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Posts tagged rapamycin

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Transplant drug could boost the power of brain tumor treatments

Every day, organ transplant patients around the world take a drug called rapamycin to keep their immune systems from rejecting their new kidneys and hearts. New research suggests that the same drug could help brain tumor patients by boosting the effect of new immune-based therapies.

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In experiments in animals, researchers from the University of Michigan Medical School showed that adding rapamycin to an immunotherapy approach strengthened the immune response against brain tumor cells.

What’s more, the drug also increased the immune system’s “memory” cells so that they could attack the tumor if it ever reared its head again. The mice and rats in the study that received rapamycin lived longer than those that didn’t.

Now, the U-M team plans to add rapamycin to clinical gene therapy and immunotherapy trials to improve the treatment of brain tumors. They currently have a trial under way at the U-M Health System which tests a two-part gene therapy approach in patients with brain tumors called gliomas in an effort to get the immune system to attack the tumor. In future clinical trials, adding rapamycin could increase the therapeutic response.

The new findings, published online in the journal Molecular Cancer Therapeutics, show that combining rapamycin with a gene therapy approach enhanced the animals’ ability to summon immune cells called CD8+ T cells to kill tumor cells directly. Due to this cytotoxic effect, the tumors shrank and the animals lived longer.

But the addition of rapamycin to immunotherapy even for a short while also allowed the rodents to develop tumor-specific memory CD8+ T cells that remember the specific “signature” of the glioma tumor cells and attacked them swiftly when a tumor was introduced into the brain again.

“We had some indication that rapamycin would enhance the cytotoxic T cell effect, from previous experiments in both animals and humans showing that the drug produced modest effects by itself,” says Maria Castro, Ph.D., senior author of the new paper. Past clinical trials of rapamycin in brain tumors have failed.

“But in combination with immunotherapy, it became a dramatic effect, and enhanced the efficacy of memory T cells too. This highlights the versatility of the immunotherapy approach to glioma,” says Castro, who is the R.C. Schneider Collegiate Professor in the Department of Neurosurgery and a professor of cell and developmental biology at U-M.

Rapamycin is an FDA-approved drug that produces few side effects in transplant patients and others who take it to modify their immune response. So in the future, Castro and her colleagues plan to propose new clinical trials that will add rapamycin to immune gene therapy trials like those already ongoing at UMHS.

She notes that other researchers currently studying immunotherapies for glioma and other brain tumors should also consider doing the same. “This could be a universal mechanism for enhancing efficacy of immunotherapies in glioma,” she says.

Rapamycin inhibits a specific molecule in cells, called mTOR. As part of the research, Castro and her colleagues determined that brain tumor cells use the mTOR pathway to hamper the immune response of patients.

This allows the tumor to trick the immune system, so it can continue growing without alerting the body’s T cells that a foreign entity is present. Inhibiting mTOR with rapamycin, then, uncloaks the cells and makes them vulnerable to attack.

Castro notes that if the drug proves useful in human patients, it could also be used for long-term prevention of recurrence in patients who have had the bulk of their tumor removed. “This tumor always comes back,” she says.

Filed under rapamycin brain tumors glioma t cells immune system neuroscience science

