New Test Developed at TGen Uses the Unique Genetics of Women to Uncover a devastating Neurologic Disorder

Study published today by investigators with TGen’s Dorrance Center for Rare Childhood Disorders

Using a basic genetic difference between men and women, the Translational Genomics Research Institute (TGen) has uncovered a way to track down the source of a neurological disorder in a young girl.

TGen’s discovery relies on a simple genetic fact: Men have one X and one Y chromosome, while women have two X chromosomes. This women-only factor was leveraged by TGen investigators to develop a highly accurate method of tracking down a previously unrecognized disorder of the X-chromosome.

The study of a pre-teen girl, who went years with an undiagnosed neurobehavioral condition, was published today in the scientific journal PLOS ONE.

TGen’s findings were made within its Dorrance Center for Rare Childhood Disorders, where investigators and clinicians apply the latest tools of genomic medicine to provide answers for parents seeking to identify the disease or disorder affecting their child.

The scientists sequenced, or spelled out in order, the complete genetic codes of DNA and RNA of the girl. Because girls inherit an X chromosome from each of their parents (boys inherit a Y chromosome from their father), they also sequenced her mother and father. On average, about half of all X chromosomes active in a female come from the mother and the other half from the father.

“We now have the tools to significantly accelerate the diagnostic process, reducing the need for children to undergo multiple tests that can be emotionally and physically taxing for the entire family,” said Dr. David Craig, TGen’s Deputy Director of Bioinformatics, Co-Director of the Dorrance Center and the paper’s senior author.

Sequencing would reveal the proportion of X chromosomes, and if disproportionate, whether the more abundant of the two were damaged in some way, which often leads to X-linked genetic conditions.

“At the time of enrollment, we suspected the girl had a complex neurobehavioral condition, based on her attention deficit, and delays in development and learning,” said Dr. Vinodh Narayanan, Medical Director of the Dorrance Center. “Her brain MRI scans were normal. We needed to find out more — at the genetic level — about what might be causing her disorder.”

By sequencing the DNA and RNA, TGen investigators were able to precisely identify which cells contained active X chromosomes from the girl’s mother, which contained active X chromosomes from the father, in what proportions, and whether they were associated with any known disorders.

They discovered that the X chromosome from the father contained a segment shown to be associated with neurobehavioral conditions. Interestingly, however, the proportion of X chromosomes active in the girl’s cells skewed toward the normal X inherited from her mother. This skewing may have led to a milder, harder to diagnose condition undetected by conventional methods.

“This study shows the power sequencing holds when scanning for potential disease causing and disease-modifying genetic variations,” said Dr. Matt Huentelman, the other Co-Director of the Dorrance Center and an author of the PLOS ONE paper. “I’m most excited to see the pace at which TGen has pushed the genome sequencing technology to where it can help patients — today.”

TGen Research Associate Szabolcs Szelinger, the paper’s lead author, said: “With just a small bio sample, we are now able to provide a comprehensive evaluation of the effects that genetic variation has on patients, leading to highly personalized treatment options, while at the same time providing researchers with insights into the underlying molecular processes.”

Since opening in October 2013, TGen’s Dorrance Center for Rare Childhood Disorders Dorrance Center has enrolled nearly 300 families. And with the rapid decrease in sequencing costs and improved analytical methods, comprehensive, integrative sequencing approaches will likely be used more in the future. Information on the Dorrance Center is available at www.c4rcd.org.

Funding for the study came from the State of Arizona, the Stardust Foundation, and donations to the TGen Foundation.

About TGen
Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. TGen is focused on helping patients with cancer, neurological disorders and diabetes, through cutting edge translational research (the process of rapidly moving research towards patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and rare complex diseases in adults and children. Working with collaborators in the scientific and medical communities literally worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit: www.tgen.org.

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TGen’s Dr. John Carpten Honored with AACR Distinguished Lectureship on the Science of Cancer Health Disparities

NIH director praises choice of Dr. Carpten to give award lecture on medically underserved and underrepresented at AACR conference Nov. 9

The American Association for Cancer Research (AACR), the world’s largest cancer research organization representing more than 35,000 investigators, congratulates Dr. John D. Carpten on receiving the 2014 AACR Distinguished Lectureship on the Science of Health Disparities, funded by Susan G. Komen.

He will be honored at the American Association for Cancer Research (AACR) conference on The Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, held Nov. 9-12 in San Antonio.

Dr. Francis S. Collins, Director of the National Institutes of Health (NIH), praised the selection of Dr. Carpten: “As NIH Director, this is a double delight — seeing health disparities research get the recognition it deserves, and seeing John Carpten, who I had the privilege of co-mentoring at NIH almost two decades ago, receiving this award. Bravo to John and the AACR.”

Dr. Carpten, Deputy Director of Basic Sciences at the Translational Genomics Research Institute (TGen) in Phoenix, is being recognized for his outstanding research focused on understanding the role of biology in the disparate cancer incidence and mortality rates seen among minority populations.

