Time filter

Source Type

News Article | May 19, 2017
Site: globenewswire.com

MONT-SAINT-GUIBERT, Belgium, May 19, 2017 (GLOBE NEWSWIRE) -- Celyad (Euronext Brussels:CYAD) (Paris:CYAD) (NASDAQ:CYAD), a leader in the discovery and development of cell therapies, today provided an update on key clinical and operational developments for the first quarter ended March 31, 2017. Dr. Christian Homsy, CEO of Celyad commented: “Celyad had a productive first quarter, setting the tone for the remainder of 2017. Our continued focus on our NKR-T platform has led to important milestones: the initiation of the U.S. arm of our THINK trial, the successful and safe dosing of our first patients with solid, bone marrow and hematological tumors and the demonstration of the safety of our CAR-T NKR-2 product at the first dose tested.” Patrick Jeanmart, CFO of Celyad added: “The decision of the USPTO to uphold our patent related to allogeneic TCR-deficient CAR-T cells confirmed the strength of our intellectual property, and our license agreement with Novartis demonstrated the intrinsic value of this asset.” FIRST QUARTER 2017 OPERATIONAL AND FINANCIAL REVIEW In January, the U.S. Patent and Trade Office (USPTO) decided –for the third time – to uphold Celyad’s U.S. Patent No. 9,181,527, relating to allogeneic human primary T-cells that are engineered to be TCR-deficient and express a CAR. In March, the USPTO rejected another request for a re-examination of the same patent. Celyad’s critical patent remains valid and enforceable. On the operation side, the THINK trial progressed as expected. The ongoing THINK trial is comprised of two arms: a solid tumor arm, targeting colorectal, pancreatic, ovarian, triple negative breast and bladder cancers, and a liquid arm, targeting Acute myeloid leukemia (AML) and multiple myeloma (MM). All patients in the first dose (3x108) cohort of the solid tumor arm of the trial were dosed successfully with no drug related safety issues reported. The first cohort is composed of two colorectal and one pancreatic patient. In the liquid tumor arm, the first AML patients have been dosed and two MM patients have been recruited. With consent from the U.S. Food and Drug Administration (FDA) in March, the THINK trial is now global, recruiting patients both in Belgium and in the U.S. In the US, Celyad intends to recruit patients at three clinical centers, two of which have been initiated and approved (Roswell Park (NY) and University of Pittsburgh Medical Centre (PA)). The Company ended the quarter with €72.4 million in cash. Use of cash over the first quarter of 2017 amounted to €10.2 million, in line with expectations. The company confirms that existing cash and cash equivalents and short term investments are sufficient to fund operating expenses and capital expenditure requirements, based on the current scope of activities, through the first half 2019. On April 28, Celyad announced the dosing of the first patient of the second dose (1x109) in the solid tumor arm of its THINK trial. This first ovarian cancer patient was dosed at Roswell Park Cancer Institute (Buffalo, New York). On May 2, Celyad announced a non-exclusive license agreement with Novartis for Celyad’s US patents related to allogeneic CAR-T cells. This license agreement is related to two targets currently under development by Novartis. The agreement includes Celyad’s intellectual property rights under United States Patent No. 9,181,527 related to allogeneic human primary T-Cells that are engineered to be T-Cell Receptor (TCR) deficient and express a Chimeric Antigen Receptor (CAR). Under the terms of the agreement Celyad receives an upfront payment and is eligible to receive success based clinical, regulatory and commercial milestone payments. If all success based milestones are achieved, Celyad is eligible to receive payments, including the upfront payment, totalling $96 million. In addition, Celyad will receive single digit royalties based on net sales of the licensed target associated products. Novartis has the option to extend the agreement to additional targets and/or to convert its license into an exclusive license. Celyad retains all rights to grant further licenses to third parties for the use of allogeneic CAR-T