T-Mobile CEO John Legere was dropping hints last week that his carrier would play a part in the new iPad launches, and we now know just what he meant. The Apple Store mentions that both the iPad Air and iPad mini with Retina display will have options for T-Mobile LTE in addition to the AT&T, Sprint ...
Source: http://feeds.engadget.com/~r/weblogsinc/engadget/~3/WwpZ7Gth48A/ACAPULCO, Mexico (AP) — Hurricane Raymond weakened to barely a Category 1 storm Tuesday while still stalled off Mexico's Pacific coast, pumping rain onto an already sodden region recovering from a battering by a tropical storm last month.
Raymond was centered 105 miles (170 kilometers) south of the beach resort of Zihuatanejo Tuesday night, and its winds had dropped to 75 mph (120 kph), down from Category 3 on Monday, the U.S. National Hurricane Center said. It was expected to weaken to a tropical storm by Wednesday and head out to sea.
But stung by the tardy reaction to the damage and deaths from Tropical Storm Manuel in September, authorities in Guerrero state took no chances, moving hundreds of people from isolated mountain communities and low-lying shore areas. More than 1,500 soldiers were sent into the area.
Even if Raymond didn't move inland, it could still cause floods and mudslides to an area reeling from more than $1.7 billion in damage and about 120 deaths from Manuel.
"Slow and erratic motion is expected during the next 12 hours and Raymond could still move closer to the coast of Mexico," the hurricane center said.
Guerrero Gov. Angel Aguirre urged people to stay off roads because of potentially dangerous rains.
"The phenomenon's behavior is completely erratic, completely unpredictable," Aguirre said Monday night.
There were no reports of torrential downpours, but rain fell and some streets flooded in soaked Acapulco, where city workers reinforced roads with sand bags. About 400 people were evacuated from hamlets around nearby Coyuca.
In the mountain town of El Paraiso, authorities evacuated about 500 residents by Tuesday evening and planned to completely empty the village of 7,000 people because of possible landslides, said Guerrero state's deputy secretary of civil protection, Constantino Gonzalez.
Schools in most coastal communities west of Acapulco, including Zihuatanejo, were kept closed.
Forecasters said Raymond was expected to follow an erratic path through the night and could bring as much as 15 inches (38 centimeters) of rain to some parts of the coast.
About 10,000 people in Guerrero already were living away from their homes a month after Manuel inundated whole neighborhoods and caused landslides that buried much of one village. It left behind drenched hillsides that pose serious landslide risks.
A tropical storm warning was in effect from Tecpan de Galeana, up the coast from Acapulco, north to the port of Lazaro Cardenas. A hurricane watch from Acapulco to Tecpan de Galeana was discontinued.
Meanwhile in the Atlantic, Tropical Storm Lorenzo strengthened far out to sea. Lorenzo's maximum sustained winds were over 50 mph (80 kph) with little change in strength forecast. The storm was centered about 830 miles (1,335 kilometers) east of Bermuda and was moving east near 8 mph (13 kph).
Gearing up for an adventure, Reese Witherspoon stepped onto the set of her upcoming film "Wild" in Portland, Oregon on Tuesday (October 22).
The "Legally Blonde" starlet sported shorts, boots and a graphic tee while toting an oversized backpack for the long hike through the wilderness.
Per the synopsis, "Wild" is a story about "one woman's 1,100-mile solo hike undertaken as a way to recover from a recent catastrophe."
Starring along side Reese are Gaby Hoffman, Charles Baker, and Kevin Rankin. "Wild" is slated to hit theaters in 2014.
WASHINGTON (AP) — Crammed into conference rooms with pizza for dinner, some programmers building the Obama administration's showcase health insurance website were growing increasingly stressed. Some worked past 10 p.m., energy drinks in hand. Others rewrote computer code over and over to meet what they considered last-minute requests for changes from the government or other contractors.
As questions mount over the website's failure, insider interviews and a review of technical specifications by The Associated Press found a mind-numbingly complex system put together by harried programmers who pushed out a final product that congressional investigators said was tested by the government and not private developers with more expertise.
The details about problems with the website's design emerged as the White House revealed that President Barack Obama's longtime adviser Jeffrey Zients is taking on to provide management advice to help fix the system. White House press secretary Jay Carney says Zients will be on a short-term assignment at the Health and Human Services Department before he's due to take over as director of Obama's National Economic Council Jan. 1.
Carney cited Zeints' expertise as a longtime management consultant and his "proven track record" since coming to the White House in 2009, both as interim budget director and as chief performance officer, when he headed an effort to streamline government and cut costs. "We're engaged in an all-out effort to improve the online experience," Carney said.
