Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule

Researchers at the Karolinska Institute in Sweden have introduced what could possibly be a revolution in article in Cell, researchers found that molecules known as vacquinols "reliably and selectively compromised" neoplastic cell viability. Vacquinols stimulates cell death by membrane ruffling, vacuolization, and -- ultimately -- cytoplasmic membrane rupture. Although in vivo testing has been restricted to mice thus far, this paper may prove to be the beginning of a new avenue of research into the selective killing glioblastoma cells in patients.
glioblasoma treatment. In a recent

Best Post of November 2013: Nanotechnology joins with cancer genomics in silencing glioblastoma oncogene

The next in our "Best of the Month" series is from November 1, 1013:

Gold nanoparticles (yellow) with small interfering RNAs (green) knock down an oncogene in glioblastoma.

In a study of mice released this week in Science Nanomedicine, researchers were able to reduce glioblastoma size three- to four-fold by switching off the oncogene Bcl2Like12 by means of nanotechnology-assisted delivery of small interfering RNAs. Normal (linear) nucleic acids cannot get into cells, but these spherical nucleic acids can. Small interfering RNA (siRNA) surrounds a gold nanoparticle like a shell; the nucleic acids are highly oriented, densely packed and form a tiny sphere. (The gold nanoparticle core is only 13 nanometers in diameter.) The RNA’s sequence is programmed to silence the disease-causing gene.

“This is a beautiful marriage of a new technology with the genes of a terrible disease,” said Chad A. Mirkin, a nanomedicine expert and a senior co-author of the study. “Using highly adaptable spherical nucleic acids, we specifically targeted a gene associated with GBM and turned it off in vivo. This proof-of-concept further establishes a broad platform for treating a wide range of diseases, from lung and colon cancers to rheumatoid arthritis and psoriasis.”

Dr. Alexander H. Stegh discovered the Bcl2Like12 oncogene in 2007.  "The beauty of the gene we silenced in this study is that it plays many different roles in therapy resistance,." says Stegh. "Taking the gene out of the picture should allow conventional therapies to be more effective.”

Again, thanks to loyal reader and friend, Dr. Doug Shevlin (pictured above on far left with alt country singer Eef Barzelay on far right), for alerting me to this new development in the field of nanotechnogenomics.

Best Post of September 2013

The next in our "Best of the Month" series is from September 16, 2013

Two UC Davis Neurosurgeons Resign After Intentionally Infecting Intracranial Glioblastomas with Bowel Bacteria

The Sacramento Bee recently reported that two UC Davis neurosurgeons who intentionally infected three glioblastoma patients with bowel bacteria have resigned their posts after the university found they had "deliberately circumvented" internal policies, "defied directives" from top leaders and sidestepped federal regulations, according to newly released university documents.

Neurosurgeon J. Paul Muizelaar, MD

Dr. J. Paul Muizelaar, 66, the former head of the neurosurgery department, and his colleague, Dr. Rudolph J. Schrot, violated the university's faculty code of conduct. All three patients consented to the procedures in 2010 and 2011. Two of the patients died within weeks of their surgeries, while the other survived more than a year after being infected.

Read more here: http://www.sacbee.com/2013/08/25/5678851/uc-davis-surgeons-resign-after.html#storylink=cpy

Muizelaar and Schrot called their novel approach "probiotic intracranial therapy," or the introduction of live bowel bacteria, Enterobacter aerogenes, directly into their patients' brains or bone flaps. The doctors theorized that an infection might stimulate the patients' immune systems and prolong their lives. The first patient lived about 5 1/2 weeks. The second survived another year, an outcome that buoyed the doctors and seemed to bolster their theory, they said. The institutional trouble began in March 2011, when a newly diagnosed third patient developed sepsis, became unresponsive and died two weeks after being deliberately infected. The university's first internal investigation soon followed.

Muizelaar and Schrot did not complete a study on rats before they began treating the three human patients, despite an FDA directive in 2008 that "animal studies will be necessary prior to entering into the clinic with your proposed therapy," according to an email to Schrot from an FDA official. When asked by a compliance investigator why animal trials were not done first, Schrot allegedly responded that such testing would take "10 years … his entire career," one internal review states. The investigator found Schrot's "eagerness to proceed" to be concerning and his actions "reckless."


Muizelaar, one of the highest paid employees in the University of California system, stepped down effective June 27. He earned more than $907,000 last year, the 33rd-highest gross pay in the UC system.  Schrot, 45, an associate professor who made about $512,000 last year, will leave his post at the end of August. Both doctors have sharply criticized the findings, characterizing the internal investigations as biased and incomplete. The surgeons maintain they were acting in the best interests of their desperately ill patients, whose prognoses for survival were poor. Both doctors opted not to appeal the university's findings because they determined it would be fruitless."I lost confidence, if you will, in the ability of the university administration to fairly handle it," Schrot said Friday in the office of his Sacramento attorney.