He will deliver his award lecture, “Genetics and Genome Sciences in Cancer Health Disparities,” during the opening plenary session, 7:15 p.m. CST Nov. 9 in Texas Ballroom D-E of the Grand Hyatt San Antonio.

The 5th annual AACR Distinguished Lectureship on the Science of Cancer Health Disparities, funded by Susan G. Komen, recognizes an investigator whose novel and significant work has had or may have a far-reaching impact on the etiology, detection, diagnosis, treatment, or prevention of cancer health disparities.

“I’m humbled and honored by this recognition. However, I am actually accepting this on behalf of all of the amazing scientists, patients, and medical professionals that have contributed to any work that might be deemed mine,” Dr. Carpten said. “I’ve been blessed to work with some of the most outstanding scientists in the world and this award is as much theirs as it is mine. I hope to continue to pursue the purpose that’s been given me to help understand and ultimately improve health outcomes for all people, particularly the underrepresented.”

Dr. Carpten has made a number of seminal discoveries in cancer genetics and genomics. His work has applied high-throughput genomic technologies to discover important genomic alterations in cancer. In addition, he has a strong passion and commitment to understanding cancer etiology among minority populations, which is evident through his leadership role in the African-American Hereditary Prostate Cancer (AAHPC) Study Network. This network was conceived by Dr. Carpten and has become a model for genetic linkage studies in underrepresented populations and was the first to conduct a genomewide scan for prostate cancer susceptibility genes in African-Americans.

In addition, his work on multiple myeloma has led to a better biological understanding of the differences in incidence and outcomes seen among African-American patients with multiple myeloma. More recently, his group has discovered a number of single nucleotide polymorphisms, which confer increased risk of developing prostate cancer. He has recently led and co-authored a series of articles describing the roles of genetic variants in prostate cancer risk in Genome Research, Journal of the National Cancer Institute, and New England Journal of Medicine.

Dr. Carpten is an active member of the AACR. He is currently a senior editor of Cancer Research, and has previously served as a member of the Minorities in Cancer Research (MICR) Council Committee, chair of the 2010 MICR Scientific Symposium, member of the MICR-Jane Cooke Wright Lectureship Committee, member of the Research Grant Review Committee, and as a member of the editorial board of Clinical Cancer Research.

Prior to joining TGen, Dr. Carpten was an investigator with the cancer genetics branch of the National Institutes of Health’s National Human Genome Research Institute. He received his doctoral degree in molecular genetics from The Ohio State University in Columbus.

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 35,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in 97 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 over 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 www.AACR.org. Follow us: Cancer Research Catalyst http://blog.aacr.org; Twitter @AACR; and Facebookhttp://www.facebook.com/aacr.org

About TGen
Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. TGen is focused on helping patients with cancer, neurological disorders and diabetes, through cutting edge translational research (the process of rapidly moving research towards patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and rare complex diseases in adults and children. Working with collaborators in the scientific and medical communities literally worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit: www.tgen.org.

TGen News

New therapy for pancreatic cancer patients shows promising results

TGen-Scottsdale Healthcare lead international clinical trials in advance of FDA application for NAPOLI-1

SCOTTSDALE, Ariz. — June 6, 2014 — A clinical trial conducted by researchers at the Virginia G. Piper Cancer Center Clinical Trials, a partnership between Scottsdale Healthcare and the Translational Genomics Research Institute (TGen), showed that a new drug called MM-398, given in combination with 5-flourouracil (5FU) and leucovorin, produced a significant overall survival rate in patients with advanced, previously-treated pancreatic cancer.

The NAPOLI-1 (NAnoliPOsomaL Irinotecan) Phase 3 study — a final confirmation of a drug’s safety and effectiveness — was conducted among patients with metastatic pancreatic cancer who previously received gemcitibine, which has been the standard-of-care therapy for such patients.

The study, sponsored by Merrimack Pharmaceuticals, evaluated 417 patients enrolled at more than 100 sites in North America, South America, Europe, Asia and Australia, including patients at the Virginia G. Piper Cancer Center at Scottsdale Healthcare. Merrimack expects to submit a New Drug Application this year to the U.S. Food and Drug Administration (FDA) for the MM-398 combination regimen.

“This demonstration of a survival benefit from the MM-398 plus 5-FU and leucovorin combination is particularly important given that we have very few treatment options for patients in this tough clinical setting,” said Dr. Daniel D. Von Hoff, MD, FACP, global principal investigator of the NAPOLI-1 study, Chief Scientific Officer for Scottsdale Healthcare’s Virginia G. Piper Cancer Center Clinical Trials and Physician-In-Chief and Distinguished Professor at TGen. “The results of the NAPOLI-1 study are important because of the critical need to help patients with this devastating illness and move forward towards FDA approval.”

The combination of MM-398 with 5-fluorouracil (5-FU) and leucovorin achieved an overall survival of 6.1 months, a 1.9 month improvement over the 4.2 month survival demonstrated by the control arm of 5-FU and leucovorin alone.

Each year in the U.S., nearly 46,000 people are diagnosed with pancreatic cancer, and more than 39,000 patients die, making it the fourth leading cause of cancer death. Only about 1 in 4 patients survive more than one year after diagnosis, and only 6 percent survivor more than five years.

