Transplant drug could boost power of brain tumor treatments, study finds

Drs. Maria Castro and Pedro Lowenstein, both of the U-M Department of Neurosurgery, co-led the research. Credit: Image courtesy of University of Michigan Health System

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.

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." Castro is the R.C. Schneider Collegiate Professor 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.

Source: University of Michigan Health System

When you lose weight, where does the fat go? Most of the mass is breathed out as carbon dioxide, study shows

Despite a worldwide obsession with diets and fitness regimes, many health professionals cannot correctly answer the question of where body fat goes when people lose weight.
Credit: © Lovrencg / Fotolia

Despite a worldwide obsession with diets and fitness regimes, many health professionals cannot correctly answer the question of where body fat goes when people lose weight, a UNSW Australia study shows.

The most common misconception among doctors, dieticians and personal trainers is that the missing mass has been converted into energy or heat.

"There is surprising ignorance and confusion about the metabolic process of weight loss," says Professor Andrew Brown, head of the UNSW School of Biotechnology and Biomolecular Sciences.

"The correct answer is that most of the mass is breathed out as carbon dioxide. It goes into thin air," says the study's lead author, Ruben Meerman, a physicist and Australian TV science presenter.

In their paper, published in the British Medical Journal today, the authors show that losing 10 kilograms of fat requires 29 kilograms of oxygen to be inhaled and that this metabolic process produces 28 kilograms of carbon dioxide and 11 kilograms of water.

Mr Meerman became interested in the biochemistry of weight loss through personal experience.

"I lost 15 kilograms in 2013 and simply wanted to know where those kilograms were going. After a self-directed, crash course in biochemistry, I stumbled onto this amazing result," he says.

"With a worldwide obesity crisis occurring, we should all know the answer to the simple question of where the fat goes. The fact that almost nobody could answer it took me by surprise, but it was only when I showed Andrew my calculations that we both realised how poorly this topic is being taught."

The authors met when Mr Meerman interviewed Professor Brown in a story about the science of weight loss for the Catalyst science program on ABC TV in March this year.

"Ruben's novel approach to the biochemistry of weight loss was to trace every atom in the fat being lost and, as far as I am aware, his results are completely new to the field," says Professor Brown.

"He has also exposed a completely unexpected black hole in the understanding of weight loss amongst the general public and health professionals alike."

If you follow the atoms in 10 kilograms of fat as they are 'lost', 8.4 of those kilograms are exhaled as carbon dioxide through the lungs. The remaining 1.6 kilograms becomes water, which may be excreted in urine, faeces, sweat, breath, tears and other bodily fluids, the authors report.

"None of this is obvious to people because the carbon dioxide gas we exhale is invisible," says Mr Meerman.

More than 50 per cent of the 150 doctors, dieticians and personal trainers who were surveyed thought the fat was converted to energy or heat.

"This violates the Law of Conservation of Mass. We suspect this misconception is caused by the energy in/energy out mantra surrounding weight loss," says Mr Meerman.

Some respondents thought the metabolites of fat were excreted in faeces or converted to muscle.

"The misconceptions we have encountered reveal surprising unfamiliarity about basic aspects of how the human body works," the authors say.

One of the most frequently asked questions the authors have encountered is whether simply breathing more can cause weight loss. The answer is no. Breathing more than required by a person's metabolic rate leads to hyperventilation, which can result in dizziness, palpitations and loss of consciousness.

The second most frequently asked question is whether weight loss can cause global warming.

"This reveals troubling misconceptions about global warming which is caused by unlocking the ancient carbon atoms trapped underground in fossilised organisms. The carbon atoms human beings exhale are returning to the atmosphere after just a few months or years trapped in food that was made by a plant," says Mr Meerman, who also presents the science of climate change in high schools around Australia.

Mr Meerman and Professor Brown recommend that these basic concepts be included in secondary school curricula and university biochemistry courses to correct widespread misconceptions about weight loss among lay people and health professionals.

Source: University of New South Wales