Targeting Cancer’s Stem Cells

July 30, 2018 | by Kevin Chesley

Leo David Wang Bio Photo Leo David Wang, M.D., Ph.D.
To stop cancer cells from multiplying, we must first understand how cancer stem cells differ from normal stem cells. The complex process of cell division is being studied at City of Hope by a team of stem cell biologists, cancer researchers, clinicians, nanotechnologists and bioinformaticians. Leo David Wang, M.D., Ph.D., assistant professor in the departments of Immuno-Oncology and Pediatrics at City of Hope, is a key member of this important team.

Stem Cells, Good and Bad

Some stem cells, of course, benefit a patient. Wang’s main challenge is identifying the cancerous ones. “Think of all stem cells as seeds. They grow into whatever tissue they’re seeds for,” he explains. “Cancer stem cells self-renew and grow into only cancer, not normal tissues. They’re the weeds in the garden. You can cut off the tops but if you don’t treat the roots, they just grow back.”
Both solid tumor and systemic cancers are rooted in stem cells. “Cancer stem cells are better characterized in liquid tumors like leukemia, but they exist in all cancers, including multiple solid tumors like breast and lung, colon and brain cancer,” Wang says. “We try to target them all, identifying what makes each one different and what their Achilles' heels are.”

An Ongoing Challenge

Differentiating normal stem cells and cancerous ones is the current goal for Wang. “The biggest question that has dogged the field for years is how to differentiate cancer-causing stem cells from normal ones. Continuing my garden analogy, chemotherapy kills both cancerous and normal cells, like using pesticide on your entire garden, killing normal plants, too. Bone marrow transplants burn the entire field. We need to find a way to specifically kill cancer stem cells and let healthy seeds grow again. There are biomarkers, but we need to devise ways to identify these stem cells diagnostically and treat them therapeutically to take advantage of their unique properties of stemness.”

A Reproducing Danger

The self-renewable nature of cancer cells is one of their most deadly characteristics, according to Wang. “They have an amazing pluripotent — or proliferative — capacity, meaning they can remake themselves,” Wang explains. “The rapidly dividing ones are responsive to chemotherapy, but we also need to kill the stem cells so they do not grow back and cause relapse, which ultimately can be fatal.”

The Hunt for Proteins

Microscopes used to be the best tools at Wang’s disposal, but he’s seen many methods fall away as better ones are devised. “Molecular and flow cytometric techniques are not very effective at identifying stem cells. Most of the functions in cells are executed by proteins. Protein passwords get activated that are responsible for the stemness of cells, their ability to resist chemotherapy and proliferate and self-renew. We’re using mass spectrometry to look at actual protein molecules and their pathways in each cell. The hope is then we can learn to turn the cancerous ones off,” he says.

The Hope for T Cells

A promising new direction for the future involves immunotherapy using CAR T cells. “You can actually train the body to fight cancer. City of Hope is using chimeric antigen receptor T cells that have been genetically engineered to attack cancer cells specifically,” Wang says. “They tend to disappear in solid tumors, probably because they are complex environments with immunosuppressant properties, and cancer is very good at hiding itself, putting the immune system to sleep in its vicinity. We’re working to make CAR T cells last longer and work better. One way to do that is by borrowing from the stem cells, which are very persistent and good at surviving. City of Hope is a very innovative and nimble clinic, so we’re working on this as quickly as possible.”
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