Contact: Anna Mikulak amikulak@psychologicalscience.org 202-293-9300 Association for Psychological Science
When financial gain depends on cooperation, we might expect that people would put aside their differences and focus on the bottom line. But new research suggests that people's racial biases make them more likely to leave money on the table when a windfall is not split evenly between groups.
The findings are published in Psychological Science, a journal of the Association for Psychological Science.
"It has been suggested that race bias in economic decisions may not occur in a market where discrimination is costly, but these findings provide the first evidence that this assumption is false," explain psychological scientists Jennifer Kubota and Elizabeth Phelps of New York University. "Our work suggests that after offers are on the table, people perceive the fairness of those offers differently even when they are objectively identical based on race."
The research was inspired by the debt ceiling debates that raged on in the summer of 2011.
"Many members of both the House and Senate seemed willing to incur costs that would hurt their own constituents in order to vote along political lines," say Kubota and Phelps. "The debate led us to wonder: Are people willing to punish members of another group when they perceive their behavior as unfair, even when exacting that punishment comes at a personal cost?"
The researchers decided that an important first step in understanding this phenomenon, given race-based financial disparities in the United States, would be to examine interracial economic decisions.
They had 49 participants of different ethnic and racial backgrounds engage in a so-called "ultimatum game," in which players accept or reject proposed splits of money. Participants were paired off and a "proposer" in each pair was given $10 to split between them. If the other player accepted the offer, the money was doled out accordingly; if the other player rejected the offer, both participants were left empty-handed. The researchers arranged it so that participants were always responding to offers from virtual proposers.
Because of existing cultural associations in the United States that link Black American males with aggression, hostility, and untrustworthiness, the researchers hypothesized that the participants might be more likely to perceive a low financial offer as unfair if it came from a Black rather than White proposer.
Overall, participants were more likely to accept White proposers' offers compared to those from Black proposers. And the data indicated that Black proposers had to offer larger amounts in order for players to accept the deal.
The effect is likely due to specific stereotypes or prejudices associated with Black Americans, given that participants showed a similar pattern of acceptance for offers from other-race proposers (who were neither White nor Black) and from White proposers.
The researchers point out that the financial offers being made in their study were relatively small and that people might be less likely to reject offers based on race when larger financial gains are at stake. Nonetheless, they argue that their findings have broad implications, with relevance to any context in which people punish others for what they consider to be violations of fairness:
"These findings may be especially relevant for legal and economic decisions and serve as an potential example of how people punish unfair or negative behavior in real-life," Kubota and Phelps conclude.
###
For more information about this study, please contact:
Elizabeth A. Phelps at liz.phelps@nyu.edu
Jennifer T. Kubota at jennifer.kubota@nyu.edu
In addition to Phelps and Kubota, co-authors include Jian Li of Peking University, Eyal Bar-David of New York University, and Mahzarin R. Banaji of Harvard University.
The article abstract is available online at: http://pss.sagepub.com/content/early/2013/10/11/0956797613496435.abstract
This work was supported by the National Institutes of Health (Grants MH080756 and AG039283).
The APS journal Psychological Science is the highest ranked empirical journal in psychology. For a copy of the article "The Price of Racial Bias: Intergroup Negotiations in the Ultimatum Game" and access to other Psychological Science research findings, please contact Anna Mikulak at 202-293-9300 or amikulak@psychologicalscience.org.
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The cost of racial bias in economic decisions
Public release date: 17-Oct-2013 [
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Contact: Anna Mikulak amikulak@psychologicalscience.org 202-293-9300 Association for Psychological Science
When financial gain depends on cooperation, we might expect that people would put aside their differences and focus on the bottom line. But new research suggests that people's racial biases make them more likely to leave money on the table when a windfall is not split evenly between groups.
The findings are published in Psychological Science, a journal of the Association for Psychological Science.
"It has been suggested that race bias in economic decisions may not occur in a market where discrimination is costly, but these findings provide the first evidence that this assumption is false," explain psychological scientists Jennifer Kubota and Elizabeth Phelps of New York University. "Our work suggests that after offers are on the table, people perceive the fairness of those offers differently even when they are objectively identical based on race."
The research was inspired by the debt ceiling debates that raged on in the summer of 2011.
"Many members of both the House and Senate seemed willing to incur costs that would hurt their own constituents in order to vote along political lines," say Kubota and Phelps. "The debate led us to wonder: Are people willing to punish members of another group when they perceive their behavior as unfair, even when exacting that punishment comes at a personal cost?"
The researchers decided that an important first step in understanding this phenomenon, given race-based financial disparities in the United States, would be to examine interracial economic decisions.
