Breaking News
February 22, 2019 - The United States records highest drug overdose death rates
February 22, 2019 - Phase 1 data reinforce safety profile of new drug for treating Duchenne muscular dystrophy
February 22, 2019 - Vitamin D supplementation less effective in the presence of obesity, shows study
February 22, 2019 - Sarepta Announces FDA Acceptance of Golodirsen (SRP-4053) New Drug Application for Patients with Duchenne Muscular Dystrophy Amenable to Skipping Exon 53
February 22, 2019 - An institutional effort to reduce the amount of opioids prescribed following lumbar surgery
February 22, 2019 - Failure to take statins leads to higher mortality rates | News Center
February 22, 2019 - Novel preclinical model mimics persistent interneuron loss seen in preterm infants
February 22, 2019 - Global health burden of glaucoma has increased, study reveals
February 22, 2019 - A holistic approach key to minimize treatment complexity in patients with interstitial lung disease
February 22, 2019 - 1 in 10 middle-aged Chinese adults are at high risk for heart disease, finds study
February 22, 2019 - More than half a million breast cancer patient’s lives saved by improvements in treatment
February 22, 2019 - Study finds no evidence that tougher policies prevent teenage cannabis use
February 22, 2019 - New blood test detects genetic disorders in fetuses
February 22, 2019 - Lower Self-Perception Observed in Children With Amblyopia
February 22, 2019 - Up to 15 percent of children have sleep apnea, yet 90 percent go undiagnosed
February 22, 2019 - Rare pulmonary defect prompts parents’ nationwide search for answers | News Center
February 22, 2019 - Lesbian and bisexual women at greater risk of being overweight, study finds
February 22, 2019 - UQ research may explain why vitamin D is essential for brain health
February 22, 2019 - Heart Attacks Rising Among Younger Women
February 22, 2019 - How your smartphone is affecting your relationship
February 22, 2019 - Orthopaedic surgeon receives prestigious award, $10 million grant | News Center
February 22, 2019 - New sepsis test could save thousands of lives
February 22, 2019 - Cervical cancer could be eradicated by 2100
February 21, 2019 - Sustained smoking cessation can lower risk of seropositive RA
February 21, 2019 - Thousands with chronic UTIs are not receiving the treatment they need
February 21, 2019 - Are teens getting high on social media? The surprising study seeking the pot-Instagram link
February 21, 2019 - Stanford expands biobank services | News Center
February 21, 2019 - Scientists identify link between drinking contexts and early onset intoxication among adolescents
February 21, 2019 - Strong social support may reduce cardiovascular disease risk in postmenopausal women
February 21, 2019 - Rapid expansion of interventions could prevent up to 13 million cases of cervical cancer within 50 years
February 21, 2019 - Motif Bio Receives Complete Response Letter From The FDA
February 21, 2019 - Researchers map previously unknown disease in children
February 21, 2019 - A skeptical look at popular diets: Going gluten-free
February 21, 2019 - Podcast: KHN’s ‘What The Health?’ How Safe Are Your Supplements?
February 21, 2019 - Factors associated with increased risk of developing surgical site infections
February 21, 2019 - Anticipatory signals in eye movements can help measure attentive capacity, learning with greater precision
February 21, 2019 - Study explores daily exposure to indoor air pollutants
February 21, 2019 - Evening exercise does not negatively affect sleep, may also reduce hunger
February 21, 2019 - Artificial intelligence technique can be used to identify alcohol misuse in trauma setting
February 21, 2019 - Overweight, obesity in adolescence associated with increased risk of renal cancer later in life
