SPARKS, Nevada (Reuters) - A 12-year-old student armed with a handgun shot and killed a teacher and wounded two classmates before killing himself at his middle school in Nevada shortly before classes began on Monday, law enforcement officials said.
Both of the wounded students from Sparks Middle School were rushed to Renown Regional Medical Center in nearby Reno, where one of them underwent emergency surgery, said Tom Miller, acting Sparks police chief.
The Reno Gazette-Journal newspaper identified the slain school staff member as 45-year-old math teacher Michael Landsberry, quoting the man's sister-in-law. Authorities did not immediately name the teacher.
Witnesses described a chaotic scene at the school in the northwestern Nevada town of Sparks, located just east of Reno, after the gunfire erupted in an outdoor area as students were arriving for the school day.
"A kid started getting mad and he pulled out a gun and shoots my friend, one of my friends at least," a seventh-grade student identified as Andrew told local KOLO-TV. "And then he walked up to a teacher and says back up, the teacher started backing up and he pulled the trigger."
"The teacher was just lying there and he was limp, he didn't know what to do, he was just in a lot of pain," he told KOLO.
"And me and five other friends went to him and said come on we've got to get him to safety. We picked him up, carried him a little bit far and we left him because our vice principal came along and said go, go, go get to safety, get to safety. So we left the teacher there and we went to safety," Andrew said.
Family members of Landsberry described him as a hero who tried to persuade the young gunman to drop his weapon.
"To hear he was trying to protect those kids doesn't surprise me at all," his sister-in-law, Chanda Landsberry told the Gazette-Journal. "He could have ducked and hid, but he didn't. That's not who he is."
'WHY ARE YOU LAUGHING'
The incident marked the latest in a string of shooting rampages across the United States in recent years, some of them at schools, that have reignited a debate over gun control.
In Connecticut last December, 20 students and six adults were shot to death by a gunman at a school in Newtown before the attacker took his own life in what is considered one of the worst school shootings in U.S. history.
In Sparks, a 13-year-old eighth grader, Kyle Nucum, told the Gazette-Journal that he heard about half a dozen shots. Student Michelle Hernandez said she had seen the suspect before the shooting began.
"I heard him saying, 'Why you people making fun of me, why you laughing at me,'" Hernandez told the paper.
Sparks Mayor Geno Martini told a late-morning news conference that the shooting marked a tragic day for the city: "I just want to reiterate again that the city itself is very safe and this is just an isolated incident. But it's very, very tragic and I'm saddened to be here to have to tell you this."
Law enforcement officials said the student gunman opened fire at 7:16 a.m. local time, about 15 minutes before classes were scheduled to begin at the school, which serves about 700 seventh and eighth grade students.
Some 150 to 200 police officers descended on the school following the shooting and searched the grounds with bomb dogs, Reno deputy police chief Tom Robinson said. Agents from the FBI and U.S. Department of Homeland Security were assisting in the investigation, he said.
Robinson said it was too early to tell if the boy, who was not immediately identified by authorities, was targeting anyone in the shooting rampage. Authorities also declined to immediately speculate on his motives.
Classes and after school activities were canceled at Sparks Middle School for the rest of the week and counselors would be on hand to work with students and staff members who were traumatized by the shooting, the school district said.
(Additional reporting by Alex Dobuzinskis, Tim Gaynor and Dan Whitcomb; Writing by Dan Whitcomb; Editing by Cynthia Johnston, Leslie Adler, Grant McCool and Bob Burgdorfer)
ATF is held annually at Singapore's Marina Bay Sands casino, hotel and convention complex
This year’s edition of the Asia TV Forum & Market (ATF) in Singapore will debut a new three-day event dubbed Animation Lab, the event's organizers announced Monday.
Intended to help promote the region’s burgeoning animation industry, the program will seek to bring together Asian animation producers, who are seeking investment and funding opportunities, with international broadcasters and financiers, who are interested in both the growing animation talent and market opportunity of the region.
ATF organizers say the program will be open to all individuals or companies that have new animation projects in the planning or production stage, and will give them a platform to engage in closed-door pitches to various participating international commissioners.
International TV pros signed on to take part include Henrietta Hurford-Jones, director of children’s programming at the BBC Worldwide.