They had 49 participants of different ethnic and racial backgrounds engage in a so-called "ultimatum game," in which players accept or reject proposed splits of money. Participants were paired off and a "proposer" in each pair was given $10 to split between them. If the other player accepted the offer, the money was doled out accordingly; if the other player rejected the offer, both participants were left empty-handed. The researchers arranged it so that participants were always responding to offers from virtual proposers.
Because of existing cultural associations in the United States that link Black American males with aggression, hostility, and untrustworthiness, the researchers hypothesized that the participants might be more likely to perceive a low financial offer as unfair if it came from a Black rather than White proposer.
Overall, participants were more likely to accept White proposers' offers compared to those from Black proposers. And the data indicated that Black proposers had to offer larger amounts in order for players to accept the deal.
The effect is likely due to specific stereotypes or prejudices associated with Black Americans, given that participants showed a similar pattern of acceptance for offers from other-race proposers (who were neither White nor Black) and from White proposers.
The researchers point out that the financial offers being made in their study were relatively small and that people might be less likely to reject offers based on race when larger financial gains are at stake. Nonetheless, they argue that their findings have broad implications, with relevance to any context in which people punish others for what they consider to be violations of fairness:
"These findings may be especially relevant for legal and economic decisions and serve as an potential example of how people punish unfair or negative behavior in real-life," Kubota and Phelps conclude.
###
For more information about this study, please contact:
Elizabeth A. Phelps at liz.phelps@nyu.edu
Jennifer T. Kubota at jennifer.kubota@nyu.edu
In addition to Phelps and Kubota, co-authors include Jian Li of Peking University, Eyal Bar-David of New York University, and Mahzarin R. Banaji of Harvard University.
The article abstract is available online at: http://pss.sagepub.com/content/early/2013/10/11/0956797613496435.abstract
This work was supported by the National Institutes of Health (Grants MH080756 and AG039283).
The APS journal Psychological Science is the highest ranked empirical journal in psychology. For a copy of the article "The Price of Racial Bias: Intergroup Negotiations in the Ultimatum Game" and access to other Psychological Science research findings, please contact Anna Mikulak at 202-293-9300 or amikulak@psychologicalscience.org.
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
Potential new drug for some patients with treatment-resistant lung cancer
PUBLIC RELEASE DATE:
20-Oct-2013
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Contact: Lauren Riley lauren.riley@aacr.org 215-446-7155 American Association for Cancer Research
BOSTON The investigational drug AZD9291, a third-generation EGFR inhibitor, showed promise in preclinical studies and provides hope for patients with advanced lung cancers that have become resistant to existing EGFR inhibitors, according to results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.
Mutations in the growth factor gene EGFR are present in about 10 to 15 percent of patients with the most common form of lung cancer, non-small cell lung cancer (NSCLC). Most NSCLCs harboring these EGFR mutations, called activating mutations, respond to the EGFR inhibitor drugs erlotinib and gefitinib. A majority of such cancers, however, develop resistance to these drugs within about nine to 11 months. In many cases, this is due to the cancer cells acquiring a second mutation called EGFR T790M, also known as the "resistance mutation."
"There are no approved therapies to treat lung cancer patients who develop the second mutation in the EGFR that stops the currently available medicines from working," said Susan Galbraith, M.D., Ph.D., head of the Oncology Innovative Medicines Unit at AstraZeneca. "The innovative breakthrough was finding a series of molecules that could target both the activating and resistance mutant forms of EGFR more potently than normal EGFR, which led to development of the new EGFR kinase inhibitor, AZD9291.
"AZD9291 is highly active in preclinical models and is well tolerated in animal models. It inhibits both activating and resistant EGFR mutations while sparing the normal form of EGFR that is present in normal skin and gut cells, thereby reducing the side effects encountered with currently available medicines," she added.
The AstraZeneca scientists first showed that AZD9291 potently inhibited lung cancer cells with mutant EGFR, grown in lab dishes. They then tested the drug on mice bearing lung tumors with activating mutations and mice bearing lung tumors with resistance mutations. AZD9291 showed substantial tumor shrinkage in both groups of mice after 14 days of treatment. After 40 days, the researchers found no visible tumors in these mice, and this effect was sustained for more than 100 days. They also observed similar tumor shrinkage in mice that were genetically modified to develop tumors bearing both the activating and resistance mutations.
When the investigators analyzed blood samples collected from the treated mice, they identified a breakdown product of the parent compound AZD9291, which they called AZ5104, circulating in blood in addition to AZD9291. They then found that AZ5104 is also a potent inhibitor of activating and resistance EGFR mutations, and speculated that this may contribute to the efficacy seen after dosing with AZD9291.
