UNIVERSITY PARK, Pa. — A cancer drug currently in clinical trials has shown the potential to protect, cure and prevent transmission of malaria. The groundbreaking finding by an international team that includes Penn State researchers offers new hope against a disease that kills more than half a million people a year and most severely affects children under five, pregnant women and patients with HIV.
“Disruptions in malaria vaccines, treatment and care during the COVID-19 pandemic, combined with increasing reports of resistance to first-line artemisinin-based combination therapies, have led to an increase in cases. and deaths from malaria around the world,” said Manuel Llinás, distinguished professor of biochemistry and molecular biology and of chemistry at Penn State. “Identifying new ways to treat the disease is crucial to malaria control. Ideal treatments would operate differently from current first-line drugs to circumvent current drug resistance and act on multiple targets.” or stages of the life cycle of the parasite to retard future resistance”.
The research team explored whether sapanisertib, a drug currently in clinical trials for the treatment of several types of cancer, including breast cancer, endometrial cancer, glioblastoma, renal cell carcinoma, and thyroid cancer , could be used to treat malaria.
They found that sapanisertib has the potential to protect, cure and block malaria transmission by killing the malaria parasite at various stages during its life cycle within its human host. This includes when the parasite is in the liver, where it first grows and multiplies; when it is within the host’s red blood cells that clinical symptoms are observed; and when it sexually divides within the host’s red blood cells to produce the transmissible forms of the parasite. The transmissible form is usually taken up by the female Anopheles mosquito during a blood meal and transmitted during subsequent blood meals to infect another person, so killing the parasite should also prevent subsequent infections.
The researchers also established the mechanism by which sapanisertib kills the human malaria parasite and found that the drug inhibits multiple proteins called kinases in the malaria parasite.
Sapanisertib’s multistage activity and antimalarial efficacy, coupled with potent inhibition of multiple protein targets, including at least two that have already been shown to be vulnerable targets for chemotherapeutic intervention, will support further research to assess the potential of repurposing sapanisertib to treat malaria. .
Reuse of existing drugs
The research team took advantage of an approach known as drug repurposing, which aims to find new uses for an existing drug, approved by a regulatory agency in one disease area, for another disease. This approach is used to circumvent the challenges of discovering and developing a new drug from scratch, which is a lengthy and expensive process, often with low returns in terms of the number of drugs that ultimately reach the market.
“The problem is amplified in tropical and neglected diseases, such as malaria, where existing resources are scarce and financial returns are low,” said Kelly Chibale, founder and director of the UCT Center for Drug Discovery and Development, chair by Neville Isdell on Africa-focused Drug Discovery. and Development of the UCT, and leader of the research team. “The drug repurposing approach of investigating existing drugs as potential therapies for other diseases shortens the process as in most cases the candidates, in this case sapanisertib, will have gone through various stages of clinical development and will have exposure profiles and well-known safety in humans.”
While new uses for approved drugs have sometimes been found by chance in the drug repurposing approach, there are strategies to rationally identify drugs that can be used for other diseases. In this study, the team exploited drugs that act through protein targets of human origin, which could be active on similar protein targets in the malaria parasite.
Working as part of the Bill and Melinda Gates Foundation-funded Malaria Drug Accelerator project, Tarrick Qahash, a college student turned technician in the Llinás lab at Penn State, used mass spectrometry-based metabolomics to determine the parasite’s response to a variety of antimalarial drugs. .
“In cancer, sapanisertib inhibits a protein kinase called mTOR that regulates a variety of cellular processes, including the immune response and autophagy. However, until this study it was not clear how it would affect the malaria parasite,” said Llinás. “We used a process called metabolic fingerprinting profiling and found that the parasite’s response to sapanisertib resembled the inhibition of other protein kinase inhibitors we had investigated. Through its effects on the metabolism of the parasite’s hemoglobin, a protein that carries oxygen through the blood, we found that sapanisertib primarily inhibits a kinase called PfPI4Kβ, but we also found that it can target a kinase called PKG.”
Kinases have been extensively investigated as therapeutic targets in many diseases due to their importance in cellular function. This makes them attractive for reuse in other diseases, including malaria. Indeed, essential kinase targets for multiple stages of the malaria parasite life cycle have already been identified.
This study opens new avenues for the rational development of antimalarial drugs designed to inhibit two or more protein targets in the malaria parasite. This could also have advantages for patients in a clinical setting, as it is more difficult for the parasite to develop resistance to a drug that kills through multiple mechanisms.
Recognizing the potential safety concerns of using an anticancer drug in the treatment of malaria, the research team is now working to understand the drivers of sapanisertib’s efficacy, the corresponding dose requirements, and the therapeutic window for malaria. . The goal is to compare how the predicted human dose of sapanisertib for malaria differs from the maximum tolerated dose used to treat cancer.
“This work highlights the importance of local and international research partnerships in solving critical human challenges based on mutual interest and responsibility,” Chibale said. “It demonstrates how advances in science and medicine can be made when industry and academia share knowledge and expertise.”
In addition to UCT and Penn State, the research team includes scientists from Columbia University Irving Medical Center; Massachusetts Institute of Technology; Cellzome GmbH, a GSK company in Germany; GlaxoSmithKline’s Tres Cantos Drug Development Campus in Spain; the University of Pretoria in South Africa; the University of the Witwatersrand in South Africa; and the University of California, San Diego.
This work was supported by the National Institute of General Medical Sciences, the Bill and Melinda Gates Foundation, the Global Challenges Research Fund, the South African Medical Research Council, and the South African National Research Foundation.
Science Translational Medicine
Anticancer human mTOR inhibitor sapanisertib potently inhibits multiple Plasmodium kinases and life cycle stages
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