Posts tagged cancer
Articles and news from the latest research reports.
Alzheimer’s and Cancer Link Found
A team led by Houston Methodist Research Institute (HMRI) scientists has found that Alzheimer’s disease and cancer share a pathway in gene transcription, a process essential for cell reproduction and growth. They published their findings in December 2013 in the open access journal Scientific Reports by the Nature Publishing Group.
The scientists used the Lonestar and Stampede supercomputers at the Texas Advanced Computing Center (TACC) at The University of Texas at Austin to analyze and compare data from thousands of genes and to narrow the search for common cell signaling pathways of the two diseases. The Lonestar and Stampede systems are part of the Extreme Science and Engineering Discovery Environment (XSEDE), a single virtual system that scientists use to interactively share computing resources, data and expertise. The research is supported by a gift from the T.T. and W.F. Chao Foundation, and by grants from the National Institutes of Health (NIH).
Lead investigator Stephen Wong, a medical researcher and bioengineer with HMRI, said his study showed a new link between Alzheimer’s disease, the most prevalent form of neurodegenerative disease, and glioblastoma multiform (GBM), the most aggressive form of brain cancer.
"This is the first time people have found that at the molecular mechanism level there are linkages between the two diseases," Wong said.
A 2012 study in Taiwan and a 2013 study in Italy of public health data had shown an inverse association between Alzheimer’s disease, a severe degeneration of the brain’s nerve cells, and with cancer, where cells grow out of control.
"No one understands why this link is there, in a biological sense," Wong said. "And that’s the reason we did this study. I think we are among the first to study it this way."
Cancer drugs block dementia-linked brain inflammation
A class of drugs developed to treat immune-related conditions and cancer – including one currently in clinical trials for glioblastoma and other tumors – eliminates neural inflammation associated with dementia-linked diseases and brain injuries, according to UC Irvine researchers.
In their study, assistant professor of neurobiology & behavior Kim Green and colleagues discovered that the drugs, which can be delivered orally, eradicated microglia, the primary immune cells of the brain. These cells exacerbate many neural diseases, including Alzheimer’s and Parkinson’s, as well as brain injury.
“Because microglia are implicated in most brain disorders, we feel we’ve found a novel and broadly applicable therapeutic approach,” Green said. “This study presents a new way to not just modulate inflammation in the brain but eliminate it completely, making this a breakthrough option for a range of neuroinflammatory diseases.”
The researchers focused on the impact of a class of drugs called CSF1R inhibitors on microglial function. In mouse models, they learned that inhibition led to the removal of virtually all microglia from the adult central nervous system with no ill effects or deficits in behavior or cognition. Because these cells contribute to most brain diseases – and can harm or kill neurons – the ability to eradicate them is a powerful advance in the treatment of neuroinflammation-linked disorders.
Green said his group tested several selective CSF1R inhibitors that are under investigation as cancer treatments and immune system modulators. Of these compounds, they found the most effective to be a drug called PLX3397, created by Plexxikon Inc., a Berkeley, Calif.-based biotechnology company and member of the Daiichi Sankyo Group. PLX3397 is currently being evaluated in phase one and two clinical trials for multiple cancers, including glioblastoma, melanoma, breast cancer and leukemia.
Crucially, microglial elimination lasted only as long as treatment continued. Withdrawal of inhibitors produced a rapid repopulation of cells that then grew into new microglia, said Green, who’s a member of UC Irvine’s Institute for Memory Impairments and Neurological Disorders.
This means that eradication of these immune cells is fully reversible, allowing researchers to bring microglia back when desired. Green added that this work is the first to describe a new progenitor/potential stem cell in the central nervous system outside of neurogenesis, a discovery that points to novel opportunities for manipulating microglial populations during disease.
(Source: news.uci.edu)
Older People with Faster Decline In Memory and Thinking Skills May Have Lower Risk of Cancer Death
Older people who are starting to have memory and thinking problems, but do not yet have dementia may have a lower risk of dying from cancer than people who have no memory and thinking problems, according to a study published in the April 9, 2014, online issue of Neurology®, the medical journal of the American Academy of Neurology.