Read more here: http://www.sacbee.com/2013/08/25/5678851/uc-davis-surgeons-resign-after.html#storylink=cpy

One colleague, Dr. David Asmuth, an infectious disease specialist who co-chaired an oversight committee for university research, called the surgeons' procedure "the worst case of human subjects research he had ever seen."

Read more here: http://www.sacbee.com/2013/08/25/5678851/uc-davis-surgeons-resign-after.html#storylink=cpy

"I was simply thinking that I could help patients," Muizelaar said. "My whole medical practice is guided by actually only one principle, namely: What would I do for my mother, my son, myself?"

Nanotechnology joins with cancer genomics in silencing glioblastoma oncogene

Gold nanoparticles (yellow) with small interfering RNAs (green) knock down an oncogene in glioblastoma.

In a study of mice released this week in Science Nanomedicine, researchers were able to reduce glioblastoma size three- to four-fold by switching off the oncogene Bcl2Like12 by means of nanotechnology-assisted delivery of small interfering RNAs. Normal (linear) nucleic acids cannot get into cells, but these spherical nucleic acids can. Small interfering RNA (siRNA) surrounds a gold nanoparticle like a shell; the nucleic acids are highly oriented, densely packed and form a tiny sphere. (The gold nanoparticle core is only 13 nanometers in diameter.) The RNA’s sequence is programmed to silence the disease-causing gene.

“This is a beautiful marriage of a new technology with the genes of a terrible disease,” said Chad A. Mirkin, a nanomedicine expert and a senior co-author of the study. “Using highly adaptable spherical nucleic acids, we specifically targeted a gene associated with GBM and turned it off in vivo. This proof-of-concept further establishes a broad platform for treating a wide range of diseases, from lung and colon cancers to rheumatoid arthritis and psoriasis.”

Dr. Alexander H. Stegh discovered the Bcl2Like12 oncogene in 2007.  "The beauty of the gene we silenced in this study is that it plays many different roles in therapy resistance,." says Stegh. "Taking the gene out of the picture should allow conventional therapies to be more effective.”

Again, thanks to loyal reader and friend, Dr. Doug Shevlin (pictured below on far left with alt country singer Eef Barzelay on far right), for alerting me to this new development in the field of nanotechnogenomics.

L to R: Dr. Doug Shevlin, John Jordan, and alt country legend Eef Barzelay

Gamma Knife and Cyber Knife: What's the difference?

This is a guest post by Amanda who writes on behalf of the San Diego Gamma Knife Center, a shared resource for the San Diego neurosurgical and radiation oncology community.

Gamma Knife surgery has become one of the most popular and extensively tested types of what is known as “stereotactic radiosurgery”, or SRS. SRS (as depicted in the accompanying illustration) is a non-invasive medical procedure that uses highly focused radiation beams as a treatment for brain tumors and other kinds of intracranial maladies. Gamma Knife surgery has been used for treating trigeminal neuralgia, and the treatment of both benign and malignant brain tumors. But the Gamma Knife is not the only SRS system available. In recent years, the popularity and acceptance of radiosurgery procedures has led to the development of newer SRS systems. The most well known among these newer systems is the Cyber Knife. Both the Gamma Knife and the Cyber Knife can be highly effective in treating many of the same maladies, but they operate on patients in fundamentally different ways. Here is a brief comparison of the two SRS systems.

 

How They Work

During Gamma Knife surgery, patients undergo a CT scan and sometimes also an MRI scan prior to the actual procedure. These scans are used by a team of specialists to plan out the radiosurgery in minute detail. Once the planning is finished, the patient is brought over to the Gamma Knife table and his/her head is fixed onto a rigid head frame that automatically positions the target area of the brain in the spot where the radiation beams will intersect. The Gamma Knife system then delivers approximately 201 highly focused cobalt-60 source radiation beams into a single target area of the brain. The beams are delivered all at once, multiple times and in short bursts. The procedure can last as little as 30 minutes and usually a single session is all that’s needed to complete the treatment.
Unlike the Gamma Knife system, which is designed exclusively for use in non-invasive brain surgery, the Cyber Knife system is designed to conduct SRS on lesions anywhere in the body, including organs that move with the patient’s respiration. It can do so because, unlike the Gamma Knife, it does not deliver the radiation beams to the target area simultaneously. Rather, it uses a single, high-energy photon beam that’s attached to a robot arm. The arm moves to different positions during the surgery, aiming at the target area from different angles. A head frame is not necessary either. Instead, patients are secured to the treatment table with a plastic mask that helps the Cyber Knife update the position of the skull in real time, allowing the robot arm to compensate for patient movement. More than one treatment session is sometimes required.