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FDA-approved immune-modulating drug unexpectedly benefits mice with fatal mitochondrial defect The transplant anti-rejection drug rapamycin showed unexpected benefits in a mouse model of a fatal defect in the energy powerhouses of cells, the mitochondria. Children with the condition, Leigh syndrome, show progressive brain damage, muscle weakness, lack of coordination or muscle control, and weight loss, and usually succumb to respiratory failure. Leigh syndrome is often diagnosed within the first year of life. Affected children rarely survive beyond 6 or 7 years. At present, the disorder, which can result from several different underlying causes, has no effective treatment. Reporting this week in Science Express, UW researchers said that they found that treatment with rapamycin “robustly enhances survival and attenuates disease progression in a mouse model of Leigh’s syndrome.” Given as a daily injection, the drug delayed the onset of neurological symptoms, reduced brain inflammation, and prevented brain lesions. For most of their lives, the treated mice breathed normally, and did not clasp their legs against their bodies, a posture characteristic of this and related brain disorders in mice. Unlike the untreated mice, they could balance and run on a rotarod, a miniature log rolling exercise toy. Both the median and maximum lifespans within the group of treated mice were strikingly extended, the authors noted. The median lifespan for this mouse condition is 50 days. In comparison, treated males lived a median of 114 days, and females 111 days. The longest survival in the treated group was 269 days, more than triple that of the untreated animals. “We were excited at the findings because of the potential impact on treatment for kids with this or related mitochondrial diseases,” said the senior author of the study, Dr. Matt Kaeberlein, UW associate professor of pathology. “Similar intervention strategies might also prove useful for a broad range of mitochondrial diseases or for other conditions resulting from mitochondrial dysfunction.” Mitochondrial defects lessen the amount of energy available to cells. The depletion can damage or destroy vital tissues. Symptoms and severity of illness depends on which types of cells are affected, but in many cases several organ systems operate poorly as a consequence of malfunctioning mitochondria. Beyond specific mitochondrial diseases, most of them genetic in origin, the decline or dysfunction of mitochondria contribute to many common health problems, including some forms of heart disease, cancer, and muscle, nerve or brain degeneration associated with aging. Kaeberlein, who researches factors that lengthen life, has been studying the anti-aging effects of rapamycin for several years. The drug, like calorie-restricting diets, acts by inhibiting mTOR, an abbreviation for the eponymously named mechanistic target of rapamycin. Kaeberlein said, “This study suggests that this drug’s inhibition of mTOR may have a major impact on mitochondria and energy production in cells. We know that rapamycin appears to slow aging. What we don’t know is whether the effects of rapamycin on mitochondria are a major part of the effects of rapamycin on normal aging and aging-related diseases.” Alongside their work in aging and lifespan in normal mice, Kaeberlein and his lab decided to study rapamycin’s actions on mice with a severe mitochondrial defect. The mouse model for Leigh syndrome was created in the UW laboratory of Dr. Richard Palmiter, a professor of biochemistry and Howard Hughes Medical Institute investigator who was one of the early originators of transgenic mouse models. The research team included Dr. Philip G. Morgan and Dr. Margaret M. Sedensky, from the Department of Anesthesiology and Pain Medicine at Seattle Children’s Hospital, who study mitochondrial diseases in patients. The lead scientist was Simon C. Johnson from the UW Department of Pathology. After seeing unexpected benefits on health and survival, the research group looked closely at the effects on metabolism by examining the levels of more than 100 different metabolites – cellular building blocks and intermediates used to make energy – in the treated and untreated Leigh syndrome mice. The team observed that treated mice appear to burn more amino acids and fats as an energy source, rather than the sugar, glucose. This eliminated the accumulation of glucose breakdown byproducts, including lactate. These byproducts can be toxic and are seen at high levels in human Leigh syndrome patients. “The drug did not substantially alter mitochondrial composition. Instead, the mice appear to bypass the deficiency in their mitochondria through a shift in their metabolic pattern,” Kaeberlein said. “However, we can’t yet explain exactly how this rescues the mice with Leigh syndrome.” Because this was a mouse study, evidence of efficacy of rapamycin in Leigh syndrome patients will be a necessary next step. Rapamycin already has FDA approval for several uses, including preventing organ transplant rejection and for treating rare forms of cancer; however, the drug also has side-effects which might limit its utility in very young children. Kaeberlein is optimistic, however, that “even if rapamycin doesn’t turn out to be be useful as a treatment for Leigh Syndrome, the lessons learned here will pave the way to new therapies for this devastating disease.”

FDA-approved immune-modulating drug unexpectedly benefits mice with fatal mitochondrial defect

The transplant anti-rejection drug rapamycin showed unexpected benefits in a mouse model of a fatal defect in the energy powerhouses of cells, the mitochondria. Children with the condition, Leigh syndrome, show progressive brain damage, muscle weakness, lack of coordination or muscle control, and weight loss, and usually succumb to respiratory failure.