Health and Human Services Secretary Kathleen Sebelius said in a post on HealthCare.gov that her agency is also bringing in more experts and specialists from government and industry, including top Silicon Valley companies.
"This new infusion of talent will bring a powerful array of subject matter expertise and skills, including extensive experience scaling major IT systems," she said. "This effort is being marshaled as part of a cross-functional team that is working aggressively to diagnose parts of HealthCare.gov that are experiencing problems, learn from successful states, prioritize issues, and fix them."
Project developers for the health care website who spoke to the AP on condition of anonymity — because they feared they would otherwise be fired — said they raised doubts among themselves whether the website could be ready in time. They complained openly to each other about what they considered tight and unrealistic deadlines. One was nearly brought to tears over the stress of finishing on time, one developer said. Website builders saw red flags for months.
A review of internal architectural diagrams obtained by the AP revealed the system's complexity. Insurance applicants have a host of personal information verified, including income and immigration status. The system connects to other federal computer networks, including ones at the Social Security Administration, IRS, Veterans Administration, Office of Personnel Management and the Peace Corps.
Obama on Monday acknowledged technical problems that he described as "kinks in the system." But in remarks at a Rose Garden event, Obama offered no explanation for the failure except to note that high traffic to the website caused some of the slowdowns. He said it had been visited nearly 20 million times — fewer monthly visits so far than many commercial websites, such as PayPal, AOL, Wikipedia or Pinterest.
"The problem has been that the website that's supposed to make it easy to apply for and purchase the insurance is not working the way it should for everybody," Obama said. "There's no sugarcoating it. The website has been too slow. People have been getting stuck during the application process. And I think it's fair to say that nobody is more frustrated by that than I am."
The online system was envisioned as a simple way for people without health insurance to comparison-shop among competing plans offered in their state, pick their preferred level of coverage and cost and sign up. For many, it's not worked out that way so far.
Just weeks before the launch of HealthCare.gov on Oct. 1, one programmer said, colleagues huddled in conference rooms trying to patch "bugs," or deficiencies in computer code. Unresolved problems led to visitors experiencing cryptic error messages or enduring long waits trying to sign up.
Congressional investigators have concluded that the government's Centers for Medicare and Medicaid Services, not private software developers, tested the exchange's computer systems during the final weeks. That task, known as integration testing, is usually handled by software companies because it ferrets out problems before the public sees the final product.
The government spent at least $394 million in contracts to build the federal health care exchange and the data hub. Those contracts included major awards to Virginia-based CGI Federal Inc., Maryland-based Quality Software Services Inc. and Booz Allen Hamilton Inc.
CGI Federal said in a statement Monday it was working with the government and other contractors "around the clock" to improve the system, which it called "complex, ambitious and unprecedented."
The schematics from late 2012 show how officials designated a "data services hub" — a traffic cop for managing information — in lieu of a design that would have allowed state exchanges to connect directly to government servers when verifying an applicant's information. On Sunday, the Health and Human Services Department said the data hub was working but not meeting public expectations: "We are committed to doing better."
Administration officials so far have refused to say how many people actually have managed to enroll in insurance during the three weeks since the new marketplaces became available. Without enrollment numbers, it's impossible to know whether the program is on track to reach projections from the Congressional Budget Office that 7 million people would gain coverage during the first year the exchanges were available.
Instead, officials have selectively cited figures that put the insurance exchanges in a positive light. They say more than 19 million people have logged on to the federal website and nearly 500,000 have filled out applications for insurance through both the federal and state-run sites.
The flood of computer problems since the website went online has been deeply embarrassing for the White House. The snags have called into question whether the administration is capable of implementing the complex policy and why senior administration officials — including the president — appear to have been unaware of the scope of the problems when the exchange sites opened.
Even as the president spoke at the Rose Garden, more problems were coming to light. The administration acknowledged that a planned upgrade to the website had been postponed indefinitely and that online Spanish-language signups would remain unavailable, despite a promise to Hispanic groups that the capability would start this week. And the government tweaked the website's home page so visitors can now view phone numbers to apply the old-fashioned way or window-shop for insurance rates without registering first.
The House Energy and Commerce Committee was expected to conduct an oversight hearing Thursday, probably without Health and Human Services Secretary Kathleen Sebelius testifying. She could testify on Capitol Hill on the subject as early as next week.
Uninsured Americans have until about mid-February to sign up for coverage if they are to meet the law's requirement that they be insured by the end of March. If they don't, they will face a penalty. The administration says it's working to address the timing issue to provide more flexibility.
