Over the last years, survival rates for breast cancer patients have increased significantly. Improved treatments, increased awareness towards the disease, more advanced screening procedures, all these factors have led to more women being diagnosed at an earlier stage, and overall better outcomes.
Unfortunately, the risk of metastasis remains considerable and is associated with poor prognosis. The American Cancer Society estimates that patients whose tumors have spread to secondary areas only have about 22% chance of going past the initial five years. However, breaking research in one patient completely removed all tumors using this new approach.
Dr. Cyrus Ghajar from the Fred Hutchinson Cancer Research Center in Seattle took up the challenge to find ways of addressing this issue, and after years of research, has presented his work during the 3rd annual Northwest Metastatic Breast Cancer Conference.
“It’s always been assumed that dormant cells cannot be killed by any kind of chemotherapy because they’re not dividing”, explained Dr. Ghajar. “But what we’re showing is that’s not true. They’re relying on survival signaling in their microenvironment, in this case specifically from blood vessels within the bone marrow. And if you can take away that signaling, you can sensitize them to chemotherapy”.
In order to reach other locations, cancer relies on disseminated tumor cells (DTC). Before a tumor has even formed, these can begin travel to distant sites in the body where they lie dormant. A common place to hide is the bone marrow. “Tumor cells in the bone marrow predict metastasis in a variety of different sites. They even predict metastasis in cancers that never get bone mets”, he noted.
In their laboratory tests, investigators noticed that the microenvironment was more important than the cell cycle state in terms of the response to chemotherapy. The tumor cells that were nestled close to the microvasculature, the tiny blood vessels of the bone marrow, were able to survive cytotoxic treatment.
“The main thing that was being enriched when blood vessels were present — as opposed to when they weren’t present — were molecules that bind integrins”.
Integrins are proteins that help cell signaling: they integrate signals from the outside of the cell with the inside of the cell. Two inhibitors were able to disrupt the blood vessels’ protective signaling.
“When we interrupted signaling from those two integrins, we started sensitizing cells to chemotherapy”, Ghajar said. “Chemo on its own would kill one-third of all the single cells in our culture. But when we combined integrin inhibition and chemotherapy, we killed over 90 percent of the single cells in our cultures”.
Further experiments confirmed their initial findings. A combo of chemotherapy and integrin blockers was able to prevent relapse in approximately 80% of mouse models.
The team is hoping to move into clinical trials in the near future, knowing that this approach could help save countless lives.
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