“Studies have shown that people with Alzheimer’s disease are less likely to develop cancer, but we don’t know the reason for that link,” said study author Julián Benito-León, MD, PhD, of University Hospital 12 of October in Madrid, Spain. “One possibility is that cancer is underdiagnosed in people with dementia, possibly because they are less likely to mention their symptoms or caregivers and doctors are focused on the problems caused by dementia. The current study helps us discount that theory.”
The study involved 2,627 people age 65 and older in Spain who did not have dementia at the start of the study. They took tests of memory and thinking skills at the start of the study and again three years later, and were followed for an average of almost 13 years. The participants were divided into three groups: those whose scores on the thinking tests were declining the fastest, those whose scores improved on the tests, and those in the middle.
During the study, 1,003 of the participants died, including 339 deaths, or 34 percent, among those with the fastest decline in thinking skills and 664 deaths, or 66 percent, among those in the other two groups. A total of 21 percent of those in the group with the fastest decline died of cancer, according to their death certificates, compared to 29 percent of those in the other two groups.
People in the fastest declining group were still 30 percent less likely to die of cancer when the results were adjusted to control for factors such as smoking, diabetes and heart disease, among others.
“We need to understand better the relationship between a disease that causes abnormal cell death and one that causes abnormal cell growth,” Benito-León said. “With the increasing number of people with both dementia and cancer, understanding this association could help us better understand and treat both diseases.”
Experimental Cancer Drug Reverses Schizophrenia in Adolescent Mice
Johns Hopkins researchers say that an experimental anticancer compound appears to have reversed behaviors associated with schizophrenia and restored some lost brain cell function in adolescent mice with a rodent version of the devastating mental illness.
The drug is one of a class of compounds known as PAK inhibitors, which have been shown in animal experiments to confer some protection from brain damage due to Fragile X syndrome, an inherited disease in humans marked by mental retardation. There also is some evidence, experts say, suggesting PAK inhibitors could be used to treat Alzheimer’s disease. And because the PAK protein itself can initiate cancer and cell growth, PAK inhibitors have also been tested for cancer.
In the new Johns Hopkins-led study, reported online March 31 in the Proceedings of the National Academy of Sciences, the researchers found that the compound, called FRAX486, appears to halt an out-of-control biological “pruning” process in the schizophrenic brain during which important neural connections are unnecessarily destroyed.
Working with mice that mimic the pathological progression of schizophrenia and related disorders, the researchers were able to partially restore disabled neurons so they could connect to other nerve cells.
The Johns Hopkins team says the findings in teenage mice are an especially promising step in efforts to develop better therapies for schizophrenia in humans, because schizophrenia symptoms typically appear in late adolescence and early adulthood.
“By using this compound to block excess pruning in adolescent mice, we also normalized the behavior deficit,” says study leader Akira Sawa, M.D., Ph.D., a professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “That we could intervene in adolescence and still make a difference in restoring brain function in these mice is intriguing.”
For the mouse experiments, Sawa and his colleagues chemically turned down the expression of a gene known as Disrupted-in-Schizophrenia 1 (DISC1), whose protein appears to regulate the fate of neurons in the cerebral cortex responsible for “higher-order” functions, like information processing.
In studies of rodent brain cells, the researchers found that a DISC1 deficit caused deterioration of vital parts of the neuron called spines, which help neurons communicate with one another.
Reduced amounts of DISC1 protein also impact the development of a protein called Kalirin-7 (KAL7), which is needed to regulate another protein called Rac1. Without enough DISC1, KAL7 can’t adequately control Rac1 production and the development of neuronal spines. Excess Rac1 apparently erases spines and leads to excess PAK in the mice.
By using FRAX486 to reduce the activity of PAK, the researchers were able to protect against the deterioration of the spines caused by too little DISC1, halting the process. This normalized the excess pruning and resulted in the restoration of missing spines. They were able to see this by peering into the brains of the mice with DISC1 mutations on the 35th and 60th day of their lives, the equivalent of adolescence and young adulthood.