Using data from blood analyses of mice, the researchers then developed a mathematical model to evaluate the dynamics of conversion of AZD9291 to AZ5104 and cumulative tumor-inhibitory effects. These experiments helped them determine the potentially effective doses of AZD9291 for patients with NSCLC harboring both activating and resistance EGFR mutations.
"Findings from preclinical studies have recently been translated to the clinic, where the drug has already demonstrated tumor shrinkage in patients and has been well tolerated, with low rates of side effects," said Galbraith. "The degree of response to treatment with AZD9291 in such a short period of time is very exciting. This new drug has the potential to provide new treatment options for patients in this setting."
###
Galbraith is an employee of AstraZeneca, which sponsored this study.
The 2013 International Conference on Molecular Targets and Cancer Therapeutics is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).
This research will be presented at a press conference entitled "Emerging Therapeutics" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Sunday, Oct. 20 at 10 a.m. ET in room 202 of the Hynes Convention Center in Boston, Mass. Reporters who cannot attend in person may call in using the following numbers:
U.S./Canada (toll-free): 800-446-2782
International (toll): 847-413-3235
To interview Susan Galbraith, contact Ayesha Bharmal at ayesha.bharmal@astrazeneca.com. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.
About the American Association for Cancer Research
Founded in 1907, the American Association for Cancer Research (AACR) is the world's oldest and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer.
For more information about the AACR, visit http://www.AACR.org. Follow the AACR on Twitter: @AACR. Follow the AACR on Facebook: http://www.facebook.com/aacr.org.
About the National Cancer Institute
The National Cancer Institute (NCI) leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
About the European Organisation for Research and Treatment of Cancer
The European Organisation for the Research and Treatment of Cancer (EORTC) brings together European cancer clinical research experts from all disciplines for trans-national collaboration. Both multinational and multidisciplinary, the EORTC Network comprises more than 2,500 collaborators from all disciplines involved in cancer treatment and research in more than 300 hospitals in over 30 countries. Through translational and clinical research, the EORTC offers an integrated approach to drug development, drug evaluation programs and medical practices.
EORTC Headquarters, a unique pan European clinical research infrastructure, is based in Brussels, Belgium, from where its various activities are coordinated and run. http://www.eortc.org
Abstract Number: A109
Presenter: Susan Galbraith, M.D., Ph.D.
Title: AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma
Authors: Darren Cross1, Sue Ashton1, Caroline Nebhan2, Cath Eberlein1, M. Raymond V. Finlay1, Gareth Hughes1, Vivien Jacobs1, Martine Mellor1, Monica Red Brewer2, Catherine Meador2, Jonathon Orme1, Paula Spitzler2, Steve Powell1, Amar Rahi1, Paula Taylor1, Richard A. Ward1, Paula Daunt1, Anne Galer1, Teresa Klinowska1, Graham Richmond1, William Pao2. 1AstraZeneca, Macclesfield, United Kingdom; 2Department of Medicine/Division of Hematology-Oncology, Vanderbilt University, Nashville, TN
The first generation EGFR TKIs gefitinib and erlotinib provide significant clinical benefit in patients with advanced lung adenocarcinoma harbouring activating EGFR mutants (EGFRm+), but patients will ultimately develop disease progression due to acquired resistance. Acquisition of the EGFR T790M mutation is the most common mechanism of drug resistance, detected in more than 50% of gefitinib/erlotinib resistant patients. Current therapeutic strategies are limited for advanced lung adenocarcinoma patients with EGFR T790M (EGFRm+/T790M), so this remains a key area of unmet need.
AZD9291 (structure to be disclosed at meeting) is an oral, irreversible, third generation, selective inhibitor of both EGFR activating (EGFRm+) and resistance (EGFRm+/T790M) mutations. The mechanistic and functional activity of AZD9291 was characterised in vitro and in vivo across a number of cell lines harbouring various EGFR-mutations or wild type EGFR. Presented data shows AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (e.g. PC9; 500nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. In addition, AZD9291 administered once daily orally at 5mg/kg caused profound regression of tumours across EGFRm+ (PC9; 178% growth inhibition) and EGFRm+/T790M (H1975; 119% growth inhibition) tumour models in vivo, after 14 days dosing. Furthermore 5mg/kg AZD9291 was sufficient to cause significant shrinkage of EGFRm+ and EGFRm+/T790M transgenic mouse lung tumours. Tumour growth inhibition was associated with profound inhibition of EGFR phosphorylation and key downstream signaling pathways such as AKT and ERK. Chronic long-term treatment of PC9 and H1975 xenograft tumours with AZD9291 led to a complete and sustained macroscopic response, with no visible tumours after 40 days dosing, and being maintained beyond 100 days. Furthermore, pre-clinical data also indicates that AZD9291 could target tumours that have acquired resistance to the more recently identified HER2-amplification mechanism, thus potentially extending its benefit in TKI resistant patients.