February 21, 2019 - BGU develops new AI platform for monitoring and predicting ALS progression
February 21, 2019 - Researchers discover a new promising target to improve HIV vaccines
February 21, 2019 - Brief Anesthesia in Infancy Does Not Mar Neurodevelopment
February 21, 2019 - Gaming system helps with autism diagnosis
February 21, 2019 - Heart Disease: Six Things Women Should Know
February 21, 2019 - More States Say Doctors Must Offer Overdose Reversal Drug Along With Opioids
February 21, 2019 - Researchers explore case studies focused on industries that kill more people than employed
February 21, 2019 - Only half of GP practice buildings are fit for purpose
February 21, 2019 - Intense exercise, fasting and hormones can enhance waste-protein removal, study shows
February 21, 2019 - Scientists can monitor brain activity to predict epileptic seizures few minutes in advance
February 21, 2019 - Study quantifies hepatic and intestinal mRNA expression of Ugt isoforms in rats
February 21, 2019 - ‘Apple-Shaped’ Body? ‘Pear-Shaped’? Your Genes May Tell
February 21, 2019 - Can we repair the brain? The promise of stem cell technologies for treating Parkinson’s disease
February 21, 2019 - Trump Plan To Beat HIV Hits Rough Road In Rural America
February 21, 2019 - PENTAX Medical introduces new electrosurgical and argon plasma coagulation platforms
February 21, 2019 - Trump plan to beat HIV hits rough road in rural America
February 21, 2019 - Eating blueberries every day could help decrease blood pressure
February 21, 2019 - ‘No Second Chances’ report calls for new measures to combat cardiovascular disease in Australia
February 21, 2019 - Mayo clinic researchers discuss local case studies of leprosy
February 21, 2019 - Scientists demonstrate key role of salt in allergic immune reactions
February 21, 2019 - Experts propose revising the criteria for diagnosis of Parkinson’s disease
February 21, 2019 - The med student and the machine
February 21, 2019 - Hey, Hey! Ho, Ho! Is Striking For School Nurses The Way To Go?
February 21, 2019 - Latest research encourages children to move out and learn through physical activity
February 21, 2019 - Proper oral hygiene and regular visits to dentist can promote heart health
February 21, 2019 - New, versatile technique for remote control of transplanted cells in Parkinson’s
February 21, 2019 - Why melanoma tumors in the brain may be worse?
February 21, 2019 - New project aims to improve lung disease care in Appalachia
February 21, 2019 - Drug increases melanin production in some people with albinism
February 21, 2019 - Over 1 in 3 adults miss the mark on protein, finds study
February 21, 2019 - CymaBay Therapeutics Announces Seladelpar Granted Breakthrough Therapy Designation by the FDA for the Treatment of Primary Biliary Cholangitis
February 21, 2019 - A correlation between obesity and income has only developed in the past 30 years
February 21, 2019 - Baby, then work: An effort to help resident-parents in emergency medicine
February 21, 2019 - Heavy cigarette smoking could damage vision, say researchers
February 21, 2019 - Some drug combinations may be more effective than others for schizophrenic patients
February 21, 2019 - Combination of common antibiotics can eliminate multi-drug resistant E. coli
February 21, 2019 - Number of calls to U.S. Poison Control regarding kratom exposure increased
February 21, 2019 - New computational tool searches for factors that cause specific diseases
February 21, 2019 - New method to assess effectiveness of psychotherapies for social anxiety disorder
February 21, 2019 - New technology measures hormones that influence reproductive health efficiently
Study finds mutation driving deadlier brain tumors and potential therapy to stop it

