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Common drug class targets breast cancer stem cells, may benefit more patients, says study

ab18038.jpg  Woman having a mammogramRecently there have been intriguing suggestions that breast cancer patients whose tumors appear insensitive to a class of drug known as anti-HER2 (the drug trastuzumab, marketed as Herceptin, is a well-known example) may somehow still benefit from treatment with the medication. Although there's an ongoing clinical trial to determine if trastuzumab, given in combination with other treatments, really is beneficial to more patients than previously thought, the reason why it could be helpful is unknown.

Now research from the laboratory of Stanford radiation oncologist Max Diehn, MD, PhD, has started to answer some of these questions. The research was published recently in Cancer Research.

Typically, only tumors in which the cells express abnormally high levels of a receptor molecule on their surface called HER-2 -- about 25 percent of all breast cancer cases -- seem to shrink in the presence of the drugs, which bind to and inactivate the receptor. As a result, only these patients are given anti-HER2 agents. As Diehn explained in an e-mail:

Trials of anti-HER-2 agents like Herceptin in metastatic patients with HER-2 negative tumors haven't shown tumor shrinkage or improved outcomes, which is why these drugs are only approved for use in HER-2 positive tumors. However, more recent clinical analyses have indicated that patients with microscopic disease remaining after treatment for earlier stage disease may see improved survival from anti-HER-2 agents regardless of their HER-2 status.

Diehn and Cleo Yi-Fang Lee, PhD, wondered why this could be. How could trastuzumab and other anti-HER-2 agents effectively fight tumors that didn't overexpress HER-2? They hypothesized that perhaps the drugs were targeting only a few very important cells in the tumor: the cancer stem cells. Also called tumor initiating cells, or TICs, cancer stem cells are able both to renew themselves and to generate all the cells of the original tumor. Killing them is vital to ensure that a tumor does not recur after seemingly successful treatment with chemotherapy, radiation or surgery. Unfortunately, however, these cancer stem cells are uncommonly resistant to normal cancer therapies. According to Diehn:

Our hypothesis was that the clinical observations described above could be explained if the anti-HER2 drugs work against microscopic deposits of cancer stem cells in at least a subset of HER2-negative tumors. Patients with visible metastatic disease do not show responses since only a small proportion of cells in tumor deposits are cancer stem cells. However, if most of the tumor has been killed or removed through standard approaches, anti-HER-2 drugs may effectively target remaining cancer stem cells and possibly prevent recurrence.

To understand how this could occur, Diehn, Lee and their colleagues studied mouse and human breast cancer cells. They learned that, in a subset of HER-2-low tumors, the stem cells produce high levels of a molecule called neuregulin 1. Neuregulin 1 works by activating HER-2 in these cancer stem cells to promote their growth and self-renewal. Blocking HER-2 or another molecule in the pathway, EGFR, together or separately inhibited the growth of breast cancer cells grown in the laboratory and after transplantation into mice. It also made the stem cells more sensitive to the types of radiation used in cancer therapies.

The researchers hypothesize that a similar mechanism may exist in other types of cancers. Diehn said:

Anti-HER2 therapies are already being used for esophageal and gastric cancers and they have been explored for use in other cancers like those of the head and neck. It will be interesting to see if there is a similar dependence by cancer stem cells on HER2 signaling in the absence of HER2 amplification in some of these tumors.

Previously: Weakness in lung cancer stem cells identified by Stanford scientists and Red Sunshine: One doctor's journey surviving stage 3 breast cancer
Photo by Tips Times

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