cells. Celyad will not be involved in the development of Novartis’ CAR-T cells. Celyad will continue to focus on the development of its CAR-T pipeline, including its allogeneic NKR-2 T-cell immunotherapy in the EU and US territories and in collaboration with Ono Pharmaceuticals, its partner in Japan, Taiwan and Korea. On May 11, Celyad announced that the FDA had granted Fast Track designation for its C-Cure® therapy. Celyad intends to leverage this designation to accelerate the search for a strategic partner. The FDA granted Fast Track designation for reduction in mortality, hospitalization and improvement of quality of life in patients with chronic heart failure secondary to ischemic cardiomyopathy with baseline Left Ventricular End-Diastolic Volumes (LVEDV) between 200 and 370ml as Fast Track Development Program. About Celyad Celyad is a clinical-stage biopharmaceutical company focused on the development of specialized cellbased therapies. The Company utilizes its expertise in cell engineering to target cancer. Celyad’s Natural Killer Receptor based T-Cell (NKR-T) platform has the potential to treat a broad range of solid and hematologic tumors. Its lead oncology candidate, the CAR-T NKR-2, has been evaluated in a single dose - escalation Phase I clinical trial to assess the safety and feasibility of CAR-T NKR-2 cells in patients suffering from AML or MM. This Phase I study was successfully completed in September 2016. Celyad was founded in 2007 and is based in Mont-Saint Guibert, Belgium, and Boston, Massachusetts. Celyad’s ordinary shares are listed on the Euronext Brussels and Euronext Paris exchanges, and its American Depository Shares are listed on NASDAQ Global Market, all under the ticker symbol CYAD. For more information, please contact: To subscribe to Celyad’s newsletter, visit www.celyad.com Follow us on LinkedIn & Twitter @CelyadSA In addition to historical facts or statements of current condition, this press release contains forward looking statements, including statements about the potential safety and feasibility of CAR-T NKR-2 cell therapy, which reflect our current expectations and projections about future events, and involve certain known and unknown risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These forward looking statements are further qualified by important factors, which could cause actual results to differ materially from those in the forward-looking statements, including risks associated with conducting clinical trials; the risk that safety, bioactivity, feasibility and/or efficacy demonstrated in earlier clinical or pre-clinical studies may not be replicated in subsequent studies; risk associated with the timely submission and approval of anticipated regulatory filings; the successful initiation and completion of clinical trials, including Phase I clinical trial for CAR-T NKR-2; risks associated with the satisfaction of regulatory and other requirements; risks associated with the actions of regulatory bodies and other governmental authorities; risks associated with obtaining, maintaining and protecting intellectual property, our ability to enforce our patents against infringers and defend our patent portfolio against challenges from third parties; risks associated with competition from others developing products for similar uses; risks associated with our ability to manage operating expenses; and risks associated with our ability to obtain additional funding to support our business activities and establish and maintain strategic business alliances and business initiatives. A further list and description of these risks, uncertainties and other risks can be found in the Company’s Securities and Exchange Commission filings and reports, including in the Company’s Annual Report on Form 20-F filed with the SEC on April 8, 2016 and future filings and reports by the Company. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements. These forward-looking statements speak only as of the date of publication of this document. The Company expressly disclaims any obligation to update any such forward-looking statements in this document to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statement is based, unless required by law or regulation.


