Anticancer drugs have the potential to be used to treat malaria

An anti-cancer drug currently undergoing clinical trials has shown potential
to prevent, treat and prevent malaria transmission.
The groundbreaking discovery, proposed by an international team that includes researchers at Pennsylvania State University, offers new hope
in the fight against AIDS.
AIDS kills more than 500,000 people every year and disproportionately affects children under five, pregnant women and people living with AIDS
.

Manuel Llinás, distinguished professor of biochemistry, molecular biology and chemistry at Penn State, said: "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.
" "Finding new ways to treat this disease is critical
to malaria control.
The ideal treatment would be different from current first-line drugs to circumvent current resistance and target multiple goals or stages of the parasite's life cycle to slow future resistance
.
”

The research team explored whether sapanisertib could be used to treat malaria
.
Sapanisertib is currently undergoing clinical trials to treat a variety of cancers, including breast, endometrial, glioblastoma, renal cell carcinoma, and thyroid cancer
.

They found that sapanisertib has the potential to protect, treat and stop malaria transmission by killing the parasite at several stages of its life cycle in the human host
.
This includes the time the parasite grows and multiplies in the liver; When it is inside the host's erythrocytes, where clinical symptoms can be observed; When
it divides sexually within the host's erythrocytes to produce a transmissible form of the parasite.
This transmissible form is usually carried by female Anopheles mosquitoes when sucking blood and transmitted in subsequent blood sucking, thus infecting another person, so killing this parasite can also prevent subsequent infection
.

The team of scientists also established a mechanism by which sapanisertib kills the human malaria parasite and found that the drug inhibits a variety of proteins
called kinases in the malaria parasite.

The multi-phase activity and antimalarial efficacy of Sapanisertib, combined with strong inhibition of multiple protein targets, including at least two that have been shown to be vulnerable targets for chemotherapy interventions, will provide the basis for further studies evaluating the potential of Sapanisertib for the
treatment of malaria.

Reuse existing drugs

The research team utilized an approach known as "drug repurposing," which aims to find new uses for existing drugs approved by regulators in one disease area for another disease
.
This approach is used to circumvent the challenge of discovering and developing new drugs from scratch, a lengthy and expensive process that often has low
returns in terms of the number of drugs that end up on the market.

"The problem is amplified in neglected tropical diseases such as malaria, where available resources are strained and the financial returns are low," said
Kelly Chibale, founder and director of UCT's Centre for Drug Discovery and Development, Neville Isdell, Chair of the UCT Africa Center for Drug Discovery and Development, and head of the research team 。 "The approach of modifying existing drugs as potential therapies for other diseases shortens the process because, in most cases, the drug candidate (in this case, sapanisertib) will go through several clinical development stages and have well-known human exposure and safety
.
"

While new uses of approved drugs are sometimes stumbled upon in drug reuse methods, strategies
exist to reasonably identify drugs that can be used for other diseases.
In this study, the team developed drugs that work through human-derived protein targets that may work
in similar protein-like targets for malaria parasites.

As part of the Malaria Drug Acceleration Project funded by the Bill & Melinda Gates Foundation, Tarrick Qahash, an undergraduate technician at Penn State's Llinás lab, uses mass spectrometry-based metabolomics to determine the parasite's response
to multiple antimalarial drugs.

"In cancer, sapanisertib inhibits a protein kinase called mTOR, which regulates a variety of cellular processes, including immune responses and autophagy
.
Prior to this study, however, it was unclear how it would affect the malaria parasite
.
Llinás said
.
We used a process called metabolic fingerprinting and found that the parasite's response to sapanisertib was similar
to the inhibition of other protein kinase inhibitors we had studied.
Through its effect on the metabolism of parasite hemoglobin, a protein that carries oxygen in the blood, we determined that sapanisertib mainly inhibits a kinase called pfpikh β, but we also found that it can target kinases
called PKG.
”

Due to the importance of kinase in cellular function, it has been widely studied as a therapeutic target for many diseases
.
This makes them attractive
in treating other diseases, including malaria.
Kinase targets that are critical to multiple stages of the malaria parasite's life cycle have actually been identified
.

potential impact

This research opens up new avenues
for the rational development of malaria drugs aimed at inhibiting two or more protein targets in the malaria parasite.
This is also good for patients in clinical settings, as parasites are more challenging
to develop resistance to drugs that kill through multiple mechanisms.

Recognizing the potential safety concerns of using an anticancer drug to treat malaria, the research team is currently working to understand the drivers of the efficacy of sapanisertib, the corresponding dose requirements, and the window
for malaria treatment.
The aim was to compare the predicted
human dose of sapanisertib for malaria with the maximum tolerated dose used to treat cancer.

"This work highlights the importance of
local and international research partnerships in addressing critical human challenges based on shared interests and responsibilities," Chibale said.
"It shows how advances in science and medicine can be achieved when industry and academic institutions share knowledge and expertise
.
"

In addition to UCT and Penn State, the research team included scientists from Columbia Irvine Medical Center; Mit; Cellzome GmbH, a German company GlaxoSmithKline; GlaxoSmithKline's Tres Cantos Drug Development Park in Spain; University of Pretoria, South Africa; University of the Witwatersrand, South Africa; and the University of California, San
Diego.

This work was supported
by the National Institute of General Medical Sciences, the Bill & Melinda Gates Foundation, the Global Challenges Research Fund, the South African Medical Research Council and the South African National Research Foundation.