Sawa, who is also director of the Johns Hopkins Schizophrenia Center, cautions that it has not yet been shown that PAK is elevated in the brains of people with schizophrenia. Thus, he says, it is important to validate these results by determining whether this haywire PAK cascade is also occurring in humans.
In the mice, the researchers also found that their behavior improved when PAK inhibitors were used. The mice were tested for their reaction to noises. There is a neuropsychiatric phenomenon in which any organism will react less to a strong, startling sound when they have first been primed by hearing a weaker one. In schizophrenia, the first noise makes no impact on the reaction to the second one.
The mice in the study showed improvements in their reactions after being treated with the PAK inhibitor. The drug was given in small doses and appeared to be safe for the animals.
“Drugs aimed at treating a disease should be able to reverse an already existing defect as well as block future damage,” Sawa says. “This compound has the potential to do both.”
(Image: iStockphoto)
A good trip: Researchers are giving psychedelics to cancer patients to help alleviate their despair — and it’s working
On a bone-chilling morning in February last year, Nick Fernandez bundled up and took the subway from his Manhattan apartment to the Bluestone Center for Clinical Research, which is located in an art deco-style building on the Upper East Side. A 27-year-old graduate student in psychology with dark, wavy hair and delicate, bird-like features, Fernandez was excited and nervous. He had eaten a light breakfast consisting of a bagel and industrial-strength coffee in preparation for another journey he was about to take. Fernandez had signed up to be a subject in a New York University study into the use of psilocybin, the psychoactive ingredient in hallucinogenic mushrooms, to relieve mental anguish in people with terminal or recurrent cancer.
Fernandez hoped that the drug would lift the shroud of melancholy and free-floating anxiety that had enveloped him ever since he was diagnosed with leukemia in 2004 during his senior year in high school. Two and a half years of almost continuous chemotherapy vanquished the disease, but left him drained and traumatised. The former soccer star dropped more than 50 lbs from an already lean frame. ‘It was pretty brutal and forces you to grow up fast,’ said Fernandez, who became intensely interested in spiritual philosophy during this period, and went on to dabble in psychedelics in college. For years afterward, every sneeze and sniffle, every day that he felt tired or out of sorts, filled him with an unshakeable dread that the cancer had returned. When he heard the study mentioned on a radio show, he immediately signed up.
Jeffrey Guss and Erin Zerbo, the two NYU psychiatrists who would quietly monitor Fernandez’s progress throughout the day, greeted him when he arrived. After they took his vital signs, Fernandez changed into sweat pants and a shirt, and settled into a converted dental exam room that had been transformed into a hippie-style sanctum: tricked out with fresh flowers and fruits, a comfy sofa littered with plush pillows, Buddhist and shamanistic totems, and a high-tech sound system. Stephen Ross, an associate professor of psychiatry at NYU and the lead investigator for the study, made a brief appearance in the trip room. He was holding a glass vial that had been retrieved earlier that morning from a massive safe located inside a high-security storage room. It contained a single white capsule, and no one could be sure if it was a placebo – a dummy pill – or a 30 milligram dose of synthesised psilocybin.
Scientists find mechanism to reset body clock
Researchers from The University of Manchester have discovered a new mechanism that governs how body clocks react to changes in the environment.
And the discovery, which is being published in Current Biology, could provide a solution for alleviating the detrimental effects of chronic shift work and jet-lag.
The team’s findings reveal that the enzyme casein kinase 1epsilon (CK1epsilon) controls how easily the body’s clockwork can be adjusted or reset by environmental cues such as light and temperature.
Internal biological timers (circadian clocks) are found in almost every species on the planet. In mammals including humans, circadian clocks are found in most cells and tissues of the body, and orchestrate daily rhythms in our physiology, including our sleep/wake patterns and metabolism.
Dr David Bechtold, who led The University of Manchester’s research team, said: “At the heart of these clocks are a complex set of molecules whose interaction provides robust and precise 24 hour timing. Importantly, our clocks are kept in synchrony with the environment by being responsive to light and dark information.”
This work, funded by the Biotechnology and Biological Sciences Research Council, was undertaken by a team from The University of Manchester in collaboration with scientists from Pfizer led by Dr Travis Wager.