"The aim is always to try and grow the international CBeebies brand as well as our children’s portfolio worldwide,” Hurford-Jones said in a statement. “I would be delighted to find creative partners in Asia to potentially develop exciting new children’s content with.”
Also on hand to take pitches and meetings will be, Barbara Uecker, head of programming and acquisitions for children's TV at Australia’s ABC TV, and Nicole Keeb, head of international co-productions and acquisitions for children and youth programming at Germany’s ZDF Enterprises GmbH, along with her colleague Arne Lohmann, vice president of ZDFE.junior.
AFT says additional network execs will be added to the Animation Lab roster in the coming weeks.
AFT is Asia’s most established TV and cross-platform content market for buyers and sellers from the region and afar. This year’s event, ATF’s 12th edition, will take place Dec. 3-6 at Singapore’s Marina Bay Sands casino, hotel and convention complex.
Boston Red Sox's Jon Lester reacts after a double play in the fourth inning during Game 5 of the American League baseball championship series against the Detroit Tigers, Thursday, Oct. 17, 2013, in Detroit. (AP Photo/Paul Sancya)
Boston Red Sox's Jon Lester reacts after a double play in the fourth inning during Game 5 of the American League baseball championship series against the Detroit Tigers, Thursday, Oct. 17, 2013, in Detroit. (AP Photo/Paul Sancya)
Boston Red Sox's Jon Lester listens to a question during a news conference before Game 4 of the American League baseball championship series against the Detroit Tigers Wednesday, Oct. 16, 2013, in Detroit. Lester is expected to be the Game 5 starter for Boston. (AP Photo/Carlos Osorio)
Boston Red Sox starting pitcher Jon Lester delivers against the Detroit Tigers during the fifth inning in Game 1 of the American League baseball championship series Saturday, Oct. 12, 2013, in Boston. (AP Photo/Charles Krupa)
Boston Red Sox starting pitcher Jon Lester throws in the first inning during Game 5 of the American League baseball championship series against the Detroit Tigers Thursday, Oct. 17, 2013, in Detroit. (AP Photo/Matt Slocum)
Boston Red Sox starting pitcher Jon Lester throws in the first inning during Game 5 of the American League baseball championship series against the Detroit Tigers, Thursday, Oct. 17, 2013, in Detroit. (AP Photo/Paul Sancya)
BOSTON (AP) — Red Sox left-hander Jon Lester will start Game 1 of the World Series against the St. Louis Cardinals.
That's the word on Monday from Boston manager John Farrell.
Farrell says he hasn't decided on his entire lineup, but designated hitter David Ortiz will start at least once at first base when the series shifts to St. Louis for the middle three games. There is no DH allowed in the NL park, meaning Ortiz will have to play the field for just the seventh time this season.
The Red Sox worked out Monday, two days after eliminating the Detroit Tigers in Game 6 of the AL championship series. Game 1 of the World Series is Wednesday night at Fenway Park.
Whether you grew up in London or not, Sony's latest PlayStation 4 ad will assuredly trigger a memory or fifty of the past 25 years. The short video starts with the very first PlayStation and brings viewers all the way through to the upcoming PlayStation 4's November launch, bridging the gap with ...
Results from a study led by researchers at Nationwide Children's Hospital found more than three-fourths of breast milk samples purchased over the Internet contained bacteria that can cause illness, and frequently exhibited signs of poor collection, storage or shipping practices.
The study, published online today and in the November issue of Pediatrics, is the first to examine the safety of selling breast milk to others over the Internet, a trend that has become more frequent in the past several years. It is unknown exactly how common purchasing breast milk online is, but an earlier study cited 13,000 postings were placed on U.S. milk sharing websites in 2011.
The research team from the Center for Biobehavioral Health at The Research Institute at Nationwide Children's Hospital purchased breast milk listed for sale on public websites and then analyzed it in the lab. The research was completed in collaboration with Cincinnati Children's Hospital Medical Center and The Ohio State University.
"We were surprised so many samples had such high bacterial counts and even fecal contamination in the milk, most likely from poor hand hygiene. We were also surprised a few samples contained salmonella," said Sarah A. Keim, PhD, principal investigator in the Center for Biobehavioral Health. "Other harmful bacteria may have come from the use of either unclean containers or unsanitary breast milk pump parts."