Study finds mutation driving deadlier brain tumors and potential therapy to stop it

image_pdfDownload PDFimage_print

A poorly understood mutation in the brain cancer glioblastoma (GBM) is now being implicated for the first time as the driver of rare but deadlier cases of the disease, a team of researchers from the Perelman School of Medicine at the University of Pennsylvania and the Ludwig Institute for Cancer Research reported this week in Cancer Cell. While the study links the mutation to worse survival rates than what’s typically seen in GBM, it offers fresh hope for the small group of patients who harbor it: complementary preclinical work performed at Ludwig suggests targeting the mutation with an investigational drug or other targeted therapies may reduce the tumor’s size and extend lives.

Analyzing the genetic, clinical and imaging data from 260 GBM cases housed at Penn Medicine, the researchers discovered that patients with an epidermal growth factor receptor (EGFR) mutation, known as A289D/T/V, had increased tumor invasion compared to the rest of the cohort and an overall survival rate of six months. The median overall survival for GBM patients is 15 months.

EGFR is amplified in nearly 60 percent of cases, and EGFR mutations occur frequently in the disease. The most common, EGFRvIII, is found in 30 percent of patients. About six percent of patients, the researchers found, have the A289D/T/V mutation. With over 400 GBM patients, Penn has one of the largest data sets, second only to the National Institutes of Health’s Cancer Genome Atlas. Without it, researchers likely wouldn’t have been able to recognize the significance of the mutation.

“Having such a large number of cases helped paint a clearer picture about this rarer EGFR mutation, that these patients die sooner and have invasive and proliferative tumors,” said first author Zev A. Binder, MD, Ph.D., a senior research investigator in Neurosurgery. “But we also needed to drill down deeper to the cellular level to confirm and better understand what we were seeing in patients with this mutation, the so-called ‘gas pedal’ driving tumor growth, and how to potentially stop it.”

The Penn team, including lead investigator and senior author, Donald M. O’Rourke, MD, the John Templeton, Jr. MD associate professor of Neurosurgery and a member of Penn’s Abramson Cancer Center, collaborated with Frank Furnari, Ph.D. and his team at Ludwig to conduct a series of preclinical investigations to corroborate Penn’s findings.

In cell line models, researchers showed that the A289V mutation lead to EGFR activation and tumor growth, and that mice harboring the A289V mutation had significantly worse survival rates—65 percent—compared to those with wildtype (non-mutated) EGFR-expressing tumors. The study also revealed a striking increase in invasive tumors in the mice.

Next, the researchers administered a monoclonal antibody drug, mAb806, which has shown promise in phase I and II clinical trials for GBM patients, to mutated mice. The drug specifically recognizes EGFRvIII and wildtype EGFR, but it also has a high degree of specificity for the A289V mutation, hypothesized based on structural data from Laura Orellana, one of the co-authors. The therapy significantly reduced tumor growth and enhanced animal survival in mice expressing the A289V mutation, as well as mice with the EGFRvIII mutation. It only had a mild effect on the wildtype EGFR mice, the team reported.

“Glioblastoma is a heterogeneous enough of a disease that I don’t think we will find that one single target that will stop all the cancers cell from growing,” Binder said. “But showing that we can increase survival in mice by targeting this specific mutation means that we are hitting a significant number of tumor cells and blocking what is really driving their growth. That tells me that if we directly target the mutation in these patients, it may make a significant impact.”

Penn researchers will continue to focus on targeted therapeutic possibilities to treat patients with this mutation, as well as others. What’s more, because the mutation is tumor specific and extracellular, it’s an attractive target for immunotherapy approaches, the researchers said

Currently, GBM, which is diagnosed in about 22,000 Americans a year, has four U.S. Food and Drug Administration-approved therapies. But tumors often become resistant to these therapies, and in general only 50 percent of people with the cancer live longer than 15 months, underscoring the need for improved approaches to treat the disease.

Meanwhile, Ludwig researchers will continue to explore unanswered questions about the basic mechanisms underlying this invasive type of GBM to push the work further.

“This multi-institutional collaboration has allowed us to take the clinical data and combine it with basic-science aspects to present a well-rounded story of translational research into GBM,” O’Rourke said. “These results show us that mAb806 is a viable therapeutic option for tumors expressing EGFR mutations, other than EGFRvIII, that should be investigated further. And that we should not ignore these less-frequent GBM mutations, as they provide valuable insight for not only patient stratification, but also the other mutations common in this population. There is the potential for broader applicability beyond just a single target.”


Explore further:
Tarloxitinib puts tumor-seeking tail on anti-EGFR drug to precisely target lung cancer

Journal reference:
Cancer Cell

Provided by:
Perelman School of Medicine at the University of Pennsylvania

Tagged with:

About author

Related Articles