Scientists Identify Potential New Target For Breast Cancer Therapy

The American Society of Clinical Oncology (ASCO) has selected new breast cancer research conducted at the Barbara Ann Karmanos Cancer Institute in Detroit for posting on ASCO's Web site. Karmanos' potentially ground-breaking findings identify a promising new therapeutic target for aggressive hormone receptor negative breast cancer tumors.

The research appears at www.ASCO.org and www.jco.org and is entitled "Enhancer of Zeste Homologue 2 (EZH-2) expression in breast cancer: a novel marker and potential target."

Karmanos scientists tested 84 cases of hormone receptor negative human breast carcinomas and discovered that the protein EZH-2 was expressed in 74 percent of those cases. Hormone receptor negative breast carcinoma is considered an aggressive cancer and one that is hard to treat. The finding suggests that EZH-2 could be an important therapeutic target in this patient population.

"We were interested in looking at a new target," says Dr. Zeina Nahleh, M.D., co-director of the Breast Oncology Multidisciplinary Team at Karmanos Cancer Institute and assistant professor of medicine in hematology and oncology at Wayne State University School of Medicine. "We wanted to see how much expression of the protein was present. We were surprised that 74 percent of tumors expressed that EZH-2 protein."

Sixty-one samples that researchers used were triple negative breast cancer cases and 23 cases were HER-2/neu positive. Scientists found that the increased expression of EZH-2 meant an increase in tumor size and an increase in lymph node metastasis.

Dr. Nahleh says that increased identification of proteins in these aggressive forms of breast cancer is needed to develop better treatments. The discovery of the high rate of EZH-2 protein expression in breast cancer cases opens up a new avenue in doing just that.

"We are extremely excited about this discovery," she says. "This is amazing work. In the future, this could be a target for therapy."

The identification of EZH-2 represents just the first step in the mission to find more proteins that cause deadly breast cancer tumors and assess them for possible therapeutic targets. There is much work ahead, according to Dr. Nahleh.

"The ground-breaking work will come if we can identify a specific method to target this EZH-2 protein and show that this approach would lead to meaningful clinical results," she says. "We have to go back and look at survival rates. We have to consider years of follow-up work and we have to look at other associated factors.

"This will hopefully lead to new targeted therapy strategies based on our new understanding of the biology of cancer."

Dr. Nahleh says that the discovery of a potential therapeutic target wouldn't be possible without the laboratory and clinical breast cancer research at Karmanos and its collaborative partnerships.

"I think this discovery highlights the importance of multidisciplinary work in oncology between clinical and scientific researchers," she says. "This is what Karmanos is all about."

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Is Smaller Better? Minimally Invasive Oncologic Surgery Options Discussed

Cutting-edge surgery with less cutting is appealing for many, but how do minimally invasive surgical offerings rate in terms of outcomes for people with cancer? At the National Comprehensive Cancer Network's (NCCN) 14th Annual Conference, Dr. Thomas D'Amico, MD, of Duke Comprehensive Cancer Center discussed the pros and the cons of minimally invasive oncologic surgery alternatives.

D'Amico acknowledges the tremendous technological advances that have resulted in minimally invasive offerings, but emphasized three guidelines that physicians need to be aware of when presenting the option to patients; the minimally invasive option must be oncologically equivalent or superior to the open procedure, the procedure should offer quality of life outcome advantages, and cost effectiveness needs to be considered, according to a statement from the NCCN, a not-for-profit alliance of 21 of the world's leading cancer centers.

Five minimally invasive procedures for oncologic surgery including robotic prostatectomy, laparoscopic colectomy, laparoscopic adrenalectory, minimally invasive esophagectomy, and thoracoscopic lobectomy were presented by D'Amico. In each procedure, he provided a comparison of the minimally invasive option versus the traditional open approach to surgery noting operating time, cost, recovery rates, length of stay, and oncologic outcomes.

Overall, the benefits to the minimally invasive options were a shorter hospital stay, faster recovery, and less pain. However, except for the thoracoscopic lobectomy, there is no data from randomized controlled clinical trials on minimally invasive options to provide any insight into oncologic outcomes or survival rates.