Taken together, preclinical data demonstrates that AZD9291 is a potent and effective inhibitor of both EGFR activating (EGFRm+) and resistance (EGFRm+/T790M) mutations whilst sparing wild-type EGFR. These data support the further clinical investigation of AZD9291 in advanced EGFR mutant lung adenocarcinoma.
Abstract Number: B94
Presenter: Susan Galbraith, M.D., Ph.D.
Title: Discovery of and first disclosure of the clinical candidate AZD9291, a potent and selective third-generation EGFR inhibitor of both activating and T790M resistant mutations that spares the wild type form of the receptor
Authors: M. Raymond V. Finlay1, Mark Anderton1, Susan Ashton1, Peter G. Ballard1, Rob H. Bradbury1, Sam Butterworth1, Nicola Colclough1, Darren A.E. Cross1, Heather L. McFarland2, Martine J. Mellor1, Richard A. Ward1, Mike J. Waring1. 1AstraZeneca, Oncology Innovative Medicines, Macclesfield, Cheshire, SK10 4TG, United Kingdom; 2AstraZeneca, Global Medicines Development, Macclesfield, Cheshire, SK10 4TG, United Kingdom
Small molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase such as gefitinib and erlotinib have been employed successfully in the treatment of non-small cell lung cancer (NSCLC) patients harboring an activating mutation (EGFRm+). However, resistance to these inhibitors in the form of additional mutations in the kinase domain such as T790M is emerging as a growing clinical issue. This presentation will describe the discovery of AZD9291, an orally bioavailable, irreversible EGFR inhibitor of both the resistance (NCI-H1975, cell phosphorylation IC50 0.5 μM). Wild type EGFR inhibition is believed to drive the observed dose limiting toxicities (such as skin rash and diarrhea) for these first generation therapies in the clinic. New data will be discussed for the first time including the medicinal chemistry program that led to the identification of AZD9291, details of significant in vivo oral activity in pre-clinical xenograft models (including tumor regression in the L858R/T790M double mutant setting at a dose of 5 mpk) and the first disclosure of the candidate drug structure. The pre-clinical findings from this work strongly supported selection of AZD9291 as a clinical candidate, and first dose in man was achieved with AZD9291 in March 2013.
Abstract Number: B212
Presenter: Susan Galbraith, M.D., Ph.D.
Title: Integrating the pre-clinical pharmacokinetic, pharmacodynamics, and efficacy data for AZD9291, an oral, irreversible inhibitor of EGFR activating (EGFRm+) and resistant (EGFRm+/T790M) mutations and an active metabolite to predict the human pharmacokinetics and potential efficacious dose in patients.
Authors: Peter Ballard1, Susan Ashton1, Darren Cross1, Richard Dimelow2, James Yates1. 1AstraZeneca, Macclesfield, Cheshire, United Kingdom; 2Wright-Dose, Altrincham, Cheshire, United Kingdom
Small molecule tyrosine kinase inhibitors gefitinib and erlotinib have demonstrated clinical benefit in advanced NSCLC patients with the EGFR activating mutation but ultimately disease progression develops due to resistant mutations. The most common resistant mutation is EGFR T790M and remains a key area of unmet need.
AZD9291 is an irreversible inhibitor of both the EGFR activating mutant (EGFRm+) and resistance mutation (EGFRm+/T790M), while maintaining a margin to wild type EGFR. AZD9291 has demonstrated impressive efficacy and regressions at low doses in mouse xenograft models for both activating (EGFRm+) and resistant (EGFRm+/T790M) mutant forms of EGFR (PC9 and H1975 cell lines). Analysis of plasma samples from these xenograft studies identified a des-methylated metabolite circulating in addition to AZD9291 with subsequent in vitro studies indicating the metabolite was around five fold more potent than AZD9291.
A program of mouse xenograft studies was undertaken to determine the tumor pEGFR pharmacodynamics (PD) and tumor growth inhibition (TGI) of AZD9291 and metabolite. Mathematical models incorporating an irreversible binding component have been developed to describe the contribution of AZD9291 and metabolite exposure to the pEGFR PD and TGI in the mouse (a PK/PD-TGI model). Pre-clinical drug metabolism and pharmacokinetic data were used to predict the human pharmacokinetics of AZD9291 and formation of the active metabolite. The predicted human exposures of both AZD9291 and metabolite were then used to drive the PK/PD-TGI model to simulate inhibition of pEGFR and inhibition of tumor growth. Assuming that human tumours and biomarkers behave in a similar way to those in mouse xenografts, these simulations suggest that a dose of 7-17 mg of AZD9291 once a day would be efficacious in patients with advanced NSCLC harboring the EGFR activating and T790M resistant mutations.