 

Accuracy and Efficiency

Both systems can be highly effective in the treatment of brain tumors and other intracranial maladies, but the Gamma Knife has a slight advantage when it comes to accuracy (0.5mm or less, as compared with the Cyber Knife, which can have an accuracy of almost 1mm). Also, the smaller size of Gamma Knife collimators makes it less likely that healthy brain tissue surrounding the target area will be damaged during surgery. The advantage of the Cyber Knife, however, is that its guided robot arm allows it greater versatility to treat other areas of the body and certain regions of the brain that are more difficult to treat using the head-frame method of the Gamma Knife.

Alzheimer patients to get nerve growth factor directly injected into brain

The Alzheimer’s Disease Cooperative Study, a 19 year project funded by the NIA, has embarked on a clinical trial that delivers Nerve Growth Factor (NGF) directly into the brain as a possible treatment for Alzheimer’s.

 

A Phase II clinical study of Ceregene's CERE-110, a gene therapy product designed to deliver nerve growth factor (NGF) to the brain for the treatment of Alzheimer's disease (AD) is currently in progress.

This Phase II study is a randomized, double blind, placebo-controlled trial and employs gene therapy to deliver nerve growth factor (NGF) directly into the brain. The rationale behind this study is that NGF is known to promote survival of cholinergic neurons, that degenerate in AD, and therefore may provide sustained functioning of these neurons. Direct delivery of CERE-110 into the brain aims to selectively target the Nucleus Basalis of Meynert (NBM), where cholinergic neuronal degeneration occurs in AD.

A Phase I study at Rush University and the University of California San Diego indicated that a single administration of the therapy was generally safe and well tolerated. The Phase I participants underwent cognitive testing, measures of activities of daily living, MRI scans and PET (positron emission tomography) scans. Increases in brain metabolism were observed in several cortical regions of the brain at six months and 12 months in some of the subjects, as compared to other severity-matched individuals with AD, suggesting a potential reversal of patterns typically observed in AD.

This Phase II study will examine the safety and effectiveness of NGF on Alzheimer's disease in 50 patients at 11 research sites throughout the United States. All eligible participants will be randomized equally to one of two treatment groups: half of the subjects will initially receive placebo surgery, but no administration of gene therapy. In the other half, CERE-110 will be injected into the NBM of the brain. At the completion of the trial, subjects in the placebo arm will be given the opportunity to switch to the active treatment protocol if the efficacy and safety data are supportive.

For more information go to: http://www.adcs.org/Studies/NGF.aspx  or  http://www.alzheimers.org/clinicaltrials/fullrec.asp?PrimaryKey=308

Research team succeeds in intranasal delivery of stem cells to brain

"[I]t is possible without surgery to deliver stem cells to the brain," says Dr. William H. Frey (pictured) of the University of Minnesota in the August 3rd issue of Neurology Today. According to the article, a team including Frey have shown that stem cells delivered intranasally in the rat can bypass the blood-brain barrier and make their way into the brain. This kind of delivery mechanism brings us one step closer to stem cell therapy for the central nervous system. The stem cells used in the study are of two types: bone marrow derived, and human glioma cells. Both types of stem cells were shown to reach the brain within an hour. "This could revolutionize regenerative medicine," said Frey. The original report appears in the European Journal of Cell Biology (Danielyan L, Shafer R, Frey WH, et al. Intranasal delivery of cells to the brain. Eur J Cell Biol 2009;88(6)315-324. E-pub 2009 Mar 25).

Fetal stem cells pass safety test for use in combatting Batten disease

Thanks to Dr. Doug Shevlin for alerting me to a report about this study which clears the way for further investigation of the use of fetal stem cells in the treatment of Batten disease. As yet, no specific treatment is known that can halt or reverse the symptoms of Batten disease.

