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The Academy

OBTN, March 2008, Volume 2, Issue 3

The Academy delivers the latest news on biotechand oncology research, providing a link between the clinical world of cancer care and the university researchers who are pushing the envelope of knowledge and discovery. In this issue:

UNIVERSITY OF CALIFORNIA, SAN FRANCISCO

Novel Mapping Technique Has Potential to Improve Brain Surgery

In a clinical discovery likely to enhance understanding of human brain function and have profound implications on brain cancer surgery, neurosurgeons from the University of California, San Francisco (UCSF), are reporting that they have derived significant results from a new brain mapping technique. The advance allows for the safe removal of tumors near language pathways in the brain, minimizes brain exposure, and reduces the amount of time that a patient must be awake during surgery.

New England Journal of Medicine

Significantly, the study, which appeared in a recent issue of the , provides new data that yields an increased level of insight into brain mechanics, refining scientists' understanding of how language is organized within the human cortex.

First, the researchers identified new cerebral regions involved in speech production, reading, and naming. The study team then applied these data, utilizing them to generate a three-dimensional cortical language map that, according to UCSF researchers, is more detailed and integrates more data than any language map of the brain ever generated.

According to senior author Mitchel Berger, MD, professor and chairman of the UCSF Department of Neurological Surgery and director of the UCSF Brain Tumor Research Center, “This study represents a paradigm shift in language mapping during brain tumor resection. Not only have we proven this technique can be safely relied upon for brain tumor resection, we have shown functional language organization to be much more diverse and individualized than previously thought.”

According to the study’s lead author Nader Sanai, MD, senior resident in neurological surgery at UCSF, the utility of the findings are likely to extend beyond brain cancer surgery. “Accurately understanding cortical language organization has clinical implications for more than just brain tumor patients. Any patient with a seizure disorder, stroke or head injury who has language-related difficulties can now be better understood in the context of this revised anatomy,” he explained.

INDIANA UNIVERSITY SCHOOL OF MEDICINE

Combination of Taxol and Avastin Yields Robust Results for Breast Cancer

New England Journal of Medicine

A study that its researchers are touting as first to demonstrate that an antiangiogenic agent can delay progression of advanced breast cancer was recently published in the . The study, an open-label, randomized, phase III trial, coordinated by the Eastern Cooperative Oncology Group (ECOG) and Kathy Miller, MD, associate professor of medicine and Sheila D. Ward Scholar at the Indiana University School of Medicine and a researcher at the Indiana University Simon Cancer Center, Indianapolis, Indiana, looked at Taxol (paclitaxel), which is one of the standard agents for metastatic disease, with and without the addition of Avastin (bevacizumab).

According to Dr. Miller, also the study’s lead author, the cohort that received Avastin showed the biggest improvement in metastatic breast cancer ever reported in a chemotherapy-based clinical trial. It nearly doubled the time between initiation of chemotherapy for metastatic disease and progression of the breast cancer tumors.

“This study not only achieved the longest progression-free survival in advanced disease but the therapy achieved that improvement without adding to the day-to-day treatment burden and with only minor increases in toxicity,” said Dr. Miller.

The study enrolled 722 women with metastatic disease from the United States, Canada, Peru, and South Africa. Patients were randomized to one of two arms of the phase III study —Taxol alone or Taxol with Avastin. Patients were randomly assigned to receive 90 mg of paclitaxel per square meter of body-surface area on days 1, 8, and 15 every four weeks, either alone or with 10 mg of bevacizumab per kilogram of body weight on days 1 and 15. The patients, who joined the study from December 2001 through May 2004, represented a balance of age, disease-free interval, estrogen-positive receptors, and sites of disease. The primary end point was progression-free survival.

P

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The results show that treatment with Taxol and Avastin increased the period patients went without progression of their disease from 5.9 months to 11.8 months ( < 0.001). The combination therapy regimen also increased the objective response rate, when compared with patients who received Taxol monotherapy (36.9% vs. 21.2%, < 0.001).

“The next step is to move Avastin into the initial treatment of breast cancer in hopes that it will prevent recurrence in the first place,” said Dr. Miller.

Avastin is a human monoclonal antibody that acts to reduce the development of blood vessels that feed tumors. Cancer tumors need an increasing supply of blood to grow and the development of the blood vessels to supply the tumor is a process called angiogenesis. Avastin already has been approved by the FDA for treatment of colorectal and lung cancer.

M.D. ANDERSON CANCER CENTER The University of Texas

New Test Has Potential To Heighten Myelodysplastic Syndrome Assessment Accuracy

Researchers at the University of Texas M.D. Anderson Cancer Center, Houston, Texas, have announced the development of a new scoring system designed to more accurately stratify risk patients who have myelodysplastic syndrome (MDS), a form of leukemia.

Leukemia

The system, which was recently reported on-line in the journal , identifies patients who appear to have low-risk disease but actually have poor prospects of survival.

Guillermo Garcia-Manero, MD, lead author of the study and associate professor, Department of Leukemia, M.D. Anderson Cancer Center, and colleagues examined a number of potential molecular and demographic markers to develop a prognostic scoring system for this group by applying them to 856 patients treated at M. D. Anderson between 1976 and 2005. All were rated low or intermediate risk by the International Prognostic Scoring System (IPSS), which is generally accepted to be the current mainstay model for stratifying MDS risk.