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
Potential new drug for some patients with treatment-resistant lung cancer
PUBLIC RELEASE DATE:
20-Oct-2013
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Contact: Lauren Riley lauren.riley@aacr.org 215-446-7155 American Association for Cancer Research
BOSTON The investigational drug AZD9291, a third-generation EGFR inhibitor, showed promise in preclinical studies and provides hope for patients with advanced lung cancers that have become resistant to existing EGFR inhibitors, according to results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.
Mutations in the growth factor gene EGFR are present in about 10 to 15 percent of patients with the most common form of lung cancer, non-small cell lung cancer (NSCLC). Most NSCLCs harboring these EGFR mutations, called activating mutations, respond to the EGFR inhibitor drugs erlotinib and gefitinib. A majority of such cancers, however, develop resistance to these drugs within about nine to 11 months. In many cases, this is due to the cancer cells acquiring a second mutation called EGFR T790M, also known as the "resistance mutation."
"There are no approved therapies to treat lung cancer patients who develop the second mutation in the EGFR that stops the currently available medicines from working," said Susan Galbraith, M.D., Ph.D., head of the Oncology Innovative Medicines Unit at AstraZeneca. "The innovative breakthrough was finding a series of molecules that could target both the activating and resistance mutant forms of EGFR more potently than normal EGFR, which led to development of the new EGFR kinase inhibitor, AZD9291.
"AZD9291 is highly active in preclinical models and is well tolerated in animal models. It inhibits both activating and resistant EGFR mutations while sparing the normal form of EGFR that is present in normal skin and gut cells, thereby reducing the side effects encountered with currently available medicines," she added.
The AstraZeneca scientists first showed that AZD9291 potently inhibited lung cancer cells with mutant EGFR, grown in lab dishes. They then tested the drug on mice bearing lung tumors with activating mutations and mice bearing lung tumors with resistance mutations. AZD9291 showed substantial tumor shrinkage in both groups of mice after 14 days of treatment. After 40 days, the researchers found no visible tumors in these mice, and this effect was sustained for more than 100 days. They also observed similar tumor shrinkage in mice that were genetically modified to develop tumors bearing both the activating and resistance mutations.
When the investigators analyzed blood samples collected from the treated mice, they identified a breakdown product of the parent compound AZD9291, which they called AZ5104, circulating in blood in addition to AZD9291. They then found that AZ5104 is also a potent inhibitor of activating and resistance EGFR mutations, and speculated that this may contribute to the efficacy seen after dosing with AZD9291.
Using data from blood analyses of mice, the researchers then developed a mathematical model to evaluate the dynamics of conversion of AZD9291 to AZ5104 and cumulative tumor-inhibitory effects. These experiments helped them determine the potentially effective doses of AZD9291 for patients with NSCLC harboring both activating and resistance EGFR mutations.
"Findings from preclinical studies have recently been translated to the clinic, where the drug has already demonstrated tumor shrinkage in patients and has been well tolerated, with low rates of side effects," said Galbraith. "The degree of response to treatment with AZD9291 in such a short period of time is very exciting. This new drug has the potential to provide new treatment options for patients in this setting."
###
Galbraith is an employee of AstraZeneca, which sponsored this study.
The 2013 International Conference on Molecular Targets and Cancer Therapeutics is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).
This research will be presented at a press conference entitled "Emerging Therapeutics" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Sunday, Oct. 20 at 10 a.m. ET in room 202 of the Hynes Convention Center in Boston, Mass. Reporters who cannot attend in person may call in using the following numbers:
U.S./Canada (toll-free): 800-446-2782
International (toll): 847-413-3235
To interview Susan Galbraith, contact Ayesha Bharmal at ayesha.bharmal@astrazeneca.com. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.
About the American Association for Cancer Research
Founded in 1907, the American Association for Cancer Research (AACR) is the world's oldest and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer.
For more information about the AACR, visit http://www.AACR.org. Follow the AACR on Twitter: @AACR. Follow the AACR on Facebook: http://www.facebook.com/aacr.org.
About the National Cancer Institute
The National Cancer Institute (NCI) leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
About the European Organisation for Research and Treatment of Cancer
The European Organisation for the Research and Treatment of Cancer (EORTC) brings together European cancer clinical research experts from all disciplines for trans-national collaboration. Both multinational and multidisciplinary, the EORTC Network comprises more than 2,500 collaborators from all disciplines involved in cancer treatment and research in more than 300 hospitals in over 30 countries. Through translational and clinical research, the EORTC offers an integrated approach to drug development, drug evaluation programs and medical practices.
