Cancer drug could possibly be used against malaria

A cancer drug currently in clinical trials has shown the potential to protect against, cure and prevent malaria transmission. The groundbreaking discovery by an international team that includes Penn State researchers offers new hope against a disease that kills more than half a million people annually and most severely affects children under five, pregnant women and those living with HIV.

The research team, led by researchers from the University of Cape Town (UCT), published their findings in a new article appearing in the journal on October 19 Science Translational Medicine.

“Disruptions in malaria vaccination, 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 malaria cases and deaths worldwide,” said Manuel Llinás , Distinguished Professor of Biochemistry and Molecular Biology and Chemistry at Penn State.

“Identifying new ways to treat the disease is critical to malaria control. Ideal treatments would act differently than current frontline drugs to circumvent current drug resistance and act on multiple targets or stages of the parasite’s life cycle to slow future resistance.”

The research team investigated whether sapanisertib, a drug currently in clinical trials to treat various 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 multiple stages of its life cycle in its human host. This includes when the parasite is in the liver, where it first grows and multiplies; when it is in the host’s red blood cells, where 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 typically ingested by the female Anopheles mosquito during a blood meal and passed on during subsequent blood meals to infect another person, so killing the parasite should also prevent subsequent infections.

The researchers also determined the mechanism by which sapanisertib kills the human malaria parasite and found that the drug inhibits several proteins called kinases in the malaria parasite.

Sapansertib’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 underpin further research to explore the potential of reusing sapanisertib to treat assess malaria.

Repurposing existing drugs

The research team used 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 challenges in discovering and developing a new drug from scratch, which is a lengthy and expensive process that often has low returns in terms of the number of drugs that eventually make it to market, connected is.

“The problem is compounded in neglected and tropical diseases like malaria, where resources are scarce and financial returns are low,” said Kelly Chibale, founder and director of the UCT Drug Discovery and Development Centre, Neville Isdell Chair in African-centric Drug Discovery and development at UCT and leader of the research team. “The drug repurposing approach, which explores existing drugs as potential therapies for other diseases, shortens the process because the candidates, in this case sapanisertib, have in most cases passed through multiple stages of clinical development and have known exposure and exposure parameters People will have security profiles.”

While new uses for approved drugs have sometimes been found by accident as part of the drug reuse approach, there are strategies to rationally identify drugs that can be used for other diseases. In this study, the team used drugs that act through target proteins of human origin that may be active on similar protein targets in the malaria parasite.

As part of the Malaria Drug Accelerator project, Tarrick Qahash, a 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, which regulates a variety of cellular processes, including immune response and autophagy. However, until this study, it was unclear how it would affect the malaria parasite,” said Llinás.

“We used a process called metabolic fingerprint profiling and found that the parasite’s response to sapanisertib was similar to inhibition by other protein kinase inhibitors that we had studied. Through its effects on the parasite’s metabolism of 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 studied as therapeutic targets in many diseases because of their importance in cell function. This makes them attractive for reuse in other diseases, including malaria. Indeed, kinase targets essential to several stages of the life cycle of malaria parasites have already been identified.

Possible effects

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 benefits 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.

The research team recognizes the potential safety concerns of using an anticancer drug to treat malaria and is now working to understand the drivers of sapanisertib’s efficacy, the corresponding dose requirements and the therapeutic window for malaria. The aim is to compare how the predicted human dose of sapanisertib for malaria differs from the maximum tolerated dose used to treat cancer.

“This work underscores the importance of local and international research partnerships to solve critical human challenges based on mutual interests and responsibilities,” said Chibale. “It shows how advances in science and medicine can be achieved when industry and academic institutions share knowledge and expertise.”