Symptoms of pancreatic cancer usually do not appear until the cancer is in its late stages, making it difficult to treat. Once the disease spreads to other parts of the body, most patients are not candidates for surgery and receive chemotherapy as their primary treatment.

This study will be presented at the European Society for Medical Oncology World Conference on Gastrointestinal Cancer being held June 25-28 in Barcelona, Spain.

Patients seeking information about research studies may contact the Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare at 480-323-1339 or toll free at 1-877-273-3713 or e-mail: clinicaltrials@shc.org.

About the Virginia G. Piper Cancer Center at Scottsdale Healthcare
The Virginia G. Piper Cancer Center at Scottsdale Healthcare in Scottsdale, Ariz. offers comprehensive cancer treatment and research through clinical trials, diagnosis, treatment, prevention and support services in collaboration with leading scientific researchers and community oncologists. The Virginia G. Piper Cancer Center at Scottsdale Healthcare, Scottsdale Healthcare Research Institute, Scottsdale Healthcare Osborn Medical Center, Scottsdale Healthcare Shea Medical Center and Scottsdale Healthcare Thompson Peak Hospital and related entities are affiliates of the non-profit Scottsdale Lincoln Health Network. For more information, visitwww.shc.org.

About TGen
Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. TGen is focused on helping patients with cancer, neurological disorders and diabetes, through cutting edge translational research (the process of rapidly moving research towards patient benefit).  TGen physicians and scientists work to unravel the genetic components of both common and rare complex diseases in adults and children. Working with collaborators in the scientific and medical communities literally worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit:www.tgen.org.

 

 

Congratulations to TGen’s Dr. Bodour Salhia

TGen’s Dr. Bodour Salhia named to 2014 Class of 40 Under 40

Newspaper recognizes TGen cancer researcher among Phoenix’s brightest young leaders

PHOENIX, Ariz. — May 6, 2014 — Dr. Bodour Salhia, a cancer researcher at the Translational Genomics Research Institute (TGen), has been named one of the Phoenix Business Journal’s 2014 Class of 40 Under 40.

Dr. Salhia, an Assistant Professor in TGen’s Integrated Cancer Genomics Division, will be among the 40 up-and-coming Phoenix leaders — less than 40 years of age — at an awards reception June 19 at Phoenix Theater.

In his award notification letter to Dr. Salhia, PBJ Publisher Don Henninger said, “I speak for all the judges in saying that we feel honored to have seen a glimpse of your life and career. You are most certainly a valuable member of our community and a source of inspiration for all.”

All 40 Under 40 classmates will be featured in a special section of the June 20 edition of the PBJ.

“Bodour is a gem; brilliant and transparent. She is an incredible asset to TGen and to the state of Arizona. Watching her growth and career ascent has been one of the highlights of my entire career,” said Dr. John Carpten, TGen Deputy Director of Basic Science.

“She is an amazing scientist, but also frequently participates in patient advocacy and community education,” said Dr. Carpten, also Professor and Director of TGen’s Integrated Cancer Genomics Division. “We are so proud of Bodour. To me, this is not simply a recognition of her achievements, but also a reward for all that she does for others.”

Dr. Salhia, who specializes in researching breast cancer and multiple myeloma, is the fourth TGen staff member in three years to be selected to PBJ’s 40 Under 40. Dr. Matt Huentelman, an Associate Professor in TGen’s Neurogenomics Division, and Dr. Glen Weiss, a Clinical Associate Professor in TGen’s Cancer and Cell Biology Division, were named in 2013. Dr. Candice Nulsen, TGen’s former Director of Education and Community Outreach, was selected in 2012.

“I am so thankful and humbled to be selected among this year’s 40 Under 40 by the Phoenix Business Journal,” said Dr. Salhia, whose community work has included outreach to cancer patients of the Navajo Nation, and service as a board member of Susan G. Komen for the Cure, Central and Northern Arizona Affiliate. “This award is not just about me, but also reflects all the cutting-edge research that TGen conducts, using the human genome to devise better treatments for patients today.”

The 40 Under 40 program’s hundreds of alumni includes Phoenix Mayor Greg Stanton, a member of the TGen Board of Directors, and Arizona Diamondbacks President Derrick Hall, a member of TGen’s National Advisory Council for Pancreatic Cancer Research.

About TGen

Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. TGen is focused on helping patients with cancer, neurological disorders and diabetes, through cutting edge translational research (the process of rapidly moving research towards patient benefit).  TGen physicians and scientists work to unravel the genetic components of both common and rare complex diseases in adults and children. Working with collaborators in the scientific and medical communities literally worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit: www.tgen.org.

 

 

Diamondbacks Pitcher Supports his Best Friend Diagnosed with Brain Cancer

With his best friend set to undergo surgery for a highly aggressive form of brain cancer, Diamondbacks pitcher Wade Miley was hoping and praying for a sign, some kind of indication that Johnnie Santangelo III was going to be all right.

