A team of researchers from the Cancer Science Institute of Singapore (CSI Singapore) on the National University of Singapore, led by Associate Professor Takaomi Sanda and Dr Lim Fang Qi, has breathed latest life into an existing drug—combatting a variety of blood cancer called T-cell acute lymphoblastic leukemia, or T-ALL.

The drug, called PIK-75, was initially discovered over a decade ago but was dismissed in favour of newer ones. Now, it has made a comeback that deems it unmissable — the researchers established that the drug could block not only one but two crucial cancer-causing pathways of T-ALL, enabling them to develop latest treatments that would effectively stem the disease.

Predominantly afflicting children, T-ALL is aggressive and progresses rapidly, affecting stem cells within the bone marrow that produce T-cells, which help maintain a person’s ability to fight off infection. The condition ends 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’ve previously recovered from pediatric T-ALL suffer from relapse, and in some cases even fail to answer first-line therapy.

Killing two birds with one stone

Current cancer treatment strategies mostly give attention to targeting a single molecule specific to the disease, like an oncoprotein. We learned that the flexibility of cancer cells to survive and proliferate is underpinned and promoted by multiple mechanisms, of which identifying and inhibiting only one is commonly not sufficient to slow the march of the disease.”

Assoc Prof Takaomi Sanda, lead writer of the study

With that in mind, the team uncovered the relevant underlying pathways, in order that medical interventions will be deployed to destroy all of the potential routes the disease can take because 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 primary example of the previous is the overexpression of the TAL1 oncogenic transcription factor — powerful 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 characterised by the activation of an abnormal signalling pathway reminiscent of PI3K-AKT-PTEN pathway — a series of reactions by which a bunch of proteins in a cell team up to manage 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.

Of their study, the researchers performed a drug screening to hunt for potential candidates that would treat T-ALL. Amongst roughly 3,000 compounds, PIK-75 stood out for exhibiting the flexibility to dam TAL1 transcription factor activity in addition to the PI3K-AKT-PTEN signalling 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 left in oblivion as newer drugs come to the fore.

“Specializing in an ‘oncogenic collaboration’ mechanism, we demonstrated the efficacy of the novel therapeutic compound in inhibiting the core oncogenic machinery — which incorporates each type A and kind B abnormalities — that drives T-ALL progression,” explained Assoc Prof Sanda. “PIK-75 produced a powerful cytotoxicity against T-ALL cells at low doses in comparison with previous studies involving other forms of drugs that required higher concentrations to inhibit their growth.”

The team’s efforts are a notable contribution to NUS’ pursuit of research breakthroughs in biomedical science and translational medicine. Their findings were published within the scientific journal Haematologica on 8 September 2022.

Waiting for simpler treatments

Because the dual-inhibition mechanism of the novel drug is extremely feasible in a clinical setting, the researchers are actually trying to develop a soluble analogue of the drug, which is currently in an insoluble form, in order that it may well eventually be administered to patients.

“We’re delving deeper into the pathogenesis of cancers to uncover more life-saving insights,” said Dr Lim. “We also plan to unearth more novel drugs that may efficiently inhibit the first oncogenic mechanisms of T-ALL.”

Source:

National University of Singapore