Aaron Schimmer
Dr. Aaron Schimmer, Research Director at Princess Margaret Cancer Centre, has established a highly collaborative translational research program focused on developing innovative therapeutic strategies to target leukemia and leukemia stem cells. (Photo: UHN StRIDe Team)

A study by researchers at Princess Margaret Cancer Centre and The University of Texas MD Anderson Center has shown how a new molecular target in cancer cells can selectively kill them, while leaving normal cells unscathed in blood cancers such as leukemias and lymphomas.

Using genetic and chemical approaches, the researchers showed that hyperactivating a specific enzyme called ClpP in the mitochondria, or powerhouse of the cell, disrupts its structure and function in tumours, leading to cancer cell death. Normal cells, however, are not affected by ClpP activation.

The researchers also demonstrated that imipridones, a new class of clinically-available compounds, activated the enzyme in both cell culture and in pre-clinical models, killing tumours in both.

Several clinical trials of these compounds are ongoing, showing promising clinical activity in both solid tumors and blood cancers.

The study led by Drs. Aaron Schimmer and Sara Zarabi from the Princess Margaret, and Drs. Jo ishizawa and Michael Andreeff from MD Anderson, was published in the online edition of Cancer Cell.

Activating ClpP and attacking the metabolism of a tumour cell is a new way of combatting cancer, explains Dr. Schimmer, and could prove to be beneficial in those cancers that are resistant to other approaches.

"A hyperactive ClpP enzyme in overdrive gobbles up proteins in a cancer cell, destroying its energy sources in the mitochondria so that it can't survive," Dr. Schimmer says.

Need to discover anti-tumour agents with unique mechanisms of action

This approach identifies an "Achilles heel" in a cancer cell and then targets it specifically – which is different than targeting more generic vulnerabilities such as damaging DNA with standard chemotherapy.

Using crystallography, the researchers were able to determine the exact 3D binding patterns of the compounds on ClpP and showed how they increased its activity and eventual cell dysfunction and destruction.

Many blood cancers, such as leukemia, myeloma and lymphoma, may be treated with chemotherapy, which works by damaging the DNA in a cell, says Dr. Schimmer, adding that chemotherapy can cause major damage to cancer cells, as well as to some normal ones, leading to treatment side effects.

Some cancers can eventually "outwit" chemotherapy and survive, he adds, which is why some cancers can come back even after treatment.

This is why we need to discover anti-tumour agents with unique mechanisms of action, emphasizes Dr. Schimmer, because we need to prevent relapse of these diseases.

In previous work, the researchers demonstrated that ClpP is overexpressed – produced in overly large amounts – in almost half of acute myeloid leukemia patient samples.

The authors suggest that levels of the enzyme could be useful as biomarkers for select patients to see who responds best to therapy.

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