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From cancer to Alzheimer's
COLD SPRING HARBOR, N.Y.—Finding new indications for existing drugs has long been a boon in the pharmaceutical industry. The use of drugs that have already been approved for one indication eases the approval pathway for additional indications as safety and efficacy studies have already been conducted, saving time on getting new drugs to market. And recently, a team of U.S. and Chinese neuroscientists and chemists have released research showing that a certain class of cancer drugs currently in use have demonstrated the potential to reverse memory loss in animal models of Alzheimer's disease. The study, "Epidermal growth factor receptor is a preferred target for treating amyloid beta-induced memory loss," appeared online ahead of print Sept. 24 in Proceedings of the National Academy of Sciences.
The class of drugs used in the experiment consisted of inhibitors targeted to the epidermal growth factor receptor (EGFR), which is over-expressed in a variety of cancers, specifically a subset of lung cancers. The research revealed that EGFR represents what the team called a "preferred target" for treating memory loss associated with the amyloid-beta plaques that build up in the brains of Alzheimer's patients.
Dr. Yi Zhong of Cold Spring Harbor Laboratory (CSHL) led the studies, which followed previous work in which he and his colleagues had examined amyloid beta-associated memory loss in fruit flies with brain cells expressing the amyloid-beta-42 peptide (a version of amyloid beta that is composed of 42 amino acids and appears in Alzheimer's plaques). The fruit flies, which manifest amyloid beta-42 as a result of a human gene inserted in their gene, tend to suffer memory issues similar to those that present in human Alzheimer's. This latest research suggest that the signaling within cells that is induced by the activation of EGFR plays a role in the pathology involved in amyloid beta-associated memory loss in patients suffering from Alzheimer's.
In the latest experiments, Zhong and his team demonstrate that increased activation of EGFRs in brain cells led to worsening memory loss in amyloid beta-42 fruit fly models of Alzheimer's. The team then dosed the flies with two anti-cancer EGFR inhibitors, erlotinib and gefitinib, approved anti-cancer treatments that block the EGFR receptor and can prevent its activation. The inhibitors reversed memory loss, results that were also seen in mouse models of the disease (also based on the amyloid beta-42 gene).
Given the questions that still exist about the pathology of Alzheimer's, a specific mechanism of action could not be nailed down with relation to the experiments, but the evidence implies that the reversal of memory loss is the result of clumps of beta-amyloid proteins being blocked from attaching to the EGF receptor, or the prevention of phosphate groups from attaching to the receptor. Regardless, it still prevents the EGFR intracellular signaling cascade from being initiated.
The CSHL research team also tested the drug treatments on middle-aged mice with advanced memory loss. The mice were tested over 18 days, a period of time roughly six weeks shorter than the dosing period that was originally proven to be effective.
"Eighteen days—the shortest dosing period we tested—was sufficient to reverse loss in these mice, although we should note that these animals had few morphological changes in the brain despite their severe memory loss when treatment began," said Zhong in a press release.
The potential of EGFR as a druggable target for Alzheimer's treatment was corroborated in a parallel but separate undertaking by Zhong's associates. Collaborators in China screened roughly 2,000 synthetic compounds for activity against amyloid beta-induced memory loss in fruit fly models of Alzheimer's. Of those, 45 showed positive results after two months of treatment in the models, and nine were tested in mouse models, four of which displayed positive results after two months.
"We were amazed to find that three of these compounds—designated JKF-006, JKF-011 and JKF-027—not only showed effective results in rescuing memory loss in the mice, but also, in test tubes, prevented amyloid beta-42 from activating human EGFR," noted Zhong.
"We have tested a number of other chemical compounds that have been identified through our behavior screening. And for those compounds, they have a property that's very interesting in the sense that they only inhibit a-beta peptide-induced activation of EGFR, but it cannot inhibit EGF, naturally induced activation of EGFR," Zhong adds. "Therefore those compounds will have much less side effects as they're developed for treatment for cancers."
Zhong says it would be his dream to bring the compounds to clinical trials, noting that they are talking to companies interested in developing the compounds.
In terms of the next step for the research, Zhong says they will be pursuing several different avenues as they move forward. Though this most recent research has confirmed that amyloid beta is capable of activating EGFR, and that the activation is linked to memory loss, the team will be working to figure out the mechanics of exactly how amyloid beta is capable of the activation. The team will also pursue the question of how the compounds that were identified were capable of specifically inhibiting amyloid-beta-induced activation of EGFR while not inhibiting naturally occurring EGFR activation.
"We think there are several possibilities. Why is it those compounds were able to bind with specific spaces for the a-beta peptides? A-beta peptides are able to form a range of oligomers, and it was thought that some of those oligomers are toxic, not related to the memory loss. So we are hoping that we can identify how those compounds interact with those specific toxic oligomers of a-beta peptides and to gain more insights into how this inhibition, or how this rescue of memory, through this EGFR pathway happens," says Zhong.
"Secondly, the EGFR activation, the normal activation of EGFR receptor leading to memory loss, is also not understood very well. So far all the evidence supports, not only in the mouse but also in Drosophila, activation of EGFR through a-beta peptides correlated very well with the memory loss … and blocking this activation will lead to rescue of the memory loss," Zhong continues. "Yet we don't know how this activation really caused the memory loss, so we are also working on this part. We are hoping with those understandings, we will be able to not only enable us to gain insight into these mechanisms, but also provide further tools or avenue for developing some novel treatment."
In addition to Zhong, the paper's authors include Lei Wang, Hsueh-cheng Chiang, Wenjuan Wu, Bin Liang, Zuolei Xie, Xingsheng Yao, Weiwei Ma and Shuwen Du. Funding for the study came from grants from CSHL, Dart Neuroscience, the Ministry of Science and Technology of China and the Tsinghua-Yue-Yuen Medical Sciences Fund.