Leigh syndrome is often diagnosed within the first year of life. Affected children rarely survive beyond 6 or 7 years. At present, the disorder, which can result from several different underlying causes, has no effective treatment.

Reporting this week in Science Express, UW researchers said that they found that treatment with rapamycin “robustly enhances survival and attenuates disease progression in a mouse model of Leigh’s syndrome.” Given as a daily injection, the drug delayed the onset of neurological symptoms, reduced brain inflammation, and prevented brain lesions.

For most of their lives, the treated mice breathed normally, and did not clasp their legs against their bodies, a posture characteristic of this and related brain disorders in mice. Unlike the untreated mice, they could balance and run on a rotarod, a miniature log rolling exercise toy. Both the median and maximum lifespans within the group of treated mice were strikingly extended, the authors noted.

The median lifespan for this mouse condition is 50 days. In comparison, treated males lived a median of 114 days, and females 111 days. The longest survival in the treated group was 269 days, more than triple that of the untreated animals.

“We were excited at the findings because of the potential impact on treatment for kids with this or related mitochondrial diseases,” said the senior author of the study, Dr. Matt Kaeberlein, UW associate professor of pathology. “Similar intervention strategies might also prove useful for a broad range of mitochondrial diseases or for other conditions resulting from mitochondrial dysfunction.”

Mitochondrial defects lessen the amount of energy available to cells. The depletion can damage or destroy vital tissues. Symptoms and severity of illness depends on which types of cells are affected, but in many cases several organ systems operate poorly as a consequence of malfunctioning mitochondria.

Beyond specific mitochondrial diseases, most of them genetic in origin, the decline or dysfunction of mitochondria contribute to many common health problems, including some forms of heart disease, cancer, and muscle, nerve or brain degeneration associated with aging.

Kaeberlein, who researches factors that lengthen life, has been studying the anti-aging effects of rapamycin for several years. The drug, like calorie-restricting diets, acts by inhibiting mTOR, an abbreviation for the eponymously named mechanistic target of rapamycin.

Kaeberlein said, “This study suggests that this drug’s inhibition of mTOR may have a major impact on mitochondria and energy production in cells. We know that rapamycin appears to slow aging. What we don’t know is whether the effects of rapamycin on mitochondria are a major part of the effects of rapamycin on normal aging and aging-related diseases.”

Alongside their work in aging and lifespan in normal mice, Kaeberlein and his lab decided to study rapamycin’s actions on mice with a severe mitochondrial defect. The mouse model for Leigh syndrome was created in the UW laboratory of Dr. Richard Palmiter, a professor of biochemistry and Howard Hughes Medical Institute investigator who was one of the early originators of transgenic mouse models.

The research team included Dr. Philip G. Morgan and Dr. Margaret M. Sedensky, from the Department of Anesthesiology and Pain Medicine at Seattle Children’s Hospital, who study mitochondrial diseases in patients. The lead scientist was Simon C. Johnson from the UW Department of Pathology.

After seeing unexpected benefits on health and survival, the research group looked closely at the effects on metabolism by examining the levels of more than 100 different metabolites – cellular building blocks and intermediates used to make energy – in the treated and untreated Leigh syndrome mice. The team observed that treated mice appear to burn more amino acids and fats as an energy source, rather than the sugar, glucose. This eliminated the accumulation of glucose breakdown byproducts, including lactate. These byproducts can be toxic and are seen at high levels in human Leigh syndrome patients.

“The drug did not substantially alter mitochondrial composition. Instead, the mice appear to bypass the deficiency in their mitochondria through a shift in their metabolic pattern,” Kaeberlein said. “However, we can’t yet explain exactly how this rescues the mice with Leigh syndrome.”

Because this was a mouse study, evidence of efficacy of rapamycin in Leigh syndrome patients will be a necessary next step. Rapamycin already has FDA approval for several uses, including preventing organ transplant rejection and for treating rare forms of cancer; however, the drug also has side-effects which might limit its utility in very young children. Kaeberlein is optimistic, however, that “even if rapamycin doesn’t turn out to be be useful as a treatment for Leigh Syndrome, the lessons learned here will pave the way to new therapies for this devastating disease.”