This was early Tuesday morning. Santangelo was leaving Miley’s house for Barrow Neurological Institute. Miley told him he loved him, and on Santangelo’s way out the door Miley’s dog followed.

“You know how it is early in the morning; I didn’t really wake up good,” Miley said. “I remember him, in a daze I remember him looking back and saying, ‘Don’t worry, Sassy, I’m going to be back to see you.’ That just made me feel good. That comforted me. Him telling the dog that. That’s what stuck with me.”

A day after surgery, things are looking up. Doctors say they have removed the glioblastoma multiforme tumor, and concerns that existed pre-surgery about motor functions or vision problems have been mitigated. They think Santangelo is going to be OK.

“I’ve never been so happy in my life,” Miley said.

It has been a harrowing couple of weeks.

Santangelo and Miley have been best friends since childhood. Santangelo always went by “Little Man,” and it just happened he grew to 6 feet 5. Growing up in Louisiana, the two would hunt, fish, play sports and raise hell.

“Whatever you could think of that kids from the country would do,” Miley said. “There wasn’t a day that went by that we weren’t getting in trouble.”

Most recently, Santangelo, who was drafted by the Kansas City Royals in 2004 but never pitched professionally due to elbow problems, had been running his family’s mushroom farm in Louisiana. But then came the headaches. Bad ones.

“They checked out his nose, checked out his ears and sinuses and all that stuff,” Miley said. “One day his vision got all messed up. They called his dad. His dad thought he was (joking). They took him to the hospital and told him he had a brain tumor. Probably some of the worst news you could ever get.”

Miley heard the news about a half hour before the buses left Salt River Fields for the team’s trip to Australia, and the day after they returned Miley flew to Louisiana. He was worried about how his friend would look, but what he saw was the same old Johnnie. This gave Miley hope.

Every doctor Santangelo visited told him the same thing: the cancer was inoperable. They recommended a laser treatment. Miley mentioned it to Diamondbacks trainer Ken Crenshaw, and a few phone calls led them to Barrow’s Dr. Nader Sanai, who thought surgery was possible. They were told doctors would see him as soon as he could get to Arizona.

And so until Tuesday, Santangelo and his family had been staying at Miley’s house. He went to the hospital early that morning. Miley joined them later and stayed as long as he could, but he was scheduled to face the Giants that day and headed out in the middle of the afternoon.

There was concern about Santangelo not being able to move the left side of his body, but he put those to rest once he came to after surgery, picking up his left leg and fist-pumping.

“I let him squeeze my hand (Wednesday) with his left hand and he almost broke it,” Miley said.

Santangelo is having trouble focusing with his eyes heavily dilated, but doctors don’t think it will last. He watched Miley’s outing from the hospital on Tuesday night with one eye, cursing when Miley hung a slider that Brandon Belt crushed for a three-run homer in the first inning. But Miley settled down, got through seven innings and the Diamondbacks won, and after the game Miley delivered two game balls to his friend.

“He had both of them in his hands, juggling and messing with them,” Miley said. “It meant a lot when I handed those to him.”

Santangelo also gave Miley a hard time for not giving him a shoutout in his postgame interviews.

“He’s a big hunter, so he was like, ‘Get my name out there, I might get a hunting trip out of it,’ ” Miley said.

Miley said Santangelo, who has a 4-inch scar on the back of his head, will probably head home to heal and rest before coming back to start radiation and chemo.

“He’s doing about the best I can imagine,” Miley said. “I was scared to death about what I was going to see. He’s as good as he can be. He’s not out of the woods, but he’s a whole hell of a lot better than he was doing three days ago when that tumor was still in there.”

Link to the story on azcentral.com

 

Dr. Reid Goes Deeper Into the Brain

The Brain’s Inner Language

By JAMES GORMAN

SEATTLE — When Clay Reid decided to leave his job as a professor at Harvard Medical School to become a senior investigator at the Allen Institute for Brain Science in Seattle in 2012, some of his colleagues congratulated him warmly and understood right away why he was making the move.

Others shook their heads. He was, after all, leaving one of the world’s great universities to go to the academic equivalent of an Internet start-up, albeit an extremely well- financed, very ambitious one, created in 2003 by Paul Allen, a founder of Microsoft.

Still, “it wasn’t a remotely hard decision,” Dr. Reid said. He wanted to mount an all-out investigation of a part of the mouse brain. And although he was happy at Harvard, the Allen Institute offered not only great colleagues and deep pockets, but also an approach to science different from the classic university environment. The institute was already mapping the mouse brain in fantastic detail, and specialized in the large-scale accumulation of information in atlases and databases available to all of science.

Read more: http://www.nytimes.com/2014/02/25/science/the-brains-inner-language.html?nl=todaysheadlines&emc=edit_th_20140225&_r=0&referrer

A Scientific Breakthrough for Brain Tumors in Children

Stanford: Scientists Illuminate Brain Tumors in Mice

With the use of a “molecular flashlight” scientists hope to target tumors medulloblastomas in children one of the most devastating of the malignant childhood brain tumors.

