Pancreatic cancer remains a very tough-to-treat disease, but new therapeutic front-line and second-line combinations are, nonetheless, improving patient overall survival times.
However, more effective regimens are needed, and different novel agent combinations are continually being tested in clinical trials. One new avenue of research is focused on targeting the cancer stem cell pathway.
“The thought behind this approach is that we hope we may be able to reverse or control cancer, in this case pancreatic cancer, from resisting chemotherapy, which we know is one of the biggest issues doctors and their patients face,” explains Dr. Tanios Bekaii-Saab, co-leader of the Gastrointestinal Cancer Program at the Mayo Clinic in Phoenix, Arizona, and lead researcher of a stem cell pathway inhibitor called napabucasin (BBI-608).
This drug is being investigated in several trials including those for colorectal cancer as well as pancreatic cancer. In 2016, the U.S. Food and Drug Administration granted Orphan Drug Designation for napabucasin in gastric, gastroesophageal, and pancreatic cancer. “So far the early results are promising, and it is exciting because we are looking at the problem in a brand new way,” says Bekaii-Saab.
“Stemness” Versus Stem Cell
Many people are familiar with the term “stem cell.” These cells are basically divided into two types: embryonic stem cells, which exist only at the earliest stages of development, and various types of tissue-specific or adult stem cells that appear during fetal development and remain in our bodies throughout life. Stem cells are unique because these cells can regenerate, or self-renew. When it comes to cancer, stem cells also seem to play a role. And the hypothesis is rather complicated.
Simply, not all tumor cells are equal, explains Bekaii-Saab. The biggest portion of a tumor is made up of cells that are proliferative or differentiated, with both types being short-lived, he says.
But some tumor cells seem to have the same characteristics of tissue stem cells. And unlike normal stem cells that help maintain organ health by continually producing new healthy cells, these cancer stem cells boost tumor growth, metastasis, and resistance to therapy. Researchers have recently understood that even cancer cells that are not stem cells or have stem-like features can even revert back to a stem-like state, making them tough to treat, he adds.
These cells generally represent just one to three percent of all cells in a tumor, but they are the only cells with the ability to regenerate malignant cells and fuel the growth of the cancer, he says. As cancer grows and spreads, these cells will become the predominant component. And even if a patient is a surgical candidate, some cells that remain after surgery and lead to a recurrence are cancer stem cells.
Previously, there was no way to target those cells. But due to research advances it is possible today. And the thought is that targeting these cancer stem cells or inhibiting the molecular pathways they need to thrive could boost the benefits of chemotherapy for pancreatic cancer patients and other patients with various types of cancer.
“Stemness is a tough concept, but basically many people describe it as trying to think of cancer as a weed that you’re trying to get rid of in your lawn,” saw Bekaii-Saab. “The stem cells are the roots. So if you get rid of the leaves of the weed, but not the root, the weed is going to return with a vengeance.”
A Strong Signal
Napabucasin (BBI-608) blocks cancer stem cell self-renewal and induces cell death in cancer stem cells and non-stem cancer cells by inhibiting the STAT3 and beta-catenin pathways, both of which play a role in the malignant growth and spread of cancer, says Bekaii-Saab.
So far, early studies are promising and those results have led to a much larger ongoing phase III study that will assess the efficacy of napabucasin plus weekly nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine alone in patients with pancreatic cancer who have not received prior systemic anti-cancer treatment.
“What we have with early results is a very promising signal, a reason to move forward with a larger trial,” says Bekaii-Saab, adding the regimen is also very safe. “We have an opportunity to actually improve an established regimen, and that’s always a reason to move forward, also. I do think this combination might be able to change the standard of care, if the study results are as promising as earlier work.”