EORTC Headquarters, a unique pan European clinical research infrastructure, is based in Brussels, Belgium, from where its various activities are coordinated and run. http://www.eortc.org
Abstract Number: A109
Presenter: Susan Galbraith, M.D., Ph.D.
Title: AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma
Authors: Darren Cross1, Sue Ashton1, Caroline Nebhan2, Cath Eberlein1, M. Raymond V. Finlay1, Gareth Hughes1, Vivien Jacobs1, Martine Mellor1, Monica Red Brewer2, Catherine Meador2, Jonathon Orme1, Paula Spitzler2, Steve Powell1, Amar Rahi1, Paula Taylor1, Richard A. Ward1, Paula Daunt1, Anne Galer1, Teresa Klinowska1, Graham Richmond1, William Pao2. 1AstraZeneca, Macclesfield, United Kingdom; 2Department of Medicine/Division of Hematology-Oncology, Vanderbilt University, Nashville, TN
The first generation EGFR TKIs gefitinib and erlotinib provide significant clinical benefit in patients with advanced lung adenocarcinoma harbouring activating EGFR mutants (EGFRm+), but patients will ultimately develop disease progression due to acquired resistance. Acquisition of the EGFR T790M mutation is the most common mechanism of drug resistance, detected in more than 50% of gefitinib/erlotinib resistant patients. Current therapeutic strategies are limited for advanced lung adenocarcinoma patients with EGFR T790M (EGFRm+/T790M), so this remains a key area of unmet need.
AZD9291 (structure to be disclosed at meeting) is an oral, irreversible, third generation, selective inhibitor of both EGFR activating (EGFRm+) and resistance (EGFRm+/T790M) mutations. The mechanistic and functional activity of AZD9291 was characterised in vitro and in vivo across a number of cell lines harbouring various EGFR-mutations or wild type EGFR. Presented data shows AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (e.g. PC9; 500nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. In addition, AZD9291 administered once daily orally at 5mg/kg caused profound regression of tumours across EGFRm+ (PC9; 178% growth inhibition) and EGFRm+/T790M (H1975; 119% growth inhibition) tumour models in vivo, after 14 days dosing. Furthermore 5mg/kg AZD9291 was sufficient to cause significant shrinkage of EGFRm+ and EGFRm+/T790M transgenic mouse lung tumours. Tumour growth inhibition was associated with profound inhibition of EGFR phosphorylation and key downstream signaling pathways such as AKT and ERK. Chronic long-term treatment of PC9 and H1975 xenograft tumours with AZD9291 led to a complete and sustained macroscopic response, with no visible tumours after 40 days dosing, and being maintained beyond 100 days. Furthermore, pre-clinical data also indicates that AZD9291 could target tumours that have acquired resistance to the more recently identified HER2-amplification mechanism, thus potentially extending its benefit in TKI resistant patients.
Taken together, preclinical data demonstrates that AZD9291 is a potent and effective inhibitor of both EGFR activating (EGFRm+) and resistance (EGFRm+/T790M) mutations whilst sparing wild-type EGFR. These data support the further clinical investigation of AZD9291 in advanced EGFR mutant lung adenocarcinoma.
Abstract Number: B94
Presenter: Susan Galbraith, M.D., Ph.D.
Title: Discovery of and first disclosure of the clinical candidate AZD9291, a potent and selective third-generation EGFR inhibitor of both activating and T790M resistant mutations that spares the wild type form of the receptor
Authors: M. Raymond V. Finlay1, Mark Anderton1, Susan Ashton1, Peter G. Ballard1, Rob H. Bradbury1, Sam Butterworth1, Nicola Colclough1, Darren A.E. Cross1, Heather L. McFarland2, Martine J. Mellor1, Richard A. Ward1, Mike J. Waring1. 1AstraZeneca, Oncology Innovative Medicines, Macclesfield, Cheshire, SK10 4TG, United Kingdom; 2AstraZeneca, Global Medicines Development, Macclesfield, Cheshire, SK10 4TG, United Kingdom
Small molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase such as gefitinib and erlotinib have been employed successfully in the treatment of non-small cell lung cancer (NSCLC) patients harboring an activating mutation (EGFRm+). However, resistance to these inhibitors in the form of additional mutations in the kinase domain such as T790M is emerging as a growing clinical issue. This presentation will describe the discovery of AZD9291, an orally bioavailable, irreversible EGFR inhibitor of both the resistance (NCI-H1975, cell phosphorylation IC50 0.5 μM). Wild type EGFR inhibition is believed to drive the observed dose limiting toxicities (such as skin rash and diarrhea) for these first generation therapies in the clinic. New data will be discussed for the first time including the medicinal chemistry program that led to the identification of AZD9291, details of significant in vivo oral activity in pre-clinical xenograft models (including tumor regression in the L858R/T790M double mutant setting at a dose of 5 mpk) and the first disclosure of the candidate drug structure. The pre-clinical findings from this work strongly supported selection of AZD9291 as a clinical candidate, and first dose in man was achieved with AZD9291 in March 2013.