Jennifer Cochran and Matthew Scott have created a bioengineered peptide that has been shown in mice to provide better imaging of a type of brain tumor known as medulloblastoma. Credit John Todd.
Jennifer Cochran and Matthew Scott have created a bioengineered peptide that has been shown in mice to provide better imaging of a type of brain tumor known as medulloblastoma. Credit John Todd.

In a breakthrough that could have wide-ranging applications in molecular medicine, Stanford University researchers have created a bioengineered peptide that enables imaging of medulloblastomas, among the most devastating of malignant childhood brain tumors, in lab mice.

The team used their invention as a “molecular flashlight” to distinguish tumors from surrounding healthy tissue. After injecting their bioengineered knottin into the bloodstreams of mice with medulloblastomas, the researchers found that the peptide stuck tightly to the tumors and could be detected using a high-sensitivity digital camera.

The findings are described in a study published online Aug. 12 in the Proceedings of the National Academy of Sciences.

“Researchers have been interested in this class of peptides for some time,” said Jennifer Cochran, PhD, an associate professor of bioengineering and a senior author of the study. “They’re extremely stable. For example, you can boil some of these peptides or expose them to harsh chemicals, and they’ll remain intact.” That makes them potentially valuable in molecular medicine. Knottins could be used to deliver drugs to specific sites in the body or, as Cochran and her colleagues have demonstrated, as a means of illuminating tumors.
For treatment purposes, it’s critical to obtain accurate images of medulloblastomas. In conjunction with chemotherapy and radiation therapy, the tumors are often treated by surgical resection, and it can be difficult to remove them while leaving healthy tissue intact because their margins are often indistinct.

“With brain tumors, you really need to get the entire tumor and leave as much unaffected tissue as possible,” Cochran said. “These tumors can come back very aggressively if not completely removed, and their location makes cognitive impairment a possibility if healthy tissue is taken.”

The researchers’ molecular flashlight works by recognizing a biomarker on human tumors. The bioengineered knottin is conjugated to a near-infrared imaging dye. When injected into the bloodstreams of a strain of mice that develop tumors similar to human medullublastomas, the peptide attaches to the brain tumors’ integrin receptors — sticky molecules that aid in adhesion to other cells.

But while the knottins stuck like glue to tumors, they were rapidly expelled from healthy tissue. “So the mouse brain tumors are readily apparent,” Cochran said. “They differentiate beautifully from the surrounding brain tissue.”

The new peptide represents a major advance in tumor-imaging technology, said Melanie Hayden Gephart, MD, neurosurgery chief resident at the Stanford Brain Tumor Center and a lead author of the paper.

“The most common technique to identify brain tumors relies on preoperative, intravenous injection of a contrast agent, enabling most tumors to be visualized on a magnetic resonance imaging scan,” Gephart said. These MRI scans are used like in a computer program much like an intraoperative GPS system to locate and resect the tumors.

“But that has limitations,” she added. “When you’re using the contrast in an MRI scan to define the tumor margins, you’re basically working off a preoperative snapshot. The brain can sometimes shift during an operation, so there’s always the possibility you may not be as precise or accurate as you want to be. The great potential advantage of this new approach would be to illuminate the tumor in real time — you could see it directly under your microscope instead of relying on an image that was taken before surgery.”

Though the team’s research focused on medulloblastomas, Gephart said it’s likely the new knottins could prove useful in addressing other cancers.

“We know that integrins exist on many types of tumors,” she said. “The blood vessels that tumors develop to sustain themselves also contain integrins. So this has the potential for providing very detailed, real-time imaging for a wide variety of tumors.”

And imaging may not be the only application for the team’s engineered peptide.

“We’re very interested in related opportunities,” Cochran said. “We envision options we didn’t have before for getting molecules into the brain.” In other words, by substituting drugs for dye, the knottins might allow the delivery of therapeutic compounds directly to cranial tumors — something that has proved extremely difficult to date because of the blood/brain barrier, the mechanism that makes it difficult for pathogens, as well as medicines, to traverse from the bloodstream to the brain.

“We’re looking into it now,” Cochran said.

A little serendipity was involved in the peptide’s development, said Sarah Moore, a recently graduated bioengineering PhD student and another lead author of the study. Indeed, the propinquity of Cochran’s laboratory to co-author Matthew Scott’s lab at Stanford’s James H. Clark Center catalyzed the project. “Our labs are next to each other,” Moore said. “We had the peptide, and Matt had ideal models of pediatric brain tumors  —mice that develop tumors in a similar manner to human medulloblastomas. Our partnership grew out of that.”

Scott, PhD, professor of bioengineering and of developmental biology, credits the design of the Clark Center as a contributor to the project. The building is home to Stanford’s Bioengineering Department, a collaboration between the School of Engineering and the School of Medicine, and Stanford Bio-X, an initiative that encourages communication among researchers in diverse scientific disciplines.

“So in a very real sense, our project wasn’t an accident,” Scott said. “In fact, it’s exactly the kind of work the Clark Center was meant to foster. The lab spaces are wide and open, with very few walls and lots of glass. We have a restaurant that only has large tables — no tables for two, so people have to sit together. Everything is designed to increase the odds that people will meet and talk. It’s a form of social engineering that really works.”