High-Dose Bapineuzumab Puts Some Alzheimer Patients At Risk for Vasogenic Cerebral Edema

Dr. Stephen Salloway (pictured) reported at the recent American Academy of Neurology annual meeting on the much ballyhooed bapineuzumab study for Alzheimer patients. I take a particular interest in this topic: my own 89-year-old father was a subject in the study, but was removed from it due to the development of some kind of MRI changes. Salloway, Brown University neurologists and one of the study's lead investigators, reported that patients on the 2.0 mg/kg dose of bapineuzumab (the highest dose level in the study) had a significantly increased risk of developing vasogenic cerebral edema. Because it is a double-blinded study, I do not know what dose my dad was on (or if he was given a placebo). Bapineuzumab is an anti-beta-amyloid monoclonal antibody. It is thought that the antibody may have compromised cerebral blood vessel walls by attaching to mural amyloid, which tends to accumulate in Alzheimer patients. Investigators decided that "continued development of the highest dose was not advisable," said Carlos Paya, MD, PhD, president of the biotech firm Elan, which is working with Wyeth Pharmaceuticals to develop the antibody for clinical use. That being said, the antibody continues to show promise in slowing cognitive decline among patient who do not harbor a apolipoprotein E4 allele and will continue to accrue patients for the phase 3 study at lower doses.

Source: Neurology Today (May 21, 2009), page 4.

Surgical Science Museum in Chicago Features Surgicogenomics Exhibit

Karen Everingham -- formerly of the Illinois Association of Museums and now of the Historic Sites Division of the Illinois Historic Preservation Agency -- has provided me with yet another interesting link to a medical museum. The International Museum of Surgical Science, located in Chicago, is dedicated to the enhancing the understanding of the history, development, and advances of surgery and related subjects in health and medicine. Currently, there is a interesting new exhibit there titled Surgicogenomics: Genes and Stem Cells in Surgery, which addresses the use of stem cells in cutting-edge surgical procedures that have the potential to treat such conditions as Parkinson's disease and Duschenne Muscular Dystrophy. One of the scientific advisors of the exhibit is the respected pathologist Arno A. Roscher, MD of California (pictured). Thanks again to Karen Everingham for letting me know about this fascinating museum!

Tarenflurbil, a gamma-secretase modulator, does not seem to work in Alzheimer’s disease

Long-awaited results of a Phase III trial of tarenflurbil (Flurizan) have failed to achieve statistical significance on either of its two primary endpoints (cognition and activities of daily living). The company developing the drug, Myriad Genetics, is abandoning development of the compound for Alzheimer's disease.

Tarenflurbil had been shown in nonclinical studies to modulate gamma-secretase activity. The drug was in trials in people with mild Alzheimer's to determine if its ability to lower the amount of toxic beta-amyloid would slow or stop the course of the disease.

This was the largest and longest placebo-controlled Alzheimer disease treatment trial ever completed. The results were reported today at the Alzheimer's Association International Conference on Alzheimer's Disease being held in Chicago. Read more about the results of the study here.

Curcumin, the yellow pigment in curry spice, may protect against Alzheimer's disease

The illustrious Dr. Amita Singh (Southern Illinois University Department of Neurology) alerted me to this article suggesting that a staple of the Indian diet may be the reason why Indians aged 70 to 79 are 4.4 times less likely to get Alzheimer's disease than are their American counterparts:

Big Alzheimer Conference this month in Chicago

The Alzheimer’s Association International Conference on Alzheimer's Disease 2008 is coming up in Chicago on July 26-31. Among the more eagerly anticipated reports that will come out of the meeting will be preliminary results of the so-called GEM Study, which is looking at the putative protective effects that gingko biloba has against dementia. Also on the docket are preliminary results of a Phase III trial of gamma-secretase modulators (such as tarenflurbil) in the treatment of Alzheimer’s disease. I’ll let you know about any interesting developments coming out of this meeting.

Abstract from journal Cell on stem cells

This is off topic, but there's big news today regarding the
creation of pluripotent cells from human skin fibroblasts.
Here's the abstract from the Yamanaka study in Cell:
"Successful reprogramming of differentiated human
somatic cells into a pluripotent state would
allow creation of patient- and disease-specific
stem cells. We previously reported generation
of induced pluripotent stem (iPS) cells, capable
of germline transmission, from mouse somatic
cells by transduction of four defined transcription
factors. Here, we demonstrate the
generation of iPS cells from adult human dermal
fibroblasts with the same four factors: Oct3/4,
Sox2, Klf4, and c-Myc. Human iPS cells were
similar to human embryonic stem (ES) cells in
morphology, proliferation, surface antigens,
gene expression, epigenetic status of pluripotent
cell-specific genes, and telomerase activity.
Furthermore, these cells could differentiate
into cell types of the three germ layers in vitro
and in teratomas. These findings demonstrate
that iPS cells can be generated from adult
human fibroblasts."

Emerging drugs for the treatment of glioblastoma

Bevacizumab (Avastin) is an angiogenesis inhibitor that is being used in the treatment of glioblastoma multiforme (GBM). AQ4N (Banoxantrone) is a prodrug that becomes active in hypoxic regions (i.e., tumor) that is also being examined as a useful chemotherapeutic agent for GBM.