Individuals posted classified ads on websites describing the breast milk they wanted to sell or why they were seeking breast milk. Researchers responded to ads from sellers who did not ask about the infant receiving milk and who did not require a phone call before a transaction was made.
Researchers analyzed 101 samples bought online and compared the findings to 20 samples obtained from a milk bank. In the U.S., twelve non-profit milk banks follow the Human Milk Banking Association of North America guidelines and provide pasteurized milk from carefully screened donors to fragile and sick infants. Because the milk banks pasteurize their milk, harmful bacteria are killed before the milk reaches an infant, unlike milk purchased online. Even before pasteurization, the milk bank samples were less likely to contain several types of bacteria and had lower bacterial growth in many instances.
Shipping practices also played a role in the levels of bacteria in the milk purchased online. The longer the shipping time, the more contaminated the milk. Nineteen percent of sellers did not include dry ice or another cooling method, and the temperature of the milk was outside of recommended range for storage. Researchers found particularly high levels of one or more types of bacteria in 17 percent of the samples.
Information provided by sellers in their classified ads online, such as "I eat an organic diet" or "great quality" had no direct implication on the safety of the breast milk. However, sellers often did not include information about the use of hygienic milk handling or storage practices, screening for diseases transmissible by milk, or limiting or abstaining from legal or illegal drugs.
"Major milk-sharing websites post a lot of guidance about milk collection, storage, shipping and provider screening. However, results from this study showed sellers do not often follow this advice because hygiene and shipping practices were often compromised," said Dr. Keim, also a faculty member at The Ohio State University College of Medicine. "Based on our research, it is not safe to buy breast milk online, and the Food and Drug Administration recommends against sharing milk obtained in that way. Recipients are not able to determine for sure if the milk has been tampered with, or contains harmful drugs or pharmaceuticals, or if the information the provider supplied about their health was truthful."
According to Dr. Keim, it is difficult to know if a particular infant would be sickened by consuming any given bottle of milk, but the types of bacteria found in the online samples contained bacteria that could cause illnesses known to be linked to contaminated breast milk.
Milk banks are a safer alternative for breast milk for sick babies if the mother cannot provide milk because donors receive proper instructions and the milk is pasteurized, limiting the risk of bacterial illness, said Dr. Keim. Human breast milk can help strengthen the immune system and has been shown to protect against severe illnesses like necrotizing enterocolitis, a potentially deadly condition affecting thousands of infants each year.
Dr. Keim said women who have extra milk should consider donating it to a milk bank where the milk can be handled properly and they will ensure it goes to a baby who badly needs it, rather than selling it. Milk sold online and contaminated with bacteria that causes illness can be particularly harmful for premature infants or those with weakened immune systems, who are already particularly susceptible to infection.
"Our research results may not apply to situations where milk is shared among friends or relatives or donated rather than soldthe potential risks of those situations are less well understood," said Dr. Keim. Moms pumping for their own child should sanitize the parts of the breast pump that come into contact with the milk, use clean containers and wash their hands before pumping and handling milk. Also, keep milk cold and feed it to the baby soon.
"Our goal is to identify infant feeding practices that optimize child and maternal health. In addition to lactation consultants who are available at hospitals and clinics, there are community-based lactation consultants and peer-support organizations where women can help each other," said Dr. Keim. "We will continue to study breastfeeding in the context of contemporary society since where and how infants are fed is rapidly changing."
###
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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.
Study shows buying breast milk online is likely to cause illness in infants
Results from a study led by researchers at Nationwide Children's Hospital found more than three-fourths of breast milk samples purchased over the Internet contained bacteria that can cause illness, and frequently exhibited signs of poor collection, storage or shipping practices.
The study, published online today and in the November issue of Pediatrics, is the first to examine the safety of selling breast milk to others over the Internet, a trend that has become more frequent in the past several years. It is unknown exactly how common purchasing breast milk online is, but an earlier study cited 13,000 postings were placed on U.S. milk sharing websites in 2011.
The research team from the Center for Biobehavioral Health at The Research Institute at Nationwide Children's Hospital purchased breast milk listed for sale on public websites and then analyzed it in the lab. The research was completed in collaboration with Cincinnati Children's Hospital Medical Center and The Ohio State University.