Scott said he is gratified by the collaboration that led to the team’s breakthrough, and observed that the peptide has proved a direct boon to his own work. About 15 percent of Scott’s mice develop the tumors requisite for medulloblastoma research. The problem, he said, is that the cancers are cryptic in their early stages.

“By the time you know the mice have them, many of the things you want to study — the genesis and development of the tumors — are past,” Scott said. “We needed ways to detect these tumors early, and we needed methods for following the steps of tumor genesis.”

Ultimately, Scott concluded, the development of the new peptide can be attributed to Stanford’s long-established traditions of openness and relentless inquiry.

“You find not just a willingness, but an eagerness to exchange ideas and information here,” Scott said. “It transcends any competitive instinct, any impulse toward proprietary thinking. It is what makes Stanford — well, Stanford.”

The Stanford Center for Children’s Brain Tumors at Lucile Packard Children’s Hospital is supporting ongoing work by the group to translate the new technology into patient care. Additional funding came from the Wallace H. Coulter Foundation, the V Foundation for Cancer Research, the James S. McDonnell Foundation, the Stanford Cancer Institute, the National Science Foundation, a Stanford University graduate fellowship, a Siebel Scholars fellowship, a Gerald J. Lieberman fellowship, the California Institute for Regenerative Medicine and the Stanford Child Health Research Institute.

Other Stanford co-authors were postdoctoral scholar Jamie Bergen, PhD; medical student Yourong Sophie Su; and life science research assistant Helen Rayburn.

Glen Martin is a freelance writer in Santa Rosa, Calif., for the School of Engineering’s communications office.

Courtesy of the Stanford News Service

For more information: http://paloalto.patch.com/groups/around-town/p/stanford-scientists-illuminate-brain-tumors-in-mice

Five Former Phillies Battle Brain Cancer Since 1973

Ex-Phillies wonder if stadium is to blame for players’ brain cancer

Randy Miller, USA TODAY Sports4:17 p.m. EDT July 22, 2013
Larry Bowa can’t help but wonder.

He gets sick to his stomach thinking about Darren Daulton, yet another former Phillies player battling brain cancer.

Pitcher Ken Brett died in 2003. Tug McGraw, a star reliever and 1980 World Series hero, and catcher Johnny Oates lost their battles in 2004. Third baseman and longtime coach John Vukovich died in 2007.

Now Daulton, star catcher on the Phillies’ beloved 1993 World Series team, is in a fight for his life at age 51. He was diagnosed this month with glioblastoma, the most aggressive form of brain cancer.

“Yeah, it’s very scary,” said Bowa, who spent 24 seasons with the Phillies as a player, coach and manager. “I know cancer is a big illness in our society, but to have that many (Phillies) guys get brain cancer …”

A lot of people, former Phillies included, want to know if the illnesses are just bad luck or if there is some sort of connection — perhaps to Veterans Stadium, the multipurpose sports venue that was home to the franchise from 1971 to 2003 and demolished in 2004.

“Once it happened to Tug, we were all in shock,” said Dickie Noles, a pitcher on the Phillies’ 1980 World Series team. “Then once it happened to Vuk (Vukovich), the other ballplayers kind of had the feeling like, ‘Wow.’ Then when it happened to Daulton, every ballplayer I’ve seen talked about it.

“There seems to be some correlation with this and baseball. What was the Vet built on? Was it something in the building? The asbestos?”

Bowa said the same questions came up during recent conversations he had with former Phillies Dave Hollins, Greg Luzinski and Marty Bystrom.

“I know there were a lot of pipes that were exposed when we played there and we had AstroTurf,” recalled Bowa, now an in-studio analyst for the MLB Network.

“I’m not trying to blame anybody. It’s just sort of strange that that can happen to one team playing at the Vet.”

Five Phillies victims in such a short span is apparently a lot. National studies have indicated males have a 0.7 percent chance of being diagnosed with a malignant brain tumor, with women at 0.6 percent. Local figures seem to indicate that 3.14 percent of the Phillies’ 159 players from 1973 (Brett’s only year on the team) to 1983 (Daulton’s first season with the club) were diagnosed with brain cancer.

“It is sort of wild, but probably complete coincidence,” said Dr. Richard Osenbach, a brain surgeon in Fayetteville, N.C., who grew up in Philadelphia and is a lifelong Phillies fan.

“Jeez, Louise, I can’t imagine it would have anything to do with baseball.”

So far, there’s no proof the Phillies players’ cancer cases are anything but a string of misfortunes.

“There is not a known cause for brain tumors,” according to Deneen Hesser, chief mission officer for the American Brain Tumor Association.

Other than the five Phillies, just four other major leaguers were diagnosed with brain cancers and died over the last 15 years: Hall of Famer Gary Carter, Dan Quisenberry, Bobby Murcer and Dick Howser. All of them played games at the Vet, but so did hundreds of others who have never had issues.

The Eagles also played home games at the Vet for decades and it’s believed they never had a brain cancer victim.

