Might a combination of 2 cancer drugs help treat Alzheimer's disease?

Medical News Today

4 days ago

Researchers are actively seeking treatments or a cure for Alzheimer's diseaseOne current research avenue is to look at currently-approved medications that are used for other diseases, an approach that is called drug repurposing. A new study has identified two cancer medications that may help overturn brain changes caused by Alzheimer's disease, possibly slowing or even reversing the disease's symptoms. Researchers all over the world are actively seeking treatments or a cure for Alzheimer's disease — a form of dementia currently impacting about 32 million people globally. The medications used right now for Alzheimer's disease are designed to only help treat symptoms and slow disease progression. One avenue scientists are taking in an effort to find treatments for Alzheimer's disease is by looking at currently-approved medications that are used for other diseases, an approach called drug repurposing. 'The idea of drug repurposing or identifying new uses for existing drugs, can speed up the drug discovery process because the compounds already have been tested for toxicity and adverse events,' Marina Sirota, PhD, professor and interim director of the University of California — San Francisco Bakar Computational Health Sciences Institute explained to Medical News Today.'Alzheimer's disease is a complex disease, which is very difficult to treat so we need to use all the tools possible to speed up drug discovery and help patients,' said SirotaSirota is the co-senior author of a new study recently published in the journal Cellthat has identified two cancer medications that may help overturn brain changes caused by Alzheimer's disease, possibly slowing or even reversing the disease's symptoms. Focusing on cancer drugs letrozole and irinotecanFor this study, researchers began by using past studies to assess how Alzheimer's disease changed gene expression in brain cells, mainly neurons and glia. 'Glia cells are non-neuronal cells that provide support and protection to neurons in the nervous system,' Sirota explained. 'By targeting both neuronal cells and non-neuronal cells (glia) we hope to be able to more comprehensively target disease pathophysiology.' From there, scientists then took the gene expression signatures they found and used a database called the ConnectivityMap, allowing them to examine thousands of drugs to find ones that reversed the Alzheimer's disease gene expression signature.'We started with a set of 1,300 drugs and narrowed it down to the combination of letrozole and irinotecan through data driven analysis using both molecular and clinical data,' Sirota said.'We first identified compounds that reversed the cell type specific disease signatures back to normal based on the gene expression profiles. We then further filtered the list to the candidates that affect several cell types,' she explained.'Then we wanted to see whether patients who are on those drugs already have a lower risk of Alzheimer's disease by querying electronic medical records across the UC system,' she continued. 'This has allowed us to narrow our list down to a handful of drugs and focus on this combination.' The analysis of electronic medical records did indeed show that both drugs were associated with a significantly lower risk of Alzheimer's disease, confirming the selection.Combo of cancer drugs reverses brain cell damage, reduces protein build-up in mouse modelNext, researchers decided to test the combination of letrozole — used to treat breast cancer — and irinotecan — used to treat colorectal and lung cancer — in a mouse model of aggressive Alzheimer's disease. At the study's conclusion, Sirota and her team found that the drug combination overturned multiple aspects of Alzheimer's disease in the mouse model, including undoing the gene expression signature changes in the neurons and glia caused by the disease. Additionally, researchers found the combination cancer drugs helped reduce the amount of amyloid-beta and tau proteins in the brain, which are known hallmarks of Alzheimer's disease. 'This tells us that multiple levels of evidence — molecular data, clinical information and mouse model experiments are all aligning to tell us that these compounds might be helpful for Alzheimer's disease patients,' Sirota said.She further noted that:'While we don't know the exact mechanism of how these drugs work to treat Alzheimer's disease, we know that irinotecan is a chemotherapy drug that works by inhibiting the enzyme DNA topoisomerase I, specifically targeting the S and G2 phases of the cell cycle. Letrozole's mechanism of action involves inhibiting the enzyme aromatase, which is crucial in the biosynthesis of estrogen.''However, we don't know whether it is the main aforementioned mechanisms or off-target effects of these drugs which might help Alzheimer's disease patients,' Sirota cautioned. 'Additional experiments need to be carried out to better understand how these two drugs might work together to combat Alzheimer's disease in patients.'Using 'big data' and inventive approaches to find potential Alzheimer's drug targetsMNT had the opportunity to speak with John Dickson, MD, PhD, a neurologist at Massachusetts General Hospital, about this research. 'This is an interesting and innovative paper that uses 'big data' to aid in identifying potential drug targets to treat Alzheimer's disease and then tests candidates in a preclinical model of Alzheimer's disease,' Dickson, who was not involved in this research, said.'Combining the use of transcriptomic data from brain tissue from Alzheimer's disease patients, drug perturbation studies in cell lines, and patient data from electronic medical records was an inventive approach to identifying and narrowing down potential drug targets,' he added.In Dickson's view, 'the decision to use a dual-therapy approach and plan to target multiple cell types with this strategy was also innovative.''The combination of drugs showed beneficial effects on the memory testing and neuropathological findings in a mouse model of Alzheimer's disease. In addition to identifying two potential candidate therapies for Alzheimer's disease, this paper also provides an experimental paradigm for identifying new drugs to treat a variety of conditions,' he continued.Why look at repurposing existing drugs for Alzheimer's treatment? MNT also talked to Clifford Segil, DO, a neurologist at Providence Saint John's Health Center in Santa Monica, CA, about this study, who said it is refreshing to see data that supports improving memory loss through a novel mechanism that is not related to current therapies that work on brain acetylcholine, N-methyl-D-aspartate (NMDA), or amyloid.'This study's design is smart and the data is captivating,' Segil, who likewise was not involved in the research, added. 'Repurposing medications already being used has been extremely rewarding in neurologists and I truly hope something grows out of this research.' And Peter Gliebus, MD, neurologist and director of cognitive and behavioral neurology at Marcus Neuroscience Institute, part of Baptist Health South Florida, also not involved in the research, commented to MNT that this was a promising and exciting study, and said that repurposing existing drugs offers several advantages. 'Faster development since these drugs already have established safety profiles, which reduces the time and cost required for clinical trials,' Gliebus noted.'Cost-effectiveness [is achieved] by avoiding the high expenses associated with developing new drugs from scratch. And [this approach has] a broader impact, as many existing drugs may have unexplored mechanisms that could address complex Alzheimer's disease pathologies, such as neuroinflammation, synaptic dysfunction, and metabolic deficits.''Given the high failure rate of Alzheimer's drug trials, repurposing provides a practical and efficient pathway to identify effective treatments,' the neurologist concluded.