Sen. Marco Rubio, R-Fla., plans to introduce legislation to delay that requirement because: "It's not fair to punish people for not buying something that's not available," Rubio told "CBS This Morning" on Tuesday.
On Monday, the White House advised people frustrated by the online tangle that they can enroll by calling 1-800-318-2596 in a process that should take 25 minutes for an individual or 45 minutes for a family. Assistance is also available in communities from helpers who can be found at LocalHelp.HealthCare.gov.
___
Associated Press writer Ricardo Alonso-Zaldivar contributed to this report.
___
Follow Jack Gillum on Twitter at http://twitter.com/jackgillum or Julie Pace at http://twitter.com/jpaceDC.
Multitouch user interfaces are slowly finding their way into all kinds of devices, not just phones and tablets. And thanks to researchers at MIT and the Max Planck Institute who've developed a printable sensor that can be easily cut down to size with a regular old pair of scissors, any device or appliance you can think of could soon be enhanced with multitouch controls.
     |
Source: http://feeds.gawker.com/~r/gizmodo/full/~3/sjkyRrtiMRM/trimmable-printed-sensors-can-add-multitouch-to-any-dev-1450000432![[ Back to EurekAlert! ]](https://lh3.googleusercontent.com/blogger_img_proxy/AEn0k_udECmlJ43z-32tecau5AyD9XT_wWgNXPWy2UybIBKqCiJX0scxj9Gtb64lM1rsQ1VQlgkqWqPYilBnUYaJoQZNHBlxJ8hQ6EXRohrMnFQ=s0-d){kind=small}
PUBLIC RELEASE DATE: 22-Oct-2013
ShareContact: Lauren Riley
lauren.riley@aacr.org
215-446-7155
American Association for Cancer Research
BOSTON A functional biomarker that can predict whether BRAF-mutant melanomas respond to drugs targeting BRAF could help guide the treatment of patients with these cancers, according to results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19 23.
Approximately 50 percent of melanomas harbor mutations in the BRAF gene, and the U.S. Food and Drug Administration has approved two drugs that target BRAF for the treatment of such cancers. However, not all patients with BRAF-mutant melanomas respond to treatment with these, and most of those patients who initially respond eventually relapse because their tumors become resistant to the effects of the BRAF-targeted drugs.
"Our study has identified decreased phosphorylation of the protein S6 after treatment with BRAF-targeted drugs as a functional biomarker that predicts sensitivity of BRAF-mutant melanomas to these drugs," said Ryan B. Corcoran, M.D., Ph.D., a Damon Runyon clinical investigator and assistant professor at the Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston, Mass. "Importantly, we have developed a minimally invasive way to rapidly monitor post-treatment changes in S6 phosphorylation in patients' tumor cells. As a result, we think that we can quickly determine whether or not a patient is likely to respond to a BRAF-targeted drug and help speed up treatment decisions, although we need to verify this in larger clinical studies."
BRAF gene mutations lead to inappropriate BRAF protein activity, which, in turn, causes a cascade of inappropriate activation of numerous other proteins in the tumor cell. Corcoran and colleagues therefore examined whether there were differences in the activity of the proteins downstream of BRAF in BRAF-mutant melanoma cell lines responsive and resistant to the BRAF-targeted drug vemurafenib.
They found that decreased phosphorylation of the protein S6 after treatment with vemurafenib was associated with responsiveness of BRAF-mutant melanoma cell lines to the drug both in vitro and in mice.
They then analyzed S6 phosphorylation in tumor biopsies obtained from nine patients with BRAF-mutant melanomas before and after they had initiated treatment with a BRAF-targeted drug. Six patients had lower levels of tumor cell S6 phosphorylation after treatment compared with before treatment, and this was associated with an almost fivefold improvement in progression-free survival.
Finally, the researchers evaluated a method to rapidly monitor, in real time, levels of S6 phosphorylation in tumor cells. They found that they could reliably assess levels of S6 phosphorylation in tumor cells in fine-needle aspiration biopsies from patients before and during the first two weeks of treatment with a BRAF-targeted drug, and that in these patients, a decrease in S6 phosphorylation after treatment correlated with treatment response.
"Many of the signaling pathways known to drive various types of cancer regulate phosphorylation of S6, not just the BRAF pathway," said Corcoran. "Therefore, we are investigating whether S6 phosphorylation could be a biomarker of response to therapies that target these pathways in cancers other than melanoma."
###
This study was funded by a Damon Runyon Clinical Investigator Award, the National Institutes of Health, and the National Cancer Institute. Corcoran has no conflicts of interest to declare.
