FDA-approved Therapies Show Promise in Eliminating Drug-resistant Cancer Stem Cells

FDA-approved Therapies Show Promise in Eliminating Drug-resistant Cancer Stem Cells

Cancer stem cells, which give rise to all cancer cells within a tumor, were believed to proliferate slowly, which allowed them to survive cancer treatments and create new tumors in a process called recurrence and metastasis.

But researchers have now found that cancer stem cells are among the most energetically activated, migratory, and proliferative cells within tumors, and can be identified by high activity of the telomerase enzyme (hTERT), which is required for indefinite cell proliferation.

These cells could be effectively eliminated using already approved drugs, such as Doryx (doxycycline) or Ibrance (palbociclib), suggesting that these drugs could be used to treat metastatic disease in multiple cancer types.

The study, “Targeting cancer stem cell propagation with palbociclib, a CDK4/6 inhibitor: Telomerase drives tumor cell heterogeneity,” was published in Oncotarget.

Telomerase is a critical enzyme that is involved in a variety of biological processes, including cancer onset, but despite years of study, many of the functions of telomerase are still poorly understood.

Researchers had already found that osteosarcoma cell lines with high telomerase activity behaved more like stem cells, were more migratory and invasive, and showed greater capacity for drug-resistance and metastatic dissemination, than cells with low telomerase activity.

Now, researchers at the University of Salford in England sought to assess whether this was also true for ovarian, lung, and breast cancer cells.

They followed the activity of telomerase using a fluorescent protein in a manner so that cells with high levels of telomerase would appear green in the microscope, and cells with low levels of telomerase would have no fluorescence.

Consistent with prior results, the team found that the green cells were up to 15 times more active than others, having more mitochondria — the cell’s powerhouse — and more energy production. These cells also showed an increased capacity for stem cell activity, creating small colonies of cancer cells, and cell migration.

But given the current view of cancer stem cells, the results were surprising.

“What we had not expected was to find the very rapid rate of proliferation of the cancer stem cells,” Michael Lisanti, professor of translational medicine at the University of Salford, said in a press release. “Clearly, this contradicts the accepted view that stem cells do not proliferate quickly, and offers an alternative view of the process of metastasis, and moreover, a method of identifying, isolating and potentially killing tumor-forming cells.”

The researchers then proceeded to find ways of inhibiting these enhanced migratory and proliferative behaviors. They found that the FDA-approved drugs Doryx (doxycycline), which impairs mitochondria formation, and Ibrance (palbociclib), a CDK4/6 inhibitor that halts cell proliferation, could block the propagation and migration of these cancer stem cells.

“The use of these FDA-approved drugs may provide a mechanism for treating metastatic disease on a larger scale and certainly opens the way for new Phase II clinical trials in multiple cancer types,” Lisanti said.

“We can now begin to think of cancer stem cells as being at the heart of tumor regrowth and turn our efforts away from ‘bulk cancer cells’, which don’t really drive tumor recurrence and metastasis,” said Dr. Federica Sotgia, reader of translational medicine at the University of Salford.

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