Abstract Number: B212
Presenter: Susan Galbraith, M.D., Ph.D.
Title: Integrating the pre-clinical pharmacokinetic, pharmacodynamics, and efficacy data for AZD9291, an oral, irreversible inhibitor of EGFR activating (EGFRm+) and resistant (EGFRm+/T790M) mutations and an active metabolite to predict the human pharmacokinetics and potential efficacious dose in patients.
Authors: Peter Ballard1, Susan Ashton1, Darren Cross1, Richard Dimelow2, James Yates1. 1AstraZeneca, Macclesfield, Cheshire, United Kingdom; 2Wright-Dose, Altrincham, Cheshire, United Kingdom
Small molecule tyrosine kinase inhibitors gefitinib and erlotinib have demonstrated clinical benefit in advanced NSCLC patients with the EGFR activating mutation but ultimately disease progression develops due to resistant mutations. The most common resistant mutation is EGFR T790M and remains a key area of unmet need.
AZD9291 is an irreversible inhibitor of both the EGFR activating mutant (EGFRm+) and resistance mutation (EGFRm+/T790M), while maintaining a margin to wild type EGFR. AZD9291 has demonstrated impressive efficacy and regressions at low doses in mouse xenograft models for both activating (EGFRm+) and resistant (EGFRm+/T790M) mutant forms of EGFR (PC9 and H1975 cell lines). Analysis of plasma samples from these xenograft studies identified a des-methylated metabolite circulating in addition to AZD9291 with subsequent in vitro studies indicating the metabolite was around five fold more potent than AZD9291.
A program of mouse xenograft studies was undertaken to determine the tumor pEGFR pharmacodynamics (PD) and tumor growth inhibition (TGI) of AZD9291 and metabolite. Mathematical models incorporating an irreversible binding component have been developed to describe the contribution of AZD9291 and metabolite exposure to the pEGFR PD and TGI in the mouse (a PK/PD-TGI model). Pre-clinical drug metabolism and pharmacokinetic data were used to predict the human pharmacokinetics of AZD9291 and formation of the active metabolite. The predicted human exposures of both AZD9291 and metabolite were then used to drive the PK/PD-TGI model to simulate inhibition of pEGFR and inhibition of tumor growth. Assuming that human tumours and biomarkers behave in a similar way to those in mouse xenografts, these simulations suggest that a dose of 7-17 mg of AZD9291 once a day would be efficacious in patients with advanced NSCLC harboring the EGFR activating and T790M resistant mutations.
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Sony’s no stranger to waterproof tech: It’s last smartphone and tablet weren’t afraid of getting dunked in the tub—making them perfect for the accident-prone or Aquaman.
Not content with just one waterproof phone in the U.S., the company announced Tuesday that its other two liquid-friendly Android phones—the Xperia Z1 and Xperia Z Ultra—would also be making their way stateside. The phones have been available internationally for a few months now, but having a few more choices when picking out a smartphone has never been a bad thing.
SonySony’s Xperia Z Ultra is a big phone.
The Ultra comes with a monstrous 6.4-inch HD display, a quad-core processor, and an 8-megapixel camera. This phablet-sized phone ships with Android 4.2 Jelly Bean, but will likely be updated to a more recent version of the OS sometime after its release.
The Z1 has a more reasonably sized 5-inch HD display, but makes up for the difference in size with a 20.7-megapixel camera. The phone will also ship with a quad-core processor and Android 4.2, putting it on par with most of the other Android phones we’ve seen pushed out lately.
Both phones are waterproof and dust-proof, meaning you can rub them in a puddle of mud and have them come away from the encounter unscathed.
Sony
SmartWatch 2
If you prefer your water-proof gizmos on your wrist instead of your pocket, Sony also announced that its SmartWatch 2 would be making its way stateside a little later this year. The watch features NFC and works with “an ever-growing catalog of downloadable apps” from the Google Play Store.
The Xperia Z Ultra and Xperia Z1 will retail for $680 and $670 (off-contract), respectively, while the SmartWatch 2 will set you back a cool $200. No carriers have been announced for either of the two smartphones, but it’s likely we’ll see one of them make their way to T-Mobile or AT&T (judging by the supported bands).