The research identifies a new mechanism through which our clocks respond to these light inputs. During the study, mice lacking CK1epsilon, a component of the clock, were able to shift to a new light-dark environment (much like the experience in shift work or long-haul air travel) much faster than normal.
The research team went on to show that drugs that inhibit CK1epsilon were able to speed up shift responses of normal mice, and critically, that faster adaption to the new environment minimised metabolic disturbances caused by the time shift.
Dr Bechtold said: “We already know that modern society poses many challenges to our health and wellbeing - things that are viewed as commonplace, such as shift-work, sleep deprivation, and jet lag disrupt our body’s clocks. It is now becoming clear that clock disruption is increasing the incidence and severity of diseases including obesity and diabetes.
“We are not genetically pre-disposed to quickly adapt to shift-work or long-haul flights, and as so our bodies’ clocks are built to resist such rapid changes. Unfortunately, we must deal with these issues today, and there is very clear evidence that disruption of our body clocks has real and negative consequences for our health.”
He continues: “As this work progresses in clinical terms, we may be able to enhance the clock’s ability to deal with shift work, and importantly understand how maladaptation of the clock contributes to diseases such as diabetes and chronic inflammation.”
(Source: manchester.ac.uk)
New approach makes cancer cells explode
Researchers at Karolinska Institutet have discovered that a substance called Vacquinol-1 makes cells from glioblastoma, the most aggressive type of brain tumour, literally explode. When mice were given the substance, which can be given in tablet form, tumour growth was reversed and survival was prolonged. The findings are published in the journal Cell.
The established treatments that are available for glioblastoma include surgery, radiation and chemotherapy. But even if this treatment is given the average survival is just 15 months. It is therefore critical to find better treatments for malignant brain tumours.
Researchers at Karolinska Institutet and colleagues at Uppsala University have discovered an entirely new mechanism to kill tumour cells in glioblastoma. Researchers in an initial stage have exposed tumour cells to a wide range of molecules. If the cancer cells died, the molecule was considered of interest for further studies, which initially applied to over 200 kinds of molecules. Following extensive studies, a single molecule has been identified as being of particular interest. The researchers wanted to find out why it caused cancer cell death.
It was found that the molecule gave the cancer cells an uncontrolled vacuolization, a process in which the cell carries substances from outside the cell into its interior. This carrying process is made via the vacuoles, which can roughly be described as blisters or bags consisting of cell membranes. The process is similar to what was behind last year’s Nobel Prize in physiology or medicine, the discovery that describes how cellular vesicles move things from the interior of the cell to its surface.
Cell membranes collapsed
When cancer cells were filled with a large amount of vacuoles, the cell membranes, the outer wall of the cell, collapsed and the cell simply exploded and necrotized.
“This is an entirely new mechanism for cancer treatment. A possible medicine based on this principle would therefore attack the glioblastoma in an entirely new way. This principle may also work for other cancer diseases, we have not really explored this yet,” says Patrik Ernfors, professor of tissue biology at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.
Researchers made mice that had human glioblastoma cells transplanted ingest the substance for five days. The average survival was about 30 days for the control group that did not receive the substance. Of those who received the substance six of eight mice were still alive after 80 days. The study was then considered of such interest that the scientific journal wanted to publish the article immediately.
“We now want to try to take this discovery in basic research through preclinical development and all the way to the clinic. The goal is to get into a phase 1 trial,” says Patrik Ernfors.
Researchers identify a switch that controls growth of most aggressive brain tumor cells
Researchers at UT Southwestern Medical Center have identified a cellular switch that potentially can be turned off and on to slow down, and eventually inhibit the growth of the most commonly diagnosed and aggressive malignant brain tumor.
Findings of their investigation show that the protein RIP1 acts as a mediator of brain tumor cell survival, either protecting or destroying cells. Researchers believe that the protein, found in most glioblastomas, can be targeted to develop a drug treatment for these highly malignant brain tumors. The study was published online Aug. 22 in Cell Reports.