Filed under Leigh syndrome mitochondria mitochondrial dysfunction rapamycin animal model neuroscience science

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Addiction Relapse Might Be Thwarted By Turning Off Brain Trigger Researchers at the Ernest Gallo Clinic and Research Center at UC San Francisco have been able to identify and deactivate a brain pathway linked to memories that cause alcohol cravings in rats, a finding that may one day lead to a treatment option for people who suffer from alcohol abuse disorders and other addictions. In the study, researchers were able to prevent the addicted animals from seeking alcohol and drinking it, the equivalent of relapse. “One of the main causes of relapse is craving, triggered by the memory by certain cues – like going into a bar, or the smell or taste of alcohol,” said lead author Segev Barak, PhD, at the time a postdoctoral fellow in the lab of co-senior author Dorit Ron, PhD, a Gallo Center investigator and UCSF professor of neurology. “We learned that when rats were exposed to the smell or taste of alcohol, there was a small window of opportunity to target the area of the brain that reconsolidates the memory of the craving for alcohol and to weaken or even erase the memory, and thus the craving” he said. The study, also supervised by co-senior author Patricia H. Janak, PhD, a Gallo Center investigator and UCSF professor of neurology, was published online on June 23 in Nature Neuroscience. Neural Mechanism That Triggers Alcohol Memory In the first phase of the study, rats had the choice to freely drink water or alcohol over the course of seven weeks, and during this time developed a high preference for alcohol. In the next phase, they had the opportunity to access alcohol for one hour a day, which they learned to do by pressing a lever. They were then put through a 10-day period of abstinence from alcohol. Following this period, the animals were exposed for five minutes to just the smell and taste of alcohol, which cued them to remember how much they liked drinking it. The researchers then scanned the animals’ brains, and identified the neural mechanism responsible for the reactivation of the memory of the alcohol – a molecular pathway mediated by an enzyme known as mammalian target of rapamycin complex 1 (mTORC1). They found that just a small drop of alcohol presented to the rats turned on the mTORC1 pathway specifically in a select region of the amygdala, a structure linked to emotional reactions and withdrawal from alcohol, and cortical regions involved in memory processing. They further showed that once mTORC1 was activated, the alcohol-memory stabilized (reconsolidated) and the rats relapsed on the following days, meaning in this case, that they started again to push the lever to dispense more alcohol. “The smell and taste of alcohol were such strong cues that we could target the memory specifically without impacting other memories, such as a craving for sugar,” said Barak, who added that the Ron research group has been doing brain studies for many years and has never seen such a robust and specific activation in the brain. Drug that Erases the Memory of Alcohol In the next part of the study, the researchers set out to see if they could prevent the reconsolidation of the memory of alcohol by inhibiting mTORC1, thus preventing relapse. When mTORC1 was inactivated using a drug called rapamycin, administered immediately after the exposure to the cue (smell, taste), there was no relapse to alcohol-seeking the next day. Strikingly, drinking remained suppressed for up to 14 days, the end point of the study. These results suggest that rapamycin erased the memory of alcohol for a long period, said Ron. The authors said the study is an important first step, but that more research is needed to determine how mTORC1 contributes to alcohol memory reconsolidation and whether turning off mTORC1 with rapamycin would prevent relapse for more than two weeks. The authors also said it would be interesting to test if rapamycin, an FDA-approved drug currently used to prevent organ rejection after transplantation, or other mTORC1 inhibitors that are currently being developed in pharmaceutical companies, would prevent relapse in human alcoholics. “One of the main problems in alcohol abuse disorders is relapse, and current treatment options are very limited.” Barak said. “Even after detoxification and a period of rehabilitation, 70 to 80 percent of patients will relapse in the first several years. It is really thrilling that we were able to completely erase the memory of alcohol and prevent relapse in these animals. This could be a revolution in treatment approaches for addiction, in terms of erasing unwanted memories and thereby manipulating the brain triggers that are so problematic for people with addictions.”

