A team of researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore, has revisited an existing drug to combat a type of blood cancer called T-cell acute lymphoblastic leukemia, or T-ALL.
The research was led by Takaomi Sanda and Lim Fang Qi.
The drug, PIK-75, was initially discovered more than a decade ago but was dismissed in favor of newer ones. Now, it has made a comeback. The researchers established that the drug could block not just one but two crucial cancer-causing pathways of T-ALL, enabling them to develop new treatments that could effectively stem the disease.
Predominantly afflicting children, T-ALL is aggressive and progresses rapidly, affecting stem cells in the bone marrow that produce T-cells, which help maintain an individual’s ability to fight off infection. The condition results in the formation of immature, or ill-developed, T-cells that accumulate and overwhelm their normal counterparts, thereby compromising the patient’s immunity. Many patients who have previously recovered from pediatric T-ALL suffer from relapse, and in some cases even fail to respond to first-line therapy.
Finding pathways
“Current cancer treatment strategies mostly focus on targeting a single molecule specific to the disease, like an oncoprotein,” said Sanda, lead author of the study.
“We learned that the ability of cancer cells to survive and proliferate is underpinned and promoted by multiple mechanisms, of which identifying and inhibiting just one is often not sufficient to slow the march of the disease.”
The team then uncovered the relevant underlying pathways, so that medical interventions can be deployed to destroy all the potential routes the disease can take as it attempts to spread throughout the patient’s body.
In T-ALL, the mechanisms that drive the disease progression are differentiated into type A and type B abnormalities. A prime example of the former is the overexpression of the TAL1 oncogenic transcription factor — proteins that sustain the multiplication of cancer cells and are prevalent in nearly half of all human T-ALL cases. In contrast, type B is characterized by the activation of an abnormal signaling pathway such as PI3K-AKT-PTEN pathway — a series of reactions in which a group of proteins in a cell team up to control the function of the cell, ultimately promoting the emergence of cancer cells. Together, these two mechanisms work together to support the proliferation of malignant T-ALL cells in patients.
Drug screening
In their study, the researchers performed a drug screening to hunt for potential candidates that could treat T-ALL. Among roughly 3,000 compounds, PIK-75 stood out for exhibiting the ability to block TAL1 transcription factor activity as well as the PI3K-AKT-PTEN signaling pathway, thereby greatly reducing the survivability of T-ALL cells.
To the researchers’ surprise, PIK-75 had originally been touted as an inhibitor of the PI3K-AKT-PTEN pathway 15 years ago but has since been set aside for newer drugs.
“Focusing on an ‘oncogenic collaboration’ mechanism, we demonstrated the efficacy of the novel therapeutic compound in inhibiting the core oncogenic machinery — which includes both type A and type B abnormalities — that drives T-ALL progression,” Sanda noted.
“PIK-75 produced a strong cytotoxicity against T-ALL cells at low doses compared to previous studies involving other types of drugs that required higher concentrations to inhibit their growth.”
The team’s findings were published in the scientific journal Haematologica.
Looking ahead to more effective treatments for T-ALL
As the dual-inhibition mechanism of the novel drug is highly feasible in a clinical setting, the researchers are now looking to develop a soluble analogue of the drug, which is currently in an insoluble form, so that it can eventually be administered to patients.
“We are delving deeper into the pathogenesis of cancers to uncover more life-saving insights,” said Lim.
“We also plan to unearth more novel drugs that can efficiently inhibit the primary oncogenic mechanisms of T-ALL.”
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