News Article | May 19, 2017
Site: globenewswire.com

MONT-SAINT-GUIBERT, Belgium, May 19, 2017 (GLOBE NEWSWIRE) -- Celyad (Euronext Brussels:CYAD) (Paris:CYAD) (NASDAQ:CYAD), a leader in the discovery and development of cell therapies, today provided an update on key clinical and operational developments for the first quarter ended March 31, 2017. Dr. Christian Homsy, CEO of Celyad commented: “Celyad had a productive first quarter, setting the tone for the remainder of 2017. Our continued focus on our NKR-T platform has led to important milestones: the initiation of the U.S. arm of our THINK trial, the successful and safe dosing of our first patients with solid, bone marrow and hematological tumors and the demonstration of the safety of our CAR-T NKR-2 product at the first dose tested.” Patrick Jeanmart, CFO of Celyad added: “The decision of the USPTO to uphold our patent related to allogeneic TCR-deficient CAR-T cells confirmed the strength of our intellectual property, and our license agreement with Novartis demonstrated the intrinsic value of this asset.” FIRST QUARTER 2017 OPERATIONAL AND FINANCIAL REVIEW In January, the U.S. Patent and Trade Office (USPTO) decided –for the third time – to uphold Celyad’s U.S. Patent No. 9,181,527, relating to allogeneic human primary T-cells that are engineered to be TCR-deficient and express a CAR. In March, the USPTO rejected another request for a re-examination of the same patent. Celyad’s critical patent remains valid and enforceable. On the operation side, the THINK trial progressed as expected. The ongoing THINK trial is comprised of two arms: a solid tumor arm, targeting colorectal, pancreatic, ovarian, triple negative breast and bladder cancers, and a liquid arm, targeting Acute myeloid leukemia (AML) and multiple myeloma (MM). All patients in the first dose (3x108) cohort of the solid tumor arm of the trial were dosed successfully with no drug related safety issues reported. The first cohort is composed of two colorectal and one pancreatic patient. In the liquid tumor arm, the first AML patients have been dosed and two MM patients have been recruited. With consent from the U.S. Food and Drug Administration (FDA) in March, the THINK trial is now global, recruiting patients both in Belgium and in the U.S. In the US, Celyad intends to recruit patients at three clinical centers, two of which have been initiated and approved (Roswell Park (NY) and University of Pittsburgh Medical Centre (PA)). The Company ended the quarter with €72.4 million in cash. Use of cash over the first quarter of 2017 amounted to €10.2 million, in line with expectations. The company confirms that existing cash and cash equivalents and short term investments are sufficient to fund operating expenses and capital expenditure requirements, based on the current scope of activities, through the first half 2019. On April 28, Celyad announced the dosing of the first patient of the second dose (1x109) in the solid tumor arm of its THINK trial. This first ovarian cancer patient was dosed at Roswell Park Cancer Institute (Buffalo, New York). On May 2, Celyad announced a non-exclusive license agreement with Novartis for Celyad’s US patents related to allogeneic CAR-T cells. This license agreement is related to two targets currently under development by Novartis. The agreement includes Celyad’s intellectual property rights under United States Patent No. 9,181,527 related to allogeneic human primary T-Cells that are engineered to be T-Cell Receptor (TCR) deficient and express a Chimeric Antigen Receptor (CAR). Under the terms of the agreement Celyad receives an upfront payment and is eligible to receive success based clinical, regulatory and commercial milestone payments. If all success based milestones are achieved, Celyad is eligible to receive payments, including the upfront payment, totalling $96 million. In addition, Celyad will receive single digit royalties based on net sales of the licensed target associated products. Novartis has the option to extend the agreement to additional targets and/or to convert its license into an exclusive license. Celyad retains all rights to grant further licenses to third parties for the use of allogeneic CAR-T cells. Celyad will not be involved in the development of Novartis’ CAR-T cells. Celyad will continue to focus on the development of its CAR-T pipeline, including its allogeneic NKR-2 T-cell immunotherapy in the EU and US territories and in collaboration with Ono Pharmaceuticals, its partner in Japan, Taiwan and Korea. On May 11, Celyad announced that the FDA had granted Fast Track designation for its C-Cure® therapy. Celyad intends to leverage this designation to accelerate the search for a strategic partner. The FDA granted Fast Track designation for reduction in mortality, hospitalization and improvement of quality of life in patients with chronic heart failure secondary to ischemic cardiomyopathy with baseline Left Ventricular End-Diastolic Volumes (LVEDV) between 200 and 370ml as Fast Track Development Program. About Celyad Celyad is a clinical-stage biopharmaceutical company focused on the development of specialized cellbased therapies. The Company utilizes its expertise in cell engineering to target cancer. Celyad’s Natural Killer Receptor based T-Cell (NKR-T) platform has the potential to treat a broad range of solid and hematologic tumors. Its lead oncology candidate, the CAR-T NKR-2, has been evaluated in a single dose - escalation Phase I clinical trial to assess the safety and feasibility of CAR-T NKR-2 cells in patients suffering from AML or MM. This Phase I study was successfully completed in September 2016. Celyad was founded in 2007 and is based in Mont-Saint Guibert, Belgium, and Boston, Massachusetts. Celyad’s ordinary shares are listed on the Euronext Brussels and Euronext Paris exchanges, and its American Depository Shares are listed on NASDAQ Global Market, all under the ticker symbol CYAD. For more information, please contact: To subscribe to Celyad’s newsletter, visit www.celyad.com Follow us on LinkedIn & Twitter @CelyadSA In addition to historical facts or statements of current condition, this press release contains forward looking statements, including statements about the potential safety and feasibility of CAR-T NKR-2 cell therapy, which reflect our current expectations and projections about future events, and involve certain known and unknown risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These forward looking statements are further qualified by important factors, which could cause actual results to differ materially from those in the forward-looking statements, including risks associated with conducting clinical trials; the risk that safety, bioactivity, feasibility and/or efficacy demonstrated in earlier clinical or pre-clinical studies may not be replicated in subsequent studies; risk associated with the timely submission and approval of anticipated regulatory filings; the successful initiation and completion of clinical trials, including Phase I clinical trial for CAR-T NKR-2; risks associated with the satisfaction of regulatory and other requirements; risks associated with the actions of regulatory bodies and other governmental authorities; risks associated with obtaining, maintaining and protecting intellectual property, our ability to enforce our patents against infringers and defend our patent portfolio against challenges from third parties; risks associated with competition from others developing products for similar uses; risks associated with our ability to manage operating expenses; and risks associated with our ability to obtain additional funding to support our business activities and establish and maintain strategic business alliances and business initiatives. A further list and description of these risks, uncertainties and other risks can be found in the Company’s Securities and Exchange Commission filings and reports, including in the Company’s Annual Report on Form 20-F filed with the SEC on April 8, 2016 and future filings and reports by the Company. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements. These forward-looking statements speak only as of the date of publication of this document. The Company expressly disclaims any obligation to update any such forward-looking statements in this document to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statement is based, unless required by law or regulation.