“Can I say definitively that it’s a fluke? No,” said Jill Barnholtz-Sloan, a Cleveland-based brain-tumor epidemiologist who does research at Case Western Reserve University.

“They all played for the Phillies, but not in the same year. One played for a year, one for 10 years. So it’s really difficult to say, ‘Oh, it’s because they played for the Phillies that this has happened.’

“Unfortunately, I think what you may end up with is just a very bizarre circumstance.”

From 1989 to 1999, Amoco, an American oil giant that later merged with British Petroleum to form BP, spent millions of dollars on a investigation after a cluster of employees at an Illinois plant were diagnosed with brain tumors and several of them died.

The Amoco Research Center building was demolished and the victims’ families won a financial settlement from the company.

But the investigation proved nothing.

“I can tell you that I know of multiple other clusters of people living in the same area who have been diagnosed with the same cancer that have been studied,” Barnholtz-Sloan said. “They’ve been investigated by state health and local health departments and, in most, they’ve not been able to find anything.

“As a brain tumor epidemiologist — and there aren’t very many of us worldwide — one of the most difficult things to prove is causation. There are so many things going on. You have to account for the way an individual lived, things that they ate, whether they smoke or drank, whether or not they had a family history of cancer, how old they were.”

The Phillies’ brain cancer cluster has not yet yielded a case study, which would be headed by the Pennsylvania Department of Health.

“I know the department of health is aware of the situation and is not currently conducting an investigation,” Kait Gillis, the organization’s deputy press secretary, wrote in an email. “I will let you know if that changes.”

Bowa wishes somebody would do something.

“I think for guys that are still alive, it would ease some of their questions.”

If Barnholtz-Sloan were to lead an investigation, the first thing she’d do is take a detailed look into each Phillies’ case and compare them to national figures.

“The reason cancer is called a complex disease is because it’s a combination of lots of different things happening all at the same time that cause a normal cell to convert to a cancer cell,” she explained.

Meantime, Daulton is fighting his battle against long odds. According to the American Brain Tumor Association, median survival for patients with glioblastoma is 12 to 14 months and the two-year survival rate is just 30 percent.

“It is a challenging disease, a very aggressive type of tumor, but more and more we’re learning that there are some biologic differences in these tumors,” Hesser noted. “There are long-term survivors.”

Noles and former Phillies player Glenn Wilson, both born-again Christians, are praying for their former teammate.

“I’m still kind of numb,” said Wilson, a Phillies outfielder from 1984 to 1987 who now lives in Houston. “First and foremost, God has his reasons and his ways are not our ways. I want to rejoice the lives of the ones who have passed and pray for those that are struggling with that disease.”

Noles, now working for the Phillies as an employee assistance professional, admits losing baseball friends makes him think of his mortality.

“Ain’t this crazy?” he asked. “Vukovich was one of the biggest mentors in my life and I loved Vuk dearly. Tug, I don’t think I’ve met a better person in my life. And Dutch, he’s just a great human being.

“Life is difficult and there’s bumps in the road all over the place. Cancer happens to be one of the major ones. When you hear about it, it hits home.

“I think we should be doing what we can when we’re healthy to live our life.”

Bowa is among the few with connections to all five of the cancer-stricken Phillies. He coached Daulton and was a teammate to the others.

He wants answers that aren’t there.

“It’s hard to believe that there’s no documentation. It’s very ironic that four or five of our guys have gotten brain cancer.

“It seems very, very rare.”

http://www.usatoday.com/story/sports/mlb/phillies/2013/07/22/darren-daulton-brain-cancer-philadelphia-phillies-tug-mcgraw/2574139/

Watch Dr. Sam Gambhir of Stanford University

Dr. Sam Gambhir of Stanford University says the support of the Ben and Catherine Ivy Foundation allows for multi-center trials to research Glioblastoma brain tumors.

A Promising New Cancer Drug

Promising New Cancer Drugs Empower the Body’s Own Defense System

“If you look five years out, most of this meeting will be about immunotherapy,” said Dr. Mario Sznol.
SCOTT MORGAN / ASCO
By ANDREW POLLACK
June 3, 2013

CHICAGO — The early success of a new class of cancer drugs, revealed in test results released here over the last several days, has raised hope among the world’s top cancer specialists that they may be on the verge of an important milestone in the fight against the disease.

The excitement has spread to Wall Street. Shares of Merck and Bristol-Myers Squibb, which are developing such drugs, rose more than 3 percent on Monday after data from their studies was presented over the weekend at the meeting of the American Society of Clinical Oncology.

The drugs, still generally in early testing, work in an entirely new way, by unleashing the immune system to attack cancer cells much as it attacks bacteria. That could be an alternative to often-debilitating chemotherapy.

Finding ways to use the body’s own defenses has been a goal since the late 1800s, when a New York surgeon named William B. Coley noticed that cancer disappeared in a patient who had a severe bacterial infection.

He then began injecting bacteria into cancer patients to rev up their immune systems. His claims of success were disputed and most attempts since then to harness the immune system have not worked.