"Our study identifies a new mechanism involving RIP1that regulates cell division and death in glioblastomas," said senior author Dr. Amyn Habib, associate professor of neurology and neurotherapeutics at UT Southwestern, and staff neurologist at VA North Texas Health Care System. "For individuals with glioblastomas, this finding identified a target for the development of a drug treatment option that currently does not exist."
In the study, researchers used animal models to examine the interactions of the cell receptor EGFRvIII and RIP1. Both are used to activate NFκB, a family of proteins that is important to the growth of cancerous tumor cells. When RIP1 is switched off in the experimental model, NFκB and the signaling that promotes tumor growth is also inhibited. Furthermore, the findings show that RIP1 can be activated to divert cancer cells into a death mode so that they self-destruct.
According to the American Cancer Society, about 30 percent of brain tumors are gliomas, a fast-growing, treatment-resistant type of tumor that includes glioblastomas, astrocytomas, oligodendrogliomas, and ependymomas. In many cases, survival is tied to novel clinical trial treatments and research that will lead to drug development.
(Source: eurekalert.org)
Mental Fog with Tamoxifen is Real; Scientists Find Possible Antidote
A team from the University of Rochester Medical Center has shown scientifically what many women report anecdotally: that the breast cancer drug tamoxifen is toxic to cells of the brain and central nervous system, producing mental fogginess similar to “chemo brain.”
However, in the Journal of Neuroscience, researchers also report they’ve discovered an existing drug compound that appears to counteract or rescue brain cells from the adverse effects of the breast cancer drug.
Corresponding author Mark Noble, Ph.D., professor of Biomedical Genetics and director of the UR Stem Cell and Regenerative Medicine Institute, said it’s exciting to potentially be able to prevent a toxic reaction to one of the oldest and most widely used breast cancer medications on the market. Although tamoxifen is more easily tolerated compared to most cancer treatments, it nonetheless produces troubling side effects in a subset of the large number of people who take it.
By studying tamoxifen’s impact on central nervous system cell populations and then screening a library of 1,040 compounds already in clinical use or clinical trials, his team identified a substance known as AZD6244, and showed that it essentially eliminated tamoxifen-induced killing of brain cells in mice.
“As far as I know, no one else has discovered an agent that singles out and protects brain and central nervous system cells while also not protecting cancer cells,” said Noble, who also collaborates with researchers at the UR’s James P. Wilmot Cancer Center. “This creates a whole new paradigm; it’s where we need to go.”
The research is the result of two separate but related projects from Noble’s lab. One investigates the science underlying a condition known as “chemo brain,” and another is looking at how to exploit tamoxifen’s attributes for use in other types of cancer besides early-stage, less-aggressive breast cancer. (The drug is a type of hormonal therapy, which works by stopping the growth of estrogen-sensitive tumors.)
In the Journal of Neuroscience paper, Noble’s team first identified central nervous system (CNS) cells that are most vulnerable to tamoxifen toxicity. Chief among these were oligodendrocyte-type 2 astrocyte progenitor cells (O-2A/OPCs), cells that are essential for making the insulating sheaths (called myelin) required for nerve cells to work properly. Exposure to clinically relevant levels of tamoxifen for 48 hours killed more than 75 percent of these cells.
In earlier work, while studying the biology of the cognitive difficulties that linger in some people being treated for cancer, Noble and colleagues discovered that 5-fluorouracil, (cisplatin, cytarabine, carmustine), and multiple other types of chemotherapy, damages populations of stem cells in the CNS. Published in the Journal of Biology (1, 2) in 2006 and 2008, these studies pioneered analysis of the biological foundations of chemo brain.
“It’s critical to find safe treatments that can rescue the brain from impairment,” Noble said, “because despite increasing awareness and research in this area, some people continue to endure short-term memory loss, mental cloudiness, and trouble concentrating. For some patients the effects wear off over time, but others experience symptoms that can lead to job loss, depression, and other debilitating events.”
Noble’s lab, led by post-doctoral fellow Hsing-Yu Chen, Ph.D., identified 27 drugs that protected O-2A/OPCs from the effects of tamoxifen. Further testing resulted in singling out AZD6244, by other laboratories as a potential cancer therapy.
