Trial targeting stem cells in advanced breast ca begins

ABSTRACT: The stem cell hypothesis is being clinically tested in advanced breast cancer in a trial combining an agent, MK-0752, that targets a stem cell pathway with docetaxel as second-line therapy.

CHICAGO-The first clinical trial targeting stem cells in breast cancer is underway with the potential to revolutionize therapeutic targets, according to one of the pioneers in stem cell research.

The stem cell hypothesis suggests that stem cells drive tumor invasion and metastases. “Cytotoxic chemotherapies have not been very effective for patients
with advanced cancer,” Max Wicha, MD, told ONI. “I think the stem cell model is a potential explanation for why we haven’t done better in treating cancer.”

Dr. Wicha, director, University of Michigan Comprehensive Cancer Center, said that the phase I/II trial is evaluating combining a stem cell pathway inhibitor (MK-0752) with docetaxel (Taxotere) in women with advanced breast cancer that did not respond to first-line anthracycline-based chemotherapy.

Principal investigators for the study are Anne Schott, MD, of the University of Michigan Cancer Center; Jenny Chang, MD; of Baylor College of Medicine, Houston; and Ian Krop, MD, PhD, of the Dana-Farber Cancer Institute.

MK-0752, under development by Merck, is a synthetic small molecule that inhibits the Notch signaling pathway.

During a special session at ASCO 2008, Dr. Wicha offered an overview of the stem cell hypothesis. He also served as co-editor of the June 10, 2008, Journal of Clinical Oncology supplement on stem cell research.

“The key to early transformation of normal cells to cancer cells is the process of self-renewal. Only cells that can self-renew, or that regain self-renewal properties, initiate carcinogenesis. These cells are essentially immortal,” he said. “Cancers are driven by a small subcomponent of cells that retain the properties of stem cells.”

But current treatment regimens don’t specifically address self-regenerating stem cells. “The evidence is accumulating that cancer stem cells are inherently quite resistant to chemotherapy and radiation therapy,” Dr. Wicha said. He noted, however, evidence suggesting that lapatinib (Tykerb) may succeed in advanced metastatic breast cancer in part because it directly affects stem cell function.

One of the keys to advancing this research was the discovery of a stem cell marker, aldehyde dehydrogenase (ALDH). This enzyme plays a functional role in stem cell differentiation and is strongly correlated with HER2 amplifications.

“There’s a very simple assay called the Aldefluor assay, which allows us to separate cells with ALDH activity,” he stated. “There’s also an antibody that allows us to find this in situ in cells.”

The expression of any ALDH-positive cells has been shown to be highly predictive of patient survival, he said.

Two challenges

Dr. Wicha cited two challenges moving forward: “First, can we develop treatments that can kill

cancer stem cells but not normal stem cells? Some of the side effects of these therapies may be from effects on normal stem cells. Second, how are we going to design clinical trials to evaluate the effectiveness of stem cell therapy?”

Tumor regression is an inadequate endpoint for cancer stem cell studies. Other possible approaches include measuring cancer stem cells before and after treatment, or identifying circulating cancer cells in the blood as stem cells and then using them as surrogate endpoints.

“Over the next few years, I predict there will be at least a dozen trials of stem cells,” Dr. Wicha said. “I think the technology to detect circulating cancer stem cells will be developed. This therapy will be rigorously tested so we’ll know pretty soon how effective cancer stem cell therapy is going to be.”