"We were surprised so many samples had such high bacterial counts and even fecal contamination in the milk, most likely from poor hand hygiene. We were also surprised a few samples contained salmonella," said Sarah A. Keim, PhD, principal investigator in the Center for Biobehavioral Health. "Other harmful bacteria may have come from the use of either unclean containers or unsanitary breast milk pump parts."
Individuals posted classified ads on websites describing the breast milk they wanted to sell or why they were seeking breast milk. Researchers responded to ads from sellers who did not ask about the infant receiving milk and who did not require a phone call before a transaction was made.
Researchers analyzed 101 samples bought online and compared the findings to 20 samples obtained from a milk bank. In the U.S., twelve non-profit milk banks follow the Human Milk Banking Association of North America guidelines and provide pasteurized milk from carefully screened donors to fragile and sick infants. Because the milk banks pasteurize their milk, harmful bacteria are killed before the milk reaches an infant, unlike milk purchased online. Even before pasteurization, the milk bank samples were less likely to contain several types of bacteria and had lower bacterial growth in many instances.
Shipping practices also played a role in the levels of bacteria in the milk purchased online. The longer the shipping time, the more contaminated the milk. Nineteen percent of sellers did not include dry ice or another cooling method, and the temperature of the milk was outside of recommended range for storage. Researchers found particularly high levels of one or more types of bacteria in 17 percent of the samples.
Information provided by sellers in their classified ads online, such as "I eat an organic diet" or "great quality" had no direct implication on the safety of the breast milk. However, sellers often did not include information about the use of hygienic milk handling or storage practices, screening for diseases transmissible by milk, or limiting or abstaining from legal or illegal drugs.
"Major milk-sharing websites post a lot of guidance about milk collection, storage, shipping and provider screening. However, results from this study showed sellers do not often follow this advice because hygiene and shipping practices were often compromised," said Dr. Keim, also a faculty member at The Ohio State University College of Medicine. "Based on our research, it is not safe to buy breast milk online, and the Food and Drug Administration recommends against sharing milk obtained in that way. Recipients are not able to determine for sure if the milk has been tampered with, or contains harmful drugs or pharmaceuticals, or if the information the provider supplied about their health was truthful."
According to Dr. Keim, it is difficult to know if a particular infant would be sickened by consuming any given bottle of milk, but the types of bacteria found in the online samples contained bacteria that could cause illnesses known to be linked to contaminated breast milk.
Milk banks are a safer alternative for breast milk for sick babies if the mother cannot provide milk because donors receive proper instructions and the milk is pasteurized, limiting the risk of bacterial illness, said Dr. Keim. Human breast milk can help strengthen the immune system and has been shown to protect against severe illnesses like necrotizing enterocolitis, a potentially deadly condition affecting thousands of infants each year.
Dr. Keim said women who have extra milk should consider donating it to a milk bank where the milk can be handled properly and they will ensure it goes to a baby who badly needs it, rather than selling it. Milk sold online and contaminated with bacteria that causes illness can be particularly harmful for premature infants or those with weakened immune systems, who are already particularly susceptible to infection.
"Our research results may not apply to situations where milk is shared among friends or relatives or donated rather than soldthe potential risks of those situations are less well understood," said Dr. Keim. Moms pumping for their own child should sanitize the parts of the breast pump that come into contact with the milk, use clean containers and wash their hands before pumping and handling milk. Also, keep milk cold and feed it to the baby soon.
"Our goal is to identify infant feeding practices that optimize child and maternal health. In addition to lactation consultants who are available at hospitals and clinics, there are community-based lactation consultants and peer-support organizations where women can help each other," said Dr. Keim. "We will continue to study breastfeeding in the context of contemporary society since where and how infants are fed is rapidly changing."
###
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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.
New drug combinations may benefit patients with pancreatic cancer
PUBLIC RELEASE DATE:
21-Oct-2013
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Contact: Lauren Riley lauren.riley@aacr.org 215-446-7155 American Association for Cancer Research
BOSTON Two drug combinations that simultaneously block two major signaling pathways downstream of the protein KRAS, which is aberrantly active in most pancreatic cancers, may provide a new treatment option for patients with this disease, according to preclinical results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.