In mice co-treated with tamoxifen plus AZD6244, cell death in the corpus callosum, the largest white matter (myelinated) structure in the brain, was prevented, the paper reported. Meanwhile, several national clinical trials are testing the safety and effectiveness of AZD6244 in treating multiple cancers, from breast and colon to melanoma and lung.
Researchers were also optimistic about finding that while AZD6244 protected brain cells, it did not also protect cancer cells. New drug compounds have greater value if they do not compromise the effects of existing treatments, and in this case, Noble said, the experiments in his laboratory agreed with studies by other research groups, who found that the combined use of AZD6244 and chemotherapy enhances targeting of cancer cells.
In future work, Noble’s group plans to identify the dosage of AZD6244 that provides maximum protection and minimum disruption to differentiating brain cells. Their research was supported by the U.S. Department of Defense, National Institutes of Health, Susan Komen Race for the Cure, and the Carlson Stem Cell Fund.
This is the second tamoxifen-related study to come from Noble’s lab in 2013. In April they showed in pre-clinical research they could leverage the drug’s various cellular activities so that it might work on more aggressive triple-negative breast cancer. In the journal EMBO Molecular Medicine, Noble and Chen also reported finding an experimental compound that enhances tamoxifen’s ability to work in this new way.
(Source: urmc.rochester.edu)
Brain-penetrating particle attacks deadly tumors
Scientists have developed a new approach for treating a deadly brain cancer that strikes 15,000 in the United States annually and for which there is no effective long-term therapy. The researchers, from Yale and Johns Hopkins, have shown that the approach extends the lives of laboratory animals and are preparing to seek government approval for a human clinical trial.
“We wanted to make a system that would penetrate into the brain and deliver drugs to a greater volume of tissue,” said Mark Saltzman, a biomedical engineer at Yale and principal investigator of the research. “Drugs have to get to tumor cells in order to work, and they have to be the right drugs.”
Results were published July 1 in the Proceedings of the National Academy of Sciences.
Glioblastoma multiforme is a malignant cancer originating in the brain. Median survival with standard care — surgery plus chemotherapy plus radiation — is just over a year, and the five-year survival rate is less than 10 percent.
Current methods of drug delivery have serious limitations. Oral and intravenously injected drugs have difficulty accessing the brain because of a biological defense known as the blood-brain barrier. Drugs released directly in the brain through implants can’t reach migrating tumor cells. And commonly used drugs fail to kill the cells primarily responsible for tumor development, allowing regrowth.
The researchers developed a new, ultra-small drug-delivery particle that more nimbly navigates brain tissue than do existing options. They also identified and tested an existing FDA-approved drug — a fungicide called dithiazanine iodide (DI) — and found that it can kill the most aggressive tumor-causing cells.
“This approach addresses limitations of other forms of therapy by delivering drugs directly to the area most needed, obviating systemic side-effects, and permitting the drug to reside for weeks,” said neurosurgeon Dr. Joseph M. Piepmeier, a member of the research team. Piepmeier leads clinical research for Yale Cancer Center’s brain tumor program.
The drug-loaded nanoparticles are administered in fluid directly to the brain through a catheter, bypassing the blood-brain barrier. The particles’ tiny size — their diameter is about 70 nanometers — facilitates movement within brain tissue. They release their drug load gradually, offering sustained treatment.
In tests on laboratory rats with human brain cancers, DI-loaded nanoparticles significantly increased median survival to 280 days, researchers report. Maximum median survival time for rats treated with other therapies was 180 days, and with no treatment, survival was 147 days. Tests on pigs established that the new drug-particle combination also diffuses deep into brains of large animals.
The nanoparticles are made of polymers, or strings of repeating molecules. Their size, ability to control release, and means of application help them permeate brain tissues.
Researchers screened more than 2,000 FDA-approved drugs in the hunt for candidates that would kill the cells most responsible for human tumor development, brain cancer stem cells. Overall, DI worked best.
The scientists believe the particles can be adapted to deliver other drugs and to treat other central nervous system diseases, they said.
The paper is titled “Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma.”