Sony’s made a strong push for water-resilient devices over the past year, and you just have to wonder how long it’ll be before the other big device makers join the party.
If you've ever teased a cat by waving a laser pointer around on the floor and watching it chase the red spot around the floor, you'll know animals can seem pretty dumb. But don't for one second assume that you're a higher form of intelligence.
SundaySky, a company promising to deliver video ads that are customized and updated for each viewer, has raised $20 million in Series C funding.
The round was led by Comcast Ventures, with participation from new investors Liberty Global Ventures and Vintage Investment Partners, as well as existing backers Carmel Ventures, Globespan Capital Partners, and Norwest Venture Partners. Comcast Ventures managing director Andrew Cleland will be joining SundaySky's board of directors. Source: http://feedproxy.google.com/~r/Techcrunch/~3/PUR_j0-n80E/ Related Topics: Texas A&mCameron DouglasBryan Cranstontaylor swift2 Guns
STANFORD, Calif. (AP) — Tyler Gaffney ran for 171 yards and two touchdowns, and No. 13 Stanford smothered Brett Hundley and ninth-ranked UCLA 24-10 on Saturday.
Kevin Hogan threw for 227 yards and a spectacular touchdown to Kodi Whitfield as the Cardinal (6-1, 4-1) regrouped again after losing at Utah last week. Stanford has not lost consecutive games since October 2009.
Stanford hurried Hundley all afternoon to slow down UCLA's up-tempo offense.
Hundley completed 24 of 39 passes for 192 yards, one touchdown and two interceptions to Jordan Richards — the second with a little more than 2 minutes remaining to seal Stanford's victory. UCLA (5-1, 2-1) has not started 6-0 since 2005.
The Cardinal came out on top again in a rematch of last season's Pac-12 title game and showed they're not bowing out of the conference race. Stanford has won six straight over UCLA, including three times in the last year, and 14 in a row against teams from California.
The Bruins entered the game averaging 45.8 points per game. That ranked second in the Pac-12 behind Oregon, which hosts UCLA next week before traveling to Stanford on Nov. 7 in matchups that will likely decide the Pac-12's championship game.
Stanford, which had its 13-game winning streak snapped in Salt Lake City last week, showed just why it has been so tough to keep down the last four years.
The Cardinal outgained UCLA 419 to 266 yards, won the time of possession 37:11 to 22:49 and made big the play when it mattered most again.
With Hundley and UCLA's offense taking the field late with 2:57 remaining, the Cardinal hurried Hundley twice before Richards dove for his second interception after receiver Thomas Duarte fell down. Gaffney capped off a quick Stanford drive with a 4-yard TD run that put the game out of reach.
Devon Cajuste caught seven passes for 109 yards for Stanford before leaving with a right leg injury early in the fourth quarter. UCLA also lost a key player, with inside linebacker Eric Kendricks taken to the hospital for tests on his kidney after making nine tackles in the first half.
It was not immediately clear what caused Kendricks' kidney issue.
The Cardinal controlled the flow from the start but missed opportunities in the first half to ahead big.
Ty Montgomery dropped a deep pass near the goal line on Stanford's first drive. The Cardinal later lost 10 yards on first-and-goal when they fumbled a pitch, and Ishmael Adams intercepted Hogan's pass at UCLA's 6-yard line in the final minute of the half when Cajuste bobbled the ball into his Adams' arms.
But Stanford's scoring erupted with one of the most spectacular plays of the season.
While running to his right on a post route, Whitfield leaped in the air and reached back to make a backhanded catch with his right hand between two defenders. The 30-yard TD reception put Stanford up 10-3 and left most of the crowd "oohing" every time the replay was shown on the video boards.
On UCLA's next drive, Stanford forced a turnover for the 32nd straight game — the second-longest streak in the country — when Richards intercepted Hundley's pass. Richards' return for a touchdown was called back because of a holding penalty.
No matter.
Cajuste caught a leaping 34-yard pass at UCLA's 2 on third down. And three plays later, Gaffney ran for a short TD to put the Cardinal up 17-3 late in the third quarter.
Hundley regrouped to lead UCLA on an 11-play, 75-yard scoring drive. He capped it off with a 3-yard TD pass to Shaquelle Evans that sliced Stanford's lead to 17-10 early in the fourth.
Hundley and the Bruins never looked so smooth again. Ka'imi Fairbairn kicked a tying 38-yard field on the opening drive of the second half for UCLA's only other score.
____
Antonio Gonzalez can be reached at: www.twitter.com/agonzalezAP
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