News Reports; March 2007

186-Gene Signature in Cancer Stem Cells Predicts Recurrence

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tanford University School of Medicine researchers found 186 genes that together can predict the risk of recurrence in breast cancer patients. These genes identified in cancer stem cells found inside a tumor also predict the recurrence of prostate cancer, lung cancer and medulloblastoma.

“These data suggest that there are some fundamental properties of the malignancy that are shared between many types of tumors,” explained Michael Clarke, MD, the Karel H. and Avice N. Beekhuis professor in cancer biology. Dr. Clarke is also the lead author of the study, which is published in the January 18 issue of the New England Journal of Medicine.

Dr. Clarke also found that coupling this 186-gene signature with a second group of genes implicated in normal cells surrounding the tumor, called stromal cells, one can predict aggressive cancers with an even greater accuracy. Patrick Brown, PhD, professor of biochemistry, previously discovered these genes. Dr. Clarke said the finding shows that malignancy is the result of an interaction between the cancer cells in the tumor and the environment, as many researchers had previously surmised.

Dr. Clarke and his team identified the genetic pattern in breast cancer stem cells taken from tumors and verified the results in a standard tumor biopsy containing a range of cell types. That same biopsy can also remove the stromal cells that are needed for the second genetic profile.

“This paper demonstrates, for the first time, the clinical value of isolating pure human cancer stem cells,” pointed out Irving Weissman, MD, director of the Stanford Institute for Stem Cell Biology and Medicine, who was not involved in the study. “Mike Clarke and his colleagues have now shown that the human breast cancer stem cell reveals information not evident when the whole tumor is analyzed. We plan to incorporate these findings in our approaches to the care of cancer patients, starting here at Stanford.”

Dr. Clarke has begun working with surgeons on tools to assess the best treatment for each patient. For example, he hopes that within five years, if a patient’s genetic profile implies that her tumor is unlikely to return, a surgeon will be able to leave more breast tissue intact.

Over time, Dr. Clarke said, researchers will likely be able to refine the list of genes needed to most accurately determine a patient’s risk of recurrence. Such a shorter list of genes could make a genetic profiling test more cost-effective for widespread use.

Clarke found the first cancer stem cell in a solid tumor in 2003 while at the University of Michigan. Previously, researchers thought these cells were restricted to blood cancers. Since then, other researchers have found them in brain, prostate as well as head and neck cancers.

Other Stanford researchers who contributed to this study include Piero Dalerba, MD, postdoctoral scholar, and Gavin Sherlock, PhD, assistant professor of genetics. This work was supported by grants from the National Cancer Institute, the Breast Cancer Research Foundation and the Virginia and D.K. Ludwig Foundation.

—Querida Anderson

National Prostate Cancer Coalition Commences Clinical Trial Education Program

The National Prostate Cancer Coalition (NPCC) launched a program to educate men with prostate cancer about the possibility of entering relevant clinical trials. “We’re conducting our “Get in the G.A.M.E. -Get All Men Educated” initiative because a recent survey of prostate cancer patients shows that only a very small percentage of patients—about 12 percent of men with prostate cancer—know that clinical trials are an option,” explained Richard N. Atkins, MD, NPCC CEO.

The program supports the notion that prostate cancer clinical trials are not only integral to the drug discovery and development process but also provide access to potential new therapies. “Clinical trials examine the safety and benefit of experimental drugs to find new treatments for prostate cancer aimed at extending and improving quality of lifeand ultimately a cure,” adds Dr. Atkins. “It’s important for men to ask their urologist or oncologist about trials that may be helpful.”

In particular, discussing with one’s doctor about clinical trials is important for men with recurrent disease who are at risk for or already suffering from bone metastases, according to the NPCC. “Being informed of clinical trials is particularly important for men with recurring prostate cancer for whom fewer approved therapies exist,” said Atkins. “In fact, certain cancers are more likely to spread to the bone than others and prostate cancer is one of them.”

The NPCC initiatives comes after the FDA, in June 2006, announced a series of new policy and regulatory developments—The Human Subject Protection and Bioresearch Monitoring (HSP/BIMO) Initiative—to strengthen the Agency’s ability to protect patients in clinical trials and monitor them to ensure integrity of resulting data.

The study, “Cancer Clinical Trials Awareness and Attitudes in Cancer Survivors,” conducted by the Coalition of Cancer Cooperative Groups and Northwestern University, surveyed nearly 2,000 U.S. cancer survivors. It determined that as few as one in 10 cancer survivors were given the option of being part of a trial during treatment. Among those patients who did participate in clinical trials, the survey found that 92% had a positive experience.