Pancreatic cancer is one of the deadliest types of cancer, with a five-year survival rate of just 6 percent. Most pancreatic cancers harbor mutations in the KRAS gene. Because these mutations drive many of the cancerous characteristics of pancreatic cancer cells, the KRAS protein is a prime therapeutic target. However, efforts to develop clinically useful drugs that block KRAS activity have been unsuccessful.
"KRAS has been a daunting therapeutic target," said Barry Nelkin, Ph.D., professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Md. "By combining drugs that simultaneously block two of the major signaling pathways triggered by KRAS, we have found a way to indirectly target this challenging protein.
"Our preclinical results were so positive that we have initiated a phase I clinical trial to evaluate one of the drug combinations, dinaciclib plus MK2206, in patients with pancreatic cancer."
In prior studies, Nelkin and colleagues found that an investigational drug called dinaciclib had antitumor effects in mouse models of pancreatic cancer.
"Dinaciclib blocks the activity of a protein called CDK5, which is a key part of one of the signaling pathways that KRAS uses to exert its cancer-driving effects, the Ral pathway," explained Nelkin. "We wanted to investigate whether combining dinaciclib with a second drug that blocks one of the other signaling pathways triggered by KRAS would have even greater antitumor effects."
To conduct the study, Nelkin and colleagues used models of pancreatic cancer that closely resembled the human disease: They placed tiny pieces of human pancreatic tumors in the pancreata of mice and let them grow to about the size of a pea before beginning treatment.
The combination of dinaciclib and MK2206, which blocks the PI3K/AKT pathway triggered by KRAS, substantially inhibited tumor growth and reduced tumor spread to other parts of the body, a process called metastasis, compared with either drug alone. Further, when compared with no treatment, this drug combination reduced tumor growth by 90 percent, and in three of the 14 mice, no human pancreatic tumor tissue could be detected at the end of the experiment, indicating that there had been a complete response to the treatment.
The second drug combination testeddinaciclib and SCH772984, which blocks the RAF/MEK/ERK pathway triggered by KRASalso substantially inhibited tumor growth and reduced the number of metastases. It did not, however, lead to any complete responses.
The researchers are planning to investigate whether the drug combinations they used in this study can be further combined with current treatments for pancreatic cancer and if they can identify markers that might predict whether a given pancreatic tumor will respond to the drug combinations.
###
This study was funded by the National Cancer Institute. Nelkin declares that no conflicts of interest exist.
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 "Overcoming Resistance and Hard-to-treat Cancers" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Monday, Oct. 21 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:
U.S./Canada (toll-free): 800-446-2782
International (toll): 847-413-3235
To interview Barry Nelkin, contact Vanessa Wasta at wasta@jhmi.edu or 410-736-1397. 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: B263
Presenter: Barry Nelkin, Ph.D.
Title: Combined inhibition of cyclin-dependent kinases (Dinaciclib) and AKT (MK-2206) or ERK (SCH772984) dramatically blocks pancreatic tumor growth and metastases in patient-derived orthotopic xenograft models
Authors: Chaoxin Hu1, Tikva Dadon1, Venugopal Chenna1, Shin Yabuuchi1, Rajat Bannerji2, Robert Booher2, Peter Strack2, Ahmed Samatar2, Nilofer Azad1, Barry D. Nelkin1, Anirban Maitra1. 1Johns Hopkins Univ. School of Medicine, Baltimore, MD; 2Merck and Co., Boston, MA
Pancreatic cancer is among the deadliest of all solid malignances. The 5-year survival rate of pancreatic cancer remains below 5%, mainly due to a lack of early detection and the highly metastatic properties that make surgery impossible in most cases. Therefore, it is urgent to find effective systemic therapies to treat this highly metastatic cancer. KRAS is activated in the vast majority of cases of pancreatic cancer; unfortunately, therapeutic attempts to inhibit KRAS directly have been unsuccessful. Our previous studies showed that inhibition of cyclin-dependent kinase 5 (CDK5), using genetic manipulation or the CDK inhibitor Dinaciclib, reduces pancreatic cancer growth and progression, through blockage of the Ral effector pathway, downstream of KRAS. Since Ral has been shown to be a centrally important effector of KRAS signaling in pancreatic cancer, we hypothesized that simultaneous blockage of two major downstream KRAS effectors may further inhibit the growth and metastasis of pancreatic cancer and provide an effective therapeutic strategy for this disease.