PubMed | Plymouth Hospitals NHS Trust, CHRU, Cardiff CLL Research Group, ONO Pharma UK Ltd and 4 more.
Type: Clinical Trial, Phase I | Journal: Blood | Year: 2016

We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.


Ward C.L.,ONO Pharma UK LTD | Jamieson V.,ONO Pharma UK LTD | Nabata T.,ONO Pharma UK LTD | Sharpe J.,ONO Pharma UK LTD | And 4 more authors.
Clinical Therapeutics | Year: 2016

Purpose The aim of this study was to evaluate the safety, tolerability, and pharmacokinetic parameters of up to 15 dose levels of ONO-4232, a selective agonist for the EP4 subtype of the prostaglandin E2 receptor, with a dual left ventricular lusitropic and venodilatory action, in healthy, adult, male and female volunteers. Methods In this randomized, single-center, double-blind, placebo-controlled, single-dose, sequential-group escalation, first in human study, ONO-4232 (0.001, 0.003, 0.01, 0.02, 0.04, 0.08, 0.12, 0.15, 0.18, or 0.27 ng/kg/min) or placebo was administered as a continuous intravenous infusion over 3 hours. Safety, tolerability, and pharmacokinetic data were collected during dosing and over a period of 3 days (Day -1 to Day 2), and at the follow-up visit (Day 7 [±2 days]). Findings Fifty-seven subjects received ONO-4232 and 19 subjects received placebo. Ten of the planned 15 cohorts (dose range, 0.001-0.27 ng/kg/min) were conducted. A total of 34 treatment-emergent adverse events (TEAEs) were reported in 23 subjects. Overall, the majority of TEAEs were mild. No serious TEAEs or deaths were reported and no subjects discontinued due to adverse events. The most frequently reported TEAE was infusion site erythema. A decrease in systolic blood pressure from baseline occurred for ONO-4232 subjects compared with placebo that was statistically significant for the 0.08 ng/kg/min dose, and a dose-dependent increase in heart rate starting at 0.04 ng/kg/min and achieving statistical significance compared with placebo at 0.15 ng/kg/min and above. More orthostatic events occurred in the higher-dose groups and the dose escalation was terminated due to increasing occurrences of orthostatic hypotension/intolerance. Plasma concentrations of ONO-4232 reached steady state approximately 2 hours after the start of infusion and then declined rapidly after the end of infusion, and systemic exposure appeared to increase in a dose-proportional manner. Approximately 30% of the administered dose of ONO-4232 was excreted in the urine. Implications In healthy adults ONO-4232 was generally well tolerated in the dose range of 0.001 to 0.27 ng/kg/min. There were dose-related changes in systolic blood pressure and heart rate. Infusion site erythema, which was likely associated with a venodilatory effect and possible evidence for the pharmacologic effects of ONO-4232, occurred increasingly with increasing dose. Pharmacokinetic parameters appeared to be dose-proportional. The study results support further evaluation of the cardiovascular effects of this first-in-class selective left ventricular lusitropic and venodilatory drug in patients with acutely decompensated heart failure. © 2016 The Authors.