“This survey tells us that we need to do a better job of informing men about clinical trials that may make a difference in how their disease is managed in helping determine the potential benefit of new agents,” said Matthew Smith, MD, PhD, assistant physician, division of hematology/oncology, Massachusetts General Hospital, Boston. “We are currently conducting clinical trials to evaluate the potential for an investigational therapy to prevent and treat the bone metastases in men with prostate cancer.”

—Querida Anderson

Concomitant High-Dose Radiation Therapy Plus Cetuximab Improves Locoregional Control and Reduces Mortality, with No Increase in Radiation Therapy—Associated Toxicity in Patients with Advanced Squamous-Cell Carcinoma of the Head and Neck

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adiation therapy is the standard treatment for patients with advanced, unresectable squamous-cell carcinoma of the head and neck. Unfortunately, however, the results of treatment are poor and radiation therapy—associated toxicity is a common problem. In a recent study published in the New England Journal of Medicine, patients with locally advanced squamous-cell carcinoma of the head and neck who were treated with cetuximab (a monoclonal antibody against epidermal growth factor receptor) in addition to radiation therapy showed a survival benefit, with no increase in mucositis or dysphagia compared with patients who received radiation therapy alone.

The study, performed by Bonner and colleagues, was a multinational, randomized study performed to compare radiation therapy alone with radiation therapy plus cetuximab. Patients (n=424) were randomly assigned to treatment with either high-dose radiation therapy alone (n=213) or high-dose radiation therapy plus weekly cetuximab (n=211) at an initial dose of 400 mg/m², followed by 250 mg/m² weekly for the duration of radiation therapy. The primary endpoint was the duration of control of locoregional disease; secondary end points included overall survival, progression-free survival, response rate, and safety.

The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiation therapy, compared with 14.9 months among those given radiation therapy alone (P = 0.005). The median follow-up period was 54.0 months. The median duration of overall survival was 49.0 months among patients treated with combined therapy, compared with 29.3 months among those treated with radiation therapy alone (P = 0.03). Radiation therapy plus cetuximab significantly prolonged progression-free survival (P = 0.006). With the exception of skin rash and infusion reactions, the incidence of grade 3

or greater toxic effects, including mucositis, did not differ significantly between the two groups.

The investigators concluded that treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiation therapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiation therapy to the head and neck. According to Dr. Bonner, lead author of the study and a radiation oncologist at the University of Alabama in Birmingham, AL, “These findings are important because they show that the addition

of this monoclonal antibody therapy has lifesaving benefits without any additional length of suffering from the primary acute side effects.”

STAT3 Pathway Inhibitor (Degrasyn) Drug Class Shows Promise in the Treatment of Malignant Brain Tumors

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espite improvements in surgical techniques, neuroimaging, radiation therapy, and chemotherapy, high-grade gliomas are notoriously difficult to cure, and prognosis is often abysmal. Numerous medical centers worldwide are involved in basic research in an effort to more fully elucidate the basic mechanisms of brain tumor growth and in the development of novel therapies. These efforts have led investigators to inhibitors of signal transducer and activator of transcription-3 (STAT3) phosphorylation.

Previous investigations have shown that AG490, a selective inhibitor of STAT3 phosphorylation, inhibits growth and induces

apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently

demonstrated an in vivo antitumor effect in animal models. This observation led Iwamaru and colleagues to evaluate WP1066, a novel inhibitor structurally related to AG490 but significantly more active and potent against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. Their findings were published recently in Oncogene.

The results were striking. The IC50 values for WP1066 were 5.6 μM in U87-MG cells and 3.7 μM in U373-MG cells, which represents 18- and 8-fold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c-myc, Bcl-XL and Mcl-1, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (P < 0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the surgically removed tumors showed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. The investigators concluded that WP1066 may holds promise as a therapeutic

agent against malignant gliomas.

STAT3 is activated constitutively in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. In the nucleus, it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. STAT3 pathway inhibitors (degrasyns) are a new class of drugs that were discovered by Prof. Waldemar Priebe and colleagues at The University of Texas MD Anderson Cancer Center and licensed to Callisto Pharmaceuticals in January 2006. The unique antitumor activity of STAT3 pathway inhibitors relates to their ability to selectively promote degradation of key proteins that are involved in tumor cell proliferation and survival. This degradation appears to be specific for JAK2, c-myc and BCR-ABL, all important targets for a wide range of tumors. Callisto has sponsored-research agreements in place with the MD Anderson Cancer Center, which seek to identify and develop clinical candidates from this new and interesting class.

—John D. Zoidis, MD