In the current study, the therapeutic effects of combining the CDK inhibitor Dinaciclib with inhibitors of either the PI3K/AKT effector pathway (pan-AKT inhibitor MK2206) or the RAF/MEK/ERK effector pathway (ERK inhibitor SCH772984) were evaluated using two orthotopic patient-derived human pancreatic cancer xenograft models (Panc253 and Panc265). These models closely resemble the physiological and pathological conditions of pancreatic cancer in humans. A 2-3 mm3 tumor explant was implanted into the pancreas of nude mice and ultrasound imaging was used to measure the tumor size (3D) before randomization and treatment, which began when tumors grew to 50-100 mm3. The combination of Dinaciclib (20 mg/kg, i.p., t.i.w.) and MK2206 (60 mg/kg, p.o., t.i.w.) dramatically blocked tumor growth in the orthotopic Panc265 (90.0%, p
Similarly, the combination of Dinaciclib (20 mg/kg, i.p., t.i.w.) and SCH772984 (25 mg/kg, i.p., b.i.d.) dramatically inhibited the growth of primary orthotopic Panc265 (82.5%, p
The striking results obtained in these models appear to validate our hypothesis that blocking multiple effector pathways downstream from KRAS, including the Ral effector pathway, may provide increased efficacy in pancreatic cancer. Thus, the combinations of Dinaciclib with the pan-AKT inhibitor MK2206 or the ERK inhibitor SCH772984 are novel, highly promising potential therapies against pancreatic cancer. Based on these data, an NCI-CTEP approved Phase I clinical trial for pancreatic cancer of the combination of Dinaciclib and MK2206 has now opened here at Johns Hopkins.
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New drug combinations may benefit patients with pancreatic cancer
PUBLIC RELEASE DATE:
21-Oct-2013
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Contact: Lauren Riley lauren.riley@aacr.org 215-446-7155 American Association for Cancer Research
BOSTON Two drug combinations that simultaneously block two major signaling pathways downstream of the protein KRAS, which is aberrantly active in most pancreatic cancers, may provide a new treatment option for patients with this disease, according to preclinical results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.
Pancreatic cancer is one of the deadliest types of cancer, with a five-year survival rate of just 6 percent. Most pancreatic cancers harbor mutations in the KRAS gene. Because these mutations drive many of the cancerous characteristics of pancreatic cancer cells, the KRAS protein is a prime therapeutic target. However, efforts to develop clinically useful drugs that block KRAS activity have been unsuccessful.
"KRAS has been a daunting therapeutic target," said Barry Nelkin, Ph.D., professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Md. "By combining drugs that simultaneously block two of the major signaling pathways triggered by KRAS, we have found a way to indirectly target this challenging protein.
"Our preclinical results were so positive that we have initiated a phase I clinical trial to evaluate one of the drug combinations, dinaciclib plus MK2206, in patients with pancreatic cancer."
In prior studies, Nelkin and colleagues found that an investigational drug called dinaciclib had antitumor effects in mouse models of pancreatic cancer.
"Dinaciclib blocks the activity of a protein called CDK5, which is a key part of one of the signaling pathways that KRAS uses to exert its cancer-driving effects, the Ral pathway," explained Nelkin. "We wanted to investigate whether combining dinaciclib with a second drug that blocks one of the other signaling pathways triggered by KRAS would have even greater antitumor effects."
To conduct the study, Nelkin and colleagues used models of pancreatic cancer that closely resembled the human disease: They placed tiny pieces of human pancreatic tumors in the pancreata of mice and let them grow to about the size of a pea before beginning treatment.
The combination of dinaciclib and MK2206, which blocks the PI3K/AKT pathway triggered by KRAS, substantially inhibited tumor growth and reduced tumor spread to other parts of the body, a process called metastasis, compared with either drug alone. Further, when compared with no treatment, this drug combination reduced tumor growth by 90 percent, and in three of the 14 mice, no human pancreatic tumor tissue could be detected at the end of the experiment, indicating that there had been a complete response to the treatment.
