifa University | And 16 more authors.
Journal of the National Cancer Institute | Year: 2015

Rapidly improving understanding of molecular oncology, emerging novel therapeutics, and increasingly available and affordable next-generation sequencing have created an opportunity for delivering genomically informed personalized cancer therapy. However, to implement genomically informed therapy requires that a clinician interpret the patient's molecular profile, including molecular characterization of the tumor and the patient's germline DNA. In this Commentary, we review existing data and tools for precision oncology and present a framework for reviewing the available biomedical literature on therapeutic implications of genomic alterations. Genomic alterations, including mutations, insertions/deletions, fusions, and copy number changes, need to be curated in terms of the likelihood that they alter the function of a "cancer gene" at the level of a specific variant in order to discriminate so-called "drivers" from "passengers." Alterations that are targetable either directly or indirectly with approved or investigational therapies are potentially "actionable." At this time, evidence linking predictive biomarkers to therapies is strong for only a few genomic markers in the context of specific cancer types. For these genomic alterations in other diseases and for other genomic alterations, the clinical data are either absent or insufficient to support routine clinical implementation of biomarker-based therapy. However, there is great interest in optimally matching patients to early-phase clinical trials. Thus, we need accessible, comprehensive, and frequently updated knowledge bases that describe genomic changes and their clinical implications, as well as continued education of clinicians and patients. © 2015 The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. Source


News Article
Site: http://news.yahoo.com/science/

Group Leader, Dr Masafumi Inoue of Agency for Science Technology and Research's (A*STAR) Experimental Therapeutics Centre shows a sample to be tested with the Zika virus diagnostic test kit at their laboratory in Singapore, February 10, 2016. A*STAR and Singapore's Tan Tock Seng Hospital are collaborating to equip an existing diagnostic test kit with the capability to detect the Zika virus. If preliminary results are successful, the kits could be distributed to hospitals by the end of March in preparation for any outbreaks in Singapore. according to local media. REUTERS/Edgar Su More LONDON, (Reuters) - French scientists say they have proved a link between the Zika virus and a nerve syndrome called Guillain-Barre, suggesting countries hit by the Zika epidemic will see a rise in cases of the serious neurological condition. Guillain-Barre (GBS) is a rare syndrome in which the body's immune system attacks part of the nervous system. It usually occurs a few days after exposure to a virus, bacteria or parasite. In a retrospective study analyzing data from a Zika outbreak in French Polynesia during 2013 and 2014, researchers led by Arnaud Fontanet of France's Institut Pasteur calculated the estimated risk of developing Guillain-Barre Syndrome (GBS) at 2.4 for every 10,000 people infected by Zika. "This work is significant because it allows for the confirmation of the role of Zika virus infection in the occurrences of the severe neurological complications that constitute Guillain-Barré Syndrome," said Fontanet, Pasteur's head of the emerging diseases epidemiology. "The regions which are affected by the Zika virus epidemic are likely to see a significant increase in the number of patients with serious neurological complications, and when possible, should increase the capacity of health-care facilities to receive patients needing intensive care." The World Health Organization (WHO) has declared an outbreak of the mosquito-borne Zika virus spreading from Brazil an international health emergency. This declaration was largely based on evidence linking Zika to a birth defect known as microcephaly, marked by a small head and underdeveloped brain, but the WHO is also concerned about rising reports of cases of GBS in countries hit by Zika. It is not yet clear whether the Zika virus actually causes microcephaly in babies, but experts say the evidence of a link is growing. Fontanet's team analyzed data from 42 patients who developed GBS at the time of the French Polynesian epidemic and found that every one had evidence of a previous infection with Zika. Tests also showed 93 percent of them had been infected with Zika recently - within three months prior to developing GBS. Jeremy Farrar, an infectious disease specialist and director of the Wellcome Trust global health charity, said the study, published in The Lancet medical journal, "provides the most compelling evidence to date of a causative link" between Zika and GBS. "The increase in reported cases of Guillain-Barré in Brazil and other South American countries seems to suggest that a similar situation may be occurring in the current outbreak, although the link here is yet to be proven definitively," he said in an emailed statement. According to WHO, even with the best healthcare services available, some 3 to 5 percent of GBS patients die from complications, including blood infection, lung clots, cardiac arrest and paralysis of the muscles that control breathing.


Liu G.,Experimental Therapeutics | Liu G.,Tianjin Medical University | Yang D.,Experimental Therapeutics | Rupaimoole R.,University of Houston | And 21 more authors.
Journal of the National Cancer Institute | Year: 2015

Background: Chemoresistance is a major challenge in cancer treatment. miR-506 is a potent inhibitor of the epithelial-to-mesenchymal transition (EMT), which is also associated with chemoresistance. We characterized the role of miR-506 in chemotherapy response in high-grade serous ovarian cancers. Methods: We used Kaplan-Meier and log-rank methods to analyze the relationship between miR-506 and progression-free and overall survival in The Cancer Genome Atlas (TCGA) (n = 468) and Bagnoli (n = 130) datasets, in vitro experiments to study whether miR-506 is associated with homologous recombination, and response to chemotherapy agents. We used an orthotopic ovarian cancer mouse model (n = 10 per group) to test the effect of miR-506 on cisplatin and PARP inhibitor sensitivity. All statistical tests were two-sided. Results: MiR-506 was associated with better response to therapy and longer progression-free and overall survival in two independent epithelial ovarian cancer patient cohorts (PFS: high vs low miR-506 expression; Bagnoli: hazard ratio [HR] = 3.06, 95% confidence interval [CI] = 1.90 to 4.70, P <. 0001; TCGA: HR = 1.49, 95% CI = 1.00 to 2.25, P = 0.04). MiR-506 sensitized cells to DNA damage through directly targeting the double-strand DNA damage repair gene RAD51. Systemic delivery of miR-506 in 8-12 week old female athymic nude mice statistically significantly augmented the cisplatin and olaparib response (mean tumor weight ± SD, control miRNA plus cisplatin vs miR-506 plus cisplatin: 0.36±0.05g vs 0.07±0.02g, P <. 001; control miRNA plus olaparib vs miR-506 plus olaparib: 0.32±0.13g vs 0.05±0.02g, P =. 045, respectively), thus recapitulating the clinical observation. Conclusions: MiR-506 is a robust clinical marker for chemotherapy response and survival in serous ovarian cancers and has important therapeutic value in sensitizing cancer cells to chemotherapy. © 2015 The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. Source

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