Addiction Relapse Might Be Thwarted By Turning Off Brain Trigger

Researchers at the Ernest Gallo Clinic and Research Center at UC San Francisco have been able to identify and deactivate a brain pathway linked to memories that cause alcohol cravings in rats, a finding that may one day lead to a treatment option for people who suffer from alcohol abuse disorders and other addictions.

In the study, researchers were able to prevent the addicted animals from seeking alcohol and drinking it, the equivalent of relapse.

“One of the main causes of relapse is craving, triggered by the memory by certain cues – like going into a bar, or the smell or taste of alcohol,” said lead author Segev Barak, PhD, at the time a postdoctoral fellow in the lab of co-senior author Dorit Ron, PhD, a Gallo Center investigator and UCSF professor of neurology.

“We learned that when rats were exposed to the smell or taste of alcohol, there was a small window of opportunity to target the area of the brain that reconsolidates the memory of the craving for alcohol and to weaken or even erase the memory, and thus the craving” he said.

The study, also supervised by co-senior author Patricia H. Janak, PhD, a Gallo Center investigator and UCSF professor of neurology, was published online on June 23 in Nature Neuroscience.

Neural Mechanism That Triggers Alcohol Memory

In the first phase of the study, rats had the choice to freely drink water or alcohol over the course of seven weeks, and during this time developed a high preference for alcohol.

In the next phase, they had the opportunity to access alcohol for one hour a day, which they learned to do by pressing a lever. They were then put through a 10-day period of abstinence from alcohol.

Following this period, the animals were exposed for five minutes to just the smell and taste of alcohol, which cued them to remember how much they liked drinking it. The researchers then scanned the animals’ brains, and identified the neural mechanism responsible for the reactivation of the memory of the alcohol – a molecular pathway mediated by an enzyme known as mammalian target of rapamycin complex 1 (mTORC1).

They found that just a small drop of alcohol presented to the rats turned on the mTORC1 pathway specifically in a select region of the amygdala, a structure linked to emotional reactions and withdrawal from alcohol, and cortical regions involved in memory processing.

They further showed that once mTORC1 was activated, the alcohol-memory stabilized (reconsolidated) and the rats relapsed on the following days, meaning in this case, that they started again to push the lever to dispense more alcohol.

“The smell and taste of alcohol were such strong cues that we could target the memory specifically without impacting other memories, such as a craving for sugar,” said Barak, who added that the Ron research group has been doing brain studies for many years and has never seen such a robust and specific activation in the brain.

Drug that Erases the Memory of Alcohol

In the next part of the study, the researchers set out to see if they could prevent the reconsolidation of the memory of alcohol by inhibiting mTORC1, thus preventing relapse. When mTORC1 was inactivated using a drug called rapamycin, administered immediately after the exposure to the cue (smell, taste), there was no relapse to alcohol-seeking the next day.

Strikingly, drinking remained suppressed for up to 14 days, the end point of the study. These results suggest that rapamycin erased the memory of alcohol for a long period, said Ron.

The authors said the study is an important first step, but that more research is needed to determine how mTORC1 contributes to alcohol memory reconsolidation and whether turning off mTORC1 with rapamycin would prevent relapse for more than two weeks.

The authors also said it would be interesting to test if rapamycin, an FDA-approved drug currently used to prevent organ rejection after transplantation, or other mTORC1 inhibitors that are currently being developed in pharmaceutical companies, would prevent relapse in human alcoholics.

“One of the main problems in alcohol abuse disorders is relapse, and current treatment options are very limited.” Barak said. “Even after detoxification and a period of rehabilitation, 70 to 80 percent of patients will relapse in the first several years. It is really thrilling that we were able to completely erase the memory of alcohol and prevent relapse in these animals. This could be a revolution in treatment approaches for addiction, in terms of erasing unwanted memories and thereby manipulating the brain triggers that are so problematic for people with addictions.”

Filed under alcohol abuse addiction amygdala rapamycin mTORC1 memory neuroscience science

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