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 "Guiding Treatment for BRAF- and BRCA-related Cancers" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Monday, Oct. 22 at 9 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:
To interview Ryan Corcoran, contact Katie Marquedant at kmarquedant@partners.org or 617-314-3986. 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: C137
Presenter: Ryan B. Corcoran, M.D., Ph.D.
Title: Rapid assessment of TORC1 suppression as a functional biomarker predicting responsiveness to RAF and MEK inhibitors in BRAF-mutant melanoma patients
Authors: Ryan B. Corcoran1, S. Michael Rothenberg1, Aaron N. Hata1, Anthony C. Faber1, Adriano Piris1, Rosalynn M. Nazarian1, Ronald D. Brown1, Jason T. Godfrey1, Daniel Winokur1, John Walsh1, Mari Mino-Kenudson1, Shyamala Maheswaran1, Jeffrey Settleman2, Jennifer A. Wargo1, Keith T. Flaherty1, Daniel A. Haber1, Jeffrey A. Engelman1. 1Massachusetts General Hosp. Cancer Ctr., Boston, MA; 2Genentech, South San Francisco, CA
The clinical development of selective RAF and MEK inhibitors has transformed the treatment of the ~50% of melanoma patients whose tumors harbor BRAF mutations. However, a substantial percentage of these patients fail to respond to therapy, and most responses are partial and short-lived. Although multiple mechanisms of resistance have been identified in BRAF-mutant melanoma, no clinically useful biomarkers have been established to predict which patients are most likely to demonstrate sensitivity or resistance to RAF or MEK inhibitors. We found that suppression of TORC1 activity in response to RAF or MEK inhibitors, as measured by decreased phosphorylation of ribosomal protein-S6 (P-S6), was a functional biomarker that effectively predicted sensitivity in BRAF-mutant melanoma cell lines in vitro and in mouse tumor xenografts. In sensitive melanomas, TORC1 and P-S6 were suppressed in response to RAF or MEK inhibitors, but in resistant melanomas, TORC1 activity was maintained, in some cases despite robust suppression of MAPK signaling by these inhibitors. In mouse models, suppression of TORC1 after MAPK inhibition was necessary for induction of apoptosis and tumor response in vivo. Notably, in paired biopsies obtained from patients with BRAF-mutant melanoma before treatment and after initiation of RAF inhibitor therapy, P-S6 suppression was associated with significantly improved progression-free survival [HR 0.19, 95% CI 0.01-0.84, p=0.03]. Finally, we found that changes in P-S6 in patients' tumor cells could be readily monitored in real-time by multiplexed, quantitative immunofluorescence microscopy of serial fine-needle aspiration biopsies obtained from patients before and during the first 2 weeks of RAF inhibitor therapy. This approach provides a minimally-invasive means of rapidly monitoring the efficacy of treatment, before changes in tumor volume are apparent by traditional radiographic imaging. Together, these results establish suppression of P-S6 after initiation of RAF inhibitor therapy as a robust potential functional biomarker to guide the treatment of patients with BRAF-mutant melanoma, and present a powerful methodology for monitoring changes in potentially any signaling pathway in response to targeted therapies in patients.
Share
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.
PUBLIC RELEASE DATE: 22-Oct-2013
ShareContact: Lauren Riley
lauren.riley@aacr.org
215-446-7155
American Association for Cancer Research
BOSTON A functional biomarker that can predict whether BRAF-mutant melanomas respond to drugs targeting BRAF could help guide the treatment of patients with these cancers, according to results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19 23.
Approximately 50 percent of melanomas harbor mutations in the BRAF gene, and the U.S. Food and Drug Administration has approved two drugs that target BRAF for the treatment of such cancers. However, not all patients with BRAF-mutant melanomas respond to treatment with these, and most of those patients who initially respond eventually relapse because their tumors become resistant to the effects of the BRAF-targeted drugs.
"Our study has identified decreased phosphorylation of the protein S6 after treatment with BRAF-targeted drugs as a functional biomarker that predicts sensitivity of BRAF-mutant melanomas to these drugs," said Ryan B. Corcoran, M.D., Ph.D., a Damon Runyon clinical investigator and assistant professor at the Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston, Mass. "Importantly, we have developed a minimally invasive way to rapidly monitor post-treatment changes in S6 phosphorylation in patients' tumor cells. As a result, we think that we can quickly determine whether or not a patient is likely to respond to a BRAF-targeted drug and help speed up treatment decisions, although we need to verify this in larger clinical studies."
BRAF gene mutations lead to inappropriate BRAF protein activity, which, in turn, causes a cascade of inappropriate activation of numerous other proteins in the tumor cell. Corcoran and colleagues therefore examined whether there were differences in the activity of the proteins downstream of BRAF in BRAF-mutant melanoma cell lines responsive and resistant to the BRAF-targeted drug vemurafenib.
