Researchers Investigate: Steroids and Cancer, Brain Degeneration and Growth
How steroids affect cancer immunotherapy, the powerhouse of neurodegeneration and the molecules behind learning and memory
Steroids are commonly given during cancer care, either to treat the disease or to treat the symptoms of cancer, like pain or nausea. However, steroids may suppress the immune system and interfere with immunotherapy, which is why most clinical trials for immunotherapy exclude patients treated with steroids. Outside of the controlled setting of a clinical trial, many patients have been treated with both immunotherapy and steroids, but studies specifically looking at this question have yielded mixed results.
Jefferson researchers Nikita Nikita, MD, MPH, senior author Grace Lu-Yao, PhD, and colleagues at the Sidney Kimmel Cancer Center – Jefferson Health sought to address this question with the largest population-based real-world study to date (an approach that has yielded other potentially practice-changing insights on immunotherapy). Their team queried a large national database and identified 1,671 melanoma patients who were treated with immunotherapy between 2010 and 2016, 907 of whom also received steroids within 12 months prior to immunotherapy. The results were published in the journal Cancers.
They found that patients who had steroids within a month prior to immunotherapy had a 126% higher risk of death than those without steroid exposure in the year before immunotherapy. Patients who received steroids between one and three months before immunotherapy had a 51% higher risk of death within three months of starting immunotherapy. “When possible, the cancer care team may consider delaying starting immunotherapy for one to three months to allow for steroid washout,” says Dr. Nikita. “Seeing the risk decrease when more time is allowed between steroids and immunotherapy is suggestive of a biological effect,” adds Dr. Lu-Yao “Further studies are warranted to understand the mechanism, but this research suggests longer-time interval between these two therapies may improve survival.”
Does the Cell’s Power Source Fuel Neurodegeneration?
In the past 20 years, researchers studying neurodegenerative diseases like Alzheimer’s, Parkinson’s and ALS have found that the cell’s power source – the mitochondria – are often damaged in some way. If the mitochondria are damaged, it’s no wonder the brain would be impacted, since brain cells use large amounts of power in order to function properly. But to date, it’s been unclear what goes wrong. To learn more, Jefferson’s MitoCare Center researchers examined a simpler disease that allowed them to hone in on one mitochondrial process that could be the culprit. The group discussed their study in the journal Science Advances.
Gyorgy Hajnoczky, MD, PhD, and team looked at both a mouse model and samples from patients with a mitochondrial disorder that caused symptoms of neurodegenerative diseases. In both, neurons had a mutation in the MICU-1 protein, which regulates how much calcium enters the mitochondria. Calcium is critical to mitochondrial function: it can boost energy supply or signal cell death. The researchers found that mitochondria in cells with the MICU-1 mutation were overloaded with calcium. Calcium overload is widely observed in multiple neurodegenerative diseases, though no one had pinpointed the mechanism. Identifying MICU-1 as the possible culprit, offers a target for developing a drug that not only could help those with a rare MICU-1 disease, but could also slow progression of other neurodegenerative diseases that seem to be fueled by calcium overload.
How Neurons Build Connections
Learning and memory happen when neurons form and solidify connections between one another via knobby touch points called synapses. Your brain is made of a 100 trillion of these tiny structures that enable neurons to communicate and store information. Jefferson neuroscientists Martin Hruska, PhD, Rachel Cain and senior author Matthew Dalva, PhD, used super resolution microscopes to peer into the nanoscale, see how the molecules studding the surface of the synapse are organized, and how the structure and organization of the molecules changes when synapses change size or shape.
How do synapses facilitate learning and memory? We don't know all the answers, but when they get new information, the synapses grow a little bigger, and change how many molecules they have in them. However, synapses are so small that normal light microscopes can't see their organization. A few years ago, Dr. Dalva’s team used high-tech microscopic imaging to discover that molecules were organized in a digital fashion: larger synapses had more of them.
Their newest study asks whether the molecules that mediate neurotransmission, or the flow of information between neurons, are also organized this way. Indeed, Dr. Dalva’s group saw that the molecules, or receptors, that relayed the messages involved in learning, would cluster in one part of the synapse, while those involved in information storage – or memory – are also found at increasing amounts as the synapses get larger. Interestingly, the organization depended on the function of the receptor. The receptors that help make spines bigger were found in smaller spines and those that indicate recent increases in the spine size found in larger ones.
The results demonstrate, that despite their tiny size, synapses are organized in a precise manner that likely reflects their function. It is surprising that there is such precision in the organization of receptor types, which suggests that figuring out the ways this precision happens might help us to understand diseases where synapse organization is disrupted. The results were published in Nature Communications.