"The lack of evidence-based data for the majority of minimally invasive surgical options is one of the current shortcomings in the field," says D'Amico.

Another cause of debate includes the training and credentialing of physicians who perform minimally invasive procedures. D'Amico says that the learning curve for physicians being trained needs to be addressed. Lastly, D'Amico touched upon the controversy of using minimally invasive surgery as a marketing tool particularly in the field of robotics, which can lend itself to eye-catching publicity.

The future of minimally invasive surgery will likely see an expanded use of robotics as well as an increased interest in a new technique called natural orifice surgery. D'Amico explains that natural orifice surgery is when surgeons conduct surgery through the natural orifices in the body such as the mouth, nose, or rectum. Since there are no incisions made on the body, the benefits are a reduced risk of infection and a quicker recovery, says D'Amico.

In conclusion, D'Amico emphasizes that improved outcomes should drive the utilization of minimally invasive procedures and that oncologic principles must be preserved.

"There is continued progress of minimally invasive oncology surgery," says D'Amico, "but also the need for further evolution to optimize morbidity and oncologic outcomes. The question we need to ask ourselves is not 'what can be done', but 'what should be done'."

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Study Finds Treatment With New Drug Might Make Tumor Cells More Sensitive to Therapy

Scientists at St. Jude Children's Research Hospital have shown that it might be possible to
make tumor cells more sensitive to irradiation and some types of chemotherapy by treating them with a drug that cripples their ability to repair DNA damage caused by these therapies.

The St. Jude researchers demonstrated in the laboratory that a molecule called CP466722 rapidly blocks the ATM protein's ability to orchestrate a series of biochemical events that culminate in the repair of DNA damaged by irradiation. The molecule exerted its effect in small quantities, and its effects rapidly ended after it was removed from cells, suggesting that such
a treatment in humans would not have significant or long-term side effects, the researchers say.

Results of the study were published in the Sept. 15 issue of the journal Cancer Research.

ATM plays a critical role in repairing a type of DNA damage called double-strand breaks, in which each of the two strands making up this molecule are cut, according to Dr. Michael Kastan, M.D., director of the St. Jude Comprehensive Cancer Center. This process protects cells from the potentially lethal or mutation-causing effects of free oxygen radicals and irradiation--both of which routinely threaten them, he added. Kastan is senior author of the report on these findings.
Children lacking the gene for ATM develop ataxia-teleangiectasia, a disease that causes several debilitating problems, such as neurodegeneration, cancer and sensitivity to irradiation that leads to irreparable, double-stranded DNA breaks.

"We found that inhibition of ATM activity with CP466722 produces cellular effects that are identical to those seen in cells that lack ATM," Kastan says. "It's as if we temporarily turned normal cells into cells indistinguishable from those of children with ataxia-teleangiectasia."

The protective role of ATM makes it a tempting target for researchers looking for a way to prevent cancer cells from repairing DNA damage caused by therapeutic irradiation, Kastan notes.

Previously Kastan's team found how ATM is activated by a signal from damaged DNA only seconds after the damage occurs. The activated ATM, in turn, activates other proteins by attaching a molecule called phosphate to them in a process called phosphorylation. This sets off a cascade of biochemical reactions that amplifies the initial ATM response leading to
repair of the double-stranded break.

"Our ability to rapidly and reversibly regulate ATM activity with CP466722 also gives us a new tool to study the function of this protein, which plays such a critical role in the ability of both normal and cancerous cells to repair their DNA," says Michael Rainey, a postdoctoral fellow in the St. Jude Department of Oncology. "This approach will help us learn more about the repair events triggered by ATM in response to DNA damage." Rainey is the report's first author.

Kastan also says that CP466722 provides his team with a basic chemical structure that they can build upon as they try to modify the molecule to enhance its potency and specificity and move studies from isolated cells to mouse models.

"Results of those mouse model studies would help us to determine if and how to proceed with studies in patients with cancer," Kastan says.

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