They found that decreased phosphorylation of the protein S6 after treatment with vemurafenib was associated with responsiveness of BRAF-mutant melanoma cell lines to the drug both in vitro and in mice.
They then analyzed S6 phosphorylation in tumor biopsies obtained from nine patients with BRAF-mutant melanomas before and after they had initiated treatment with a BRAF-targeted drug. Six patients had lower levels of tumor cell S6 phosphorylation after treatment compared with before treatment, and this was associated with an almost fivefold improvement in progression-free survival.
Finally, the researchers evaluated a method to rapidly monitor, in real time, levels of S6 phosphorylation in tumor cells. They found that they could reliably assess levels of S6 phosphorylation in tumor cells in fine-needle aspiration biopsies from patients before and during the first two weeks of treatment with a BRAF-targeted drug, and that in these patients, a decrease in S6 phosphorylation after treatment correlated with treatment response.
"Many of the signaling pathways known to drive various types of cancer regulate phosphorylation of S6, not just the BRAF pathway," said Corcoran. "Therefore, we are investigating whether S6 phosphorylation could be a biomarker of response to therapies that target these pathways in cancers other than melanoma."
###
This study was funded by a Damon Runyon Clinical Investigator Award, the National Institutes of Health, and the National Cancer Institute. Corcoran has no conflicts of interest to declare.
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 "Guiding Treatment for BRAF- and BRCA-related Cancers" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Monday, Oct. 22 at 9 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:
To interview Ryan Corcoran, contact Katie Marquedant at kmarquedant@partners.org or 617-314-3986. 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: C137
Presenter: Ryan B. Corcoran, M.D., Ph.D.
Title: Rapid assessment of TORC1 suppression as a functional biomarker predicting responsiveness to RAF and MEK inhibitors in BRAF-mutant melanoma patients
Authors: Ryan B. Corcoran1, S. Michael Rothenberg1, Aaron N. Hata1, Anthony C. Faber1, Adriano Piris1, Rosalynn M. Nazarian1, Ronald D. Brown1, Jason T. Godfrey1, Daniel Winokur1, John Walsh1, Mari Mino-Kenudson1, Shyamala Maheswaran1, Jeffrey Settleman2, Jennifer A. Wargo1, Keith T. Flaherty1, Daniel A. Haber1, Jeffrey A. Engelman1. 1Massachusetts General Hosp. Cancer Ctr., Boston, MA; 2Genentech, South San Francisco, CA
The clinical development of selective RAF and MEK inhibitors has transformed the treatment of the ~50% of melanoma patients whose tumors harbor BRAF mutations. However, a substantial percentage of these patients fail to respond to therapy, and most responses are partial and short-lived. Although multiple mechanisms of resistance have been identified in BRAF-mutant melanoma, no clinically useful biomarkers have been established to predict which patients are most likely to demonstrate sensitivity or resistance to RAF or MEK inhibitors. We found that suppression of TORC1 activity in response to RAF or MEK inhibitors, as measured by decreased phosphorylation of ribosomal protein-S6 (P-S6), was a functional biomarker that effectively predicted sensitivity in BRAF-mutant melanoma cell lines in vitro and in mouse tumor xenografts. In sensitive melanomas, TORC1 and P-S6 were suppressed in response to RAF or MEK inhibitors, but in resistant melanomas, TORC1 activity was maintained, in some cases despite robust suppression of MAPK signaling by these inhibitors. In mouse models, suppression of TORC1 after MAPK inhibition was necessary for induction of apoptosis and tumor response in vivo. Notably, in paired biopsies obtained from patients with BRAF-mutant melanoma before treatment and after initiation of RAF inhibitor therapy, P-S6 suppression was associated with significantly improved progression-free survival [HR 0.19, 95% CI 0.01-0.84, p=0.03]. Finally, we found that changes in P-S6 in patients' tumor cells could be readily monitored in real-time by multiplexed, quantitative immunofluorescence microscopy of serial fine-needle aspiration biopsies obtained from patients before and during the first 2 weeks of RAF inhibitor therapy. This approach provides a minimally-invasive means of rapidly monitoring the efficacy of treatment, before changes in tumor volume are apparent by traditional radiographic imaging. Together, these results establish suppression of P-S6 after initiation of RAF inhibitor therapy as a robust potential functional biomarker to guide the treatment of patients with BRAF-mutant melanoma, and present a powerful methodology for monitoring changes in potentially any signaling pathway in response to targeted therapies in patients.
Share
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.