PubMed | Gussak Consulting LLC, ONO Pharma UK LTD and Ono Pharmaceuticals Co Ltd
Type: Journal Article | Journal: Clinical therapeutics | Year: 2016

The aim of this study was to evaluate the safety, tolerability, and pharmacokinetic parameters of up to 15 dose levels of ONO-4232, a selective agonist for the EP4 subtype of the prostaglandin E2 receptor, with a dual left ventricular lusitropic and venodilatory action, in healthy, adult, male and female volunteers.In this randomized, single-center, double-blind, placebo-controlled, single-dose, sequential-group escalation, first in human study, ONO-4232 (0.001, 0.003, 0.01, 0.02, 0.04, 0.08, 0.12, 0.15, 0.18, or 0.27 ng/kg/min) or placebo was administered as a continuous intravenous infusion over 3 hours. Safety, tolerability, and pharmacokinetic data were collected during dosing and over a period of 3 days (Day -1 to Day 2), and at the follow-up visit (Day 7 [2 days]).Fifty-seven subjects received ONO-4232 and 19 subjects received placebo. Ten of the planned 15 cohorts (dose range, 0.001-0.27 ng/kg/min) were conducted. A total of 34 treatment-emergent adverse events (TEAEs) were reported in 23 subjects. Overall, the majority of TEAEs were mild. No serious TEAEs or deaths were reported and no subjects discontinued due to adverse events. The most frequently reported TEAE was infusion site erythema. A decrease in systolic blood pressure from baseline occurred for ONO-4232 subjects compared with placebo that was statistically significant for the 0.08 ng/kg/min dose, and a dose-dependent increase in heart rate starting at 0.04 ng/kg/min and achieving statistical significance compared with placebo at 0.15 ng/kg/min and above. More orthostatic events occurred in the higher-dose groups and the dose escalation was terminated due to increasing occurrences of orthostatic hypotension/intolerance. Plasma concentrations of ONO-4232 reached steady state approximately 2hours after the start of infusion and then declined rapidly after the end of infusion, and systemic exposure appeared to increase in a dose-proportional manner. Approximately 30% of the administered dose of ONO-4232 was excreted in the urine.In healthy adults ONO-4232 was generally well tolerated in the dose range of 0.001 to 0.27 ng/kg/min. There were dose-related changes in systolic blood pressure and heart rate. Infusion site erythema, which was likely associated with a venodilatory effect and possible evidence for the pharmacologic effects of ONO-4232, occurred increasingly with increasing dose. Pharmacokinetic parameters appeared to be dose-proportional. The study results support further evaluation of the cardiovascular effects of this first-in-class selective left ventricular lusitropic and venodilatory drug in patients with acutely decompensated heart failure.


Suto F.,Ono Pharmaceuticals Co Ltd | Wood A.T.,Ono Pharma United States Inc | Kobayashi M.,Ono Pharmaceuticals Co Ltd | Komaba J.,Ono Pharmaceuticals Co Ltd | And 2 more authors.
Clinical Therapeutics | Year: 2015