The new drugs work by disabling a brake on the immune system called the programmed death 1 receptor, or PD-1. And although the data presented at the meeting was from the earliest stage of testing only, the drugs were the center of attention here, with some doctors predicting that cancer treatment was about to shift.

“If you look five years out, most of this meeting will be about immunotherapy,” said Dr. Mario Sznol, a professor of medical oncology at Yale.

Analysts, who predict billions of dollars in sales, are trying to determine which of the three front-runners — Merck, Bristol-Myers and Roche — have the best drug and how soon the drugs could reach the market. Some think it could be as early as a year and a half from now.

“I think all of you recognize this is a very special moment in oncology,” Dr. Roger M. Perlmutter, head of research and development at Merck, told analysts Sunday at a standing-room-only meeting.

Harnessing the immune system is appealing for several reasons. It might be applicable to many different types of cancer. It might produce longer lasting remissions than can be achieved by chemotherapy or the newer targeted drugs. And it seems somehow more natural and holistic.

“It seems the right thing to do to stimulate our body’s defense rather than take some kind of poison,” said Therese Bocklage, a cancer patient and pathologist from Albuquerque.

Dr. Bocklage thought she had bruised her leg moving a Christmas tree in late 2011. It turned out to be the return of the melanoma she thought had been successfully eradicated by surgery 20 years earlier.

She has been taking Merck’s experimental PD-1 inhibitor, lambrolizumab, as part of a clinical trial since January 2012, and her tumors have disappeared. “If I had had this turn up not last year but six years ago, most likely I’d be dead,” she said.

But there are reasons to be cautious. This is cancer, after all. Many other hoped-for miracles have failed to materialize. This is a conference that has hailed drugs that extend lives by only a few weeks as breakthroughs.

“We’re so used to failure, we get excited very easily,” said Dr. Kim Margolin, an expert on melanoma and immune therapies at the Seattle Cancer Care Alliance.

Most of what is known about the PD-1 drugs is that they shrink tumors significantly in 15 to 50 percent of patients. It is still not clearly established, though there are some hints, that the drugs will let people live longer.

And results seen in trials, under idealized conditions, do not translate perfectly to the real world. One poster presented here looked at use in Britain of Yervoy, a melanoma drug approved in 2011 that disables a different immune system brake. Median survival has been only about half of what was seen in clinical trials.

Moreover, just because the immune system is involved does not make something safe. Ask anyone with lupus, multiple sclerosis or other diseases caused by an aberrant immune system.

Yervoy, made by Bristol-Myers, has some serious side effects caused by overstimulation of the immune system. The newer PD-1 drugs seem remarkably well tolerated so far, though lung inflammation is seen in some patients.

For the last decade or so, the emphasis in oncology has been so-called targeted therapy, in which drugs counteract particular genetic mutations that drive tumor growth. These were supposed to displace conventional chemotherapy, which tends to poison fast-growing cells, both cancerous and healthy ones, causing serious side effects.

Targeted therapy has had some great successes, particularly the leukemia drug Gleevec. But cancer cells, which tend to mutate rapidly, can develop resistance to the targeted therapies. And it is becoming more difficult to develop drugs for each narrow population of patients with a particular tumor mutation.

The PD-1 drugs are in a sense a return to a one-size-fits-all approach. And it might be harder for the tumor to become resistant to the immune system, which can adapt, than to a single drug.

In fact, what most excited researchers here this weekend was “the tail.” When researchers plot on a graph how many patients remain alive over time, the curves tend to drop to near zero for metastatic cancer. A successful drug slows the rate of decline, but eventually almost all patients die from the cancer.

But with Yervoy and, experts hope, with the PD-1 drugs, there appears to be fraction of patients who do not die of the disease, at least for a long time. The curve levels out in a plateau.

Dr. Sznol said that of five patients treated at Yale with the Bristol-Myers PD-1 blocker, nivolumab, two had no evidence of recurrence even two years after stopping the drug.

Over all, 133 melanoma patients at various clinics took nivolumab in the Phase 1 trial. Median survival was 16.8 months, with 62 percent of patients alive at one year and 43 percent alive after two years. There was no comparison group in the study, but with the existing melanoma drugs, about 24 to 33 percent of patients are alive after two years, Dr. Sznol said.

So if the immune system is so effective, why doesn’t it cure cancer on its own? One reason is that cancerous cells are the body’s own cells, though mutated, and might not be recognized by the immune system as foreign. Another is that the tumors act to suppress the immune system.

Much of the previous attempts at cancer immunotherapy have focused on the first problem — trying to train the immune system to recognize the tumor and attack it.

The PD-1 drugs tackle the second problem of immune system suppression. How many cancers this will work for is still unclear. Much of the early work has been in melanoma, which is known to be more susceptible than many other tumors to immune system attack. There are cases, though rare, in which the immune system vanquishes melanoma on its own.

What is encouraging doctors is that the drugs can shrink some lung cancer tumors, which have not been considered particularly susceptible to immune attack. There are sporadic reports of cases with other cancers as well, like colorectal cancer.

http://mobile.nytimes.com/2013/06/04/health/promising-new-cancer-drugs-empower-the-bodys-own-defense-system.html