The second drug combination testeddinaciclib and SCH772984, which blocks the RAF/MEK/ERK pathway triggered by KRASalso substantially inhibited tumor growth and reduced the number of metastases. It did not, however, lead to any complete responses.
The researchers are planning to investigate whether the drug combinations they used in this study can be further combined with current treatments for pancreatic cancer and if they can identify markers that might predict whether a given pancreatic tumor will respond to the drug combinations.
###
This study was funded by the National Cancer Institute. Nelkin declares that no conflicts of interest exist.
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 "Overcoming Resistance and Hard-to-treat Cancers" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Monday, Oct. 21 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:
U.S./Canada (toll-free): 800-446-2782
International (toll): 847-413-3235
To interview Barry Nelkin, contact Vanessa Wasta at wasta@jhmi.edu or 410-736-1397. 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: B263
Presenter: Barry Nelkin, Ph.D.
Title: Combined inhibition of cyclin-dependent kinases (Dinaciclib) and AKT (MK-2206) or ERK (SCH772984) dramatically blocks pancreatic tumor growth and metastases in patient-derived orthotopic xenograft models
Authors: Chaoxin Hu1, Tikva Dadon1, Venugopal Chenna1, Shin Yabuuchi1, Rajat Bannerji2, Robert Booher2, Peter Strack2, Ahmed Samatar2, Nilofer Azad1, Barry D. Nelkin1, Anirban Maitra1. 1Johns Hopkins Univ. School of Medicine, Baltimore, MD; 2Merck and Co., Boston, MA
Pancreatic cancer is among the deadliest of all solid malignances. The 5-year survival rate of pancreatic cancer remains below 5%, mainly due to a lack of early detection and the highly metastatic properties that make surgery impossible in most cases. Therefore, it is urgent to find effective systemic therapies to treat this highly metastatic cancer. KRAS is activated in the vast majority of cases of pancreatic cancer; unfortunately, therapeutic attempts to inhibit KRAS directly have been unsuccessful. Our previous studies showed that inhibition of cyclin-dependent kinase 5 (CDK5), using genetic manipulation or the CDK inhibitor Dinaciclib, reduces pancreatic cancer growth and progression, through blockage of the Ral effector pathway, downstream of KRAS. Since Ral has been shown to be a centrally important effector of KRAS signaling in pancreatic cancer, we hypothesized that simultaneous blockage of two major downstream KRAS effectors may further inhibit the growth and metastasis of pancreatic cancer and provide an effective therapeutic strategy for this disease.
In the current study, the therapeutic effects of combining the CDK inhibitor Dinaciclib with inhibitors of either the PI3K/AKT effector pathway (pan-AKT inhibitor MK2206) or the RAF/MEK/ERK effector pathway (ERK inhibitor SCH772984) were evaluated using two orthotopic patient-derived human pancreatic cancer xenograft models (Panc253 and Panc265). These models closely resemble the physiological and pathological conditions of pancreatic cancer in humans. A 2-3 mm3 tumor explant was implanted into the pancreas of nude mice and ultrasound imaging was used to measure the tumor size (3D) before randomization and treatment, which began when tumors grew to 50-100 mm3. The combination of Dinaciclib (20 mg/kg, i.p., t.i.w.) and MK2206 (60 mg/kg, p.o., t.i.w.) dramatically blocked tumor growth in the orthotopic Panc265 (90.0%, p
Similarly, the combination of Dinaciclib (20 mg/kg, i.p., t.i.w.) and SCH772984 (25 mg/kg, i.p., b.i.d.) dramatically inhibited the growth of primary orthotopic Panc265 (82.5%, p
The striking results obtained in these models appear to validate our hypothesis that blocking multiple effector pathways downstream from KRAS, including the Ral effector pathway, may provide increased efficacy in pancreatic cancer. Thus, the combinations of Dinaciclib with the pan-AKT inhibitor MK2206 or the ERK inhibitor SCH772984 are novel, highly promising potential therapies against pancreatic cancer. Based on these data, an NCI-CTEP approved Phase I clinical trial for pancreatic cancer of the combination of Dinaciclib and MK2206 has now opened here at Johns Hopkins.
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