Purpose To investigate safety, tolerability, and pharmacokinetic properties of single and multiple doses of novel translocator protein 18 kDa antagonist ONO-2952 in healthy subjects. Methods Double-blind, placebo-controlled single (SAD) and multiple (MAD) dose escalation studies were conducted. Healthy men and women aged 18 to 55 years inclusive and without history of psychiatric disorders were eligible. Forty-eight volunteers received single doses of ONO-2952 (3, 10, 30, 100, 200, or 400 mg) or placebo under fasted conditions (SAD study), and 36 received ONO-2952 (30, 60, or 100 mg/d) or placebo for 21 consecutive days under fed conditions (MAD study). ONO-2952 10 and 200 mg were administered under fasted and fed conditions in the SAD study to investigate the effect of food on the absorption of ONO-2952. Safety assessments included adverse events, vital signs, 12-lead ECGs, and clinical laboratory evaluations. Plasma and urine pharmacokinetic profiles of ONO-2952 were determined. Findings Across both studies, mean age ranged from 29.8 to 39.8 years, most participants were white, and the proportion of female volunteers was 52%. No treatment or dose-related trends in adverse events were observed. The most frequent adverse events were headache and presyncope (n = 2 each [SAD study]) and constipation and headache (n = 3 each [MAD study]). All headache and constipation episodes were possibly related to the study drug. Plasma ONO-2952 concentrations peaked 2.5 to 3.5 hours (SAD study) and 3.0 to 4.0 hours (MAD study) postdose. ONO-2952 systemic exposure increased less than dose proportionally under fasted conditions. Fed conditions significantly increased exposure compared with fasted conditions: geometric mean ratios of Cmax (90% CIs) were 229% (176-299 [10 mg]) and 778% (623-971 [200 mg]), and AUClast were 159% (131-192 [10 mg]) and 382% (288-506 [200 mg]). In the MAD study, the systemic exposure of ONO-2952 increased in a slightly greater than dose-proportional manner. Geometric mean accumulation ratios (95% CI) of AUC24 were 2.50 (2.09-2.98 [30 mg]), 2.23 (1.85-2.68 [60 mg]), and 2.73 (2.10-3.55 [100 mg]); and Cmax were 1.65 (1.43-1.90 [30 mg]), 1.56 (1.31-1.85 [60 mg]), and 1.85 (1.38-2.49 [100 mg]). Implications ONO-2952 was safe and well tolerated in these early clinical studies investigating safety, tolerability, and pharmacokinetic properties of single and multiple doses. ONO-2952 systemic exposure increased in a less than dose-proportional manner under fasted conditions and in a slightly greater than dose-proportional manner under fed conditions. These results support the progression of ONO-2952 to further studies in humans. SAD study: ClinicalTials.gov identifier: NCT01364441. MAD study: ClinicalTrials.gov identifier: NCT01489345. © 2015 The Authors.


Benesch M.G.K.,University of Alberta | Tang X.,University of Alberta | Maeda T.,Ono Pharmaceuticals Company | Ohhata A.,Ono Pharmaceuticals Company | And 7 more authors.
FASEB Journal | Year: 2014

Autotaxin is a secreted enzyme that produces most extracellular lysophosphatidate, which stimulates 6 G-protein-coupled receptors. Lysophosphatidate promotes cancer cell survival, growth, migration, invasion, metastasis, and resistance to chemotherapy and radiotherapy. The present work investigated whether inhibiting autotaxin could decrease breast tumor growth and metastasis. We used a new autotaxin inhibitor (ONO-8430506; IC90=100 nM), which decreased plasma autotaxin activity by >60% and concentrations of unsaturated lysophosphatidates by >75% for 24 h compared with vehicle-treated mice. The effects of ONO-8430506 on tumor growth were determined in a syngeneic orthotopic mouse model of breast cancer following injection of 20,000 BALB/c mouse 4T1 or 4T1-12B cancer cells. We show for the first time that inhibiting autotaxin decreases initial tumor growth and subsequent lung metastatic nodules both by 60% compared with vehicle-treated mice. Significantly, 4T1 cells express negligible autotaxin compared with the mammary fat pad. Autotaxin activity in the fat pad of nontreated mice was increased 2-fold by tumor growth. Our results emphasize the importance of tumor interaction with its environment and the role of autotaxin in promoting breast cancer growth and metastasis. We also established that autotaxin inhibition could provide a novel therapeutic approach to blocking the adverse effects of lysophosphatidate in cancer. © FASEB.

Loading Ono Pharmaceuticals Co Ltd collaborators
Loading Ono Pharmaceuticals Co Ltd collaborators