Researchers found that a combination of older age, low platelet counts, anemia, a higher percentage of cancerous cells, or blasts, in the bone marrow and poor-risk cytogenetics (aberrant chromosomes) divided the 856 patients into three clearly defined groups:

• The 182 patients who had few of these characteristics (Category 1) had a median survival of 80.3 months.

• The 408 patients who fell into Category 2, an intermediate score, had a median survival of 26.6 months.

• The 265 patients with the highest score had a median survival of 14.2 months.

When researchers applied the IPSS to the same patients, it failed to segregate patients with low or intermediate risk into the new test’s risk categories.

Dr. Garcia-Manero says the scoring system is being applied in prospective clinical trials that are underway or planned at M. D. Anderson. “We know an undefined group of MDS patients who are classified as low-risk by our present prognostic models will at some point have a sudden worsening of their disease. If we can identify them, we can start those with a poor prognosis on early treatment,” explained Dr. Garcia- Manero.

Previously, most patients were observed or received supportive care until MDS transformed into acute myelogenous leukemia (AML). They then received supportive care such as blood transfusions and AML treatments that included relatively harsh chemotherapy. Half the patients in the new study over the 30-year period died, and 90% of those were patients whose MDS had not transformed into AML, the researchers note.

“Identifying these low-risk, poor prognosis patients could allow us to be more aggressive, using medication at an earlier stage,” Dr. Garcia-Manero notes. For example, few patients rated as low risk receive donor bone marrow transplants, but a poor prognostic score would allow earlier consideration of that approach.

Dr. Garcia-Manero says the study needs to be replicated by other researchers and tested in prospective clinical trials, some of which are now underway and ongoing.

JAMES P. WILMOT CANCER CENTER University of Rochester Medical Center, Rochester, New York

Alternate Lymphoma Option Shows Promise

According to data compiled by oncologist researchers at the James P. Wilmot Cancer Center at the University of Rochester Medical Center, Rochester, New York, there may be new therapeutic hope for patients with recurrent and/or treatment-resistant non-Hodgkin’s lymphoma (NHL).

Journal of Clinical Oncology

Phase II trial results published in a recent issue of the provide evidence that bendamustine, branded as Treanda, can successfully achieve remission of stubborn lymphoma cases.

In the phase II multicenter trial evaluating the efficacy and toxicity of bendamustine in patients with B-cell NHL refractory to rituximab (Rixutan), bendamustine was given to 76 patients with advanced indolent lymphoma who did not respond to rituximab treatment, an agent that many clinicians consider to be the treatment standard for lymphomas. Patients received bendamustine 120 mg/m2 intravenously on days 1 and 2 of each 21-day cycle. Outcomes included response, duration of response, progression- free survival, and safety.

Seventy-six patients, ages 38 to 84 years, with predominantly stage 3 or 4 indolent (80%) or transformed (20%) disease were treated; 74 were assessable for response. Twenty-four (32%) were refractory to chemotherapy. Patients received a median of two prior unique regimens. An overall response rate of 77% (15% complete response, 19% unconfirmed complete response, and 43% partial) was observed. The median duration of response was 6.7 months (95% CI, 5.1 to 9.9 mo), 9.0 months (95% CI, 5.8 to 16.7) for patients with indolent disease, and 2.3 months (95% CI, 1.7 to 5.1) for those with transformed disease. Thirty-six percent of these responses exceeded one year.

“This is good news for patients who are running out of options for further treatment,” stated Jonathan Friedberg, MD, principal investigator on the 14-site study. “These results,” continued Dr. Friedberg, “open the door for additional studies of bendamustine in combination with other standard therapies for various forms of lymphoma.”

Bendamustine may represent a welcome addition to the arsenal of therapies for people with stubborn lymphomas. Doctors were optimistic when rituximab was developed because it prompted quick and extended remissions for many people with lymphomas. Now, however, after extended use, oncologists are seeing a growing number of patients whose rituximab-induced remission has ended. According to researchers, bendamustine, which attacks cancer cells on two levels—by altering the cancer cells’ DNA forcing them to self-destruct and also disrupting the cell-division cycle—may provide a viable option for this patient population in particular.

“Typically these patients need several different therapies over the years and none of them are curative. These data show that bendamustine will add to our treatment options for this disease,” said Dr. Friedberg, director of hematological malignancies clinical research at the Wilmot Cancer Center.

Bendamustine is making its way into the U.S. pharmaceutical market after many years of use in Germany. Cephalon Oncology bought the rights to develop the drug and is now seeking the approval of the Food and Drug Administration for standard use in patients with indolent non-Hodgkin’s lymphoma and chronic lymphocytic leukemia.

A phase III study of bendamustine for patients with indolent non-Hodgkin’s lymphoma who are resistant to rituximab is also nearing completion.

THE HORMEL INSTITUTE University of Minnesota

Cell Line Research Further Affirms Obesity as a Breast Cancer Risk Factor

The University of Minnesota Hormel Institute in Austin, Minnesota, has announced that researchers from the institution have found further evidence of a link between obesity and an increased risk of breast cancer in postmenopausal women.

British Journal of Cancer

Margot Cleary, PhD, professor of nutrition and metabolism at Hormel Institute and member of the University of Minnesota Cancer Center, led the research team in the laboratory study that provided the new evidence. Findings were published in a recent issue of the .

The study, one of the first to investigate the function of a hormone protein called adiponectin (Acrp30) that is only produced in body fat, was done in mice and breast cancer hgh cell lines developed from women of postmenopausal age and diagnosed with breast cancer.

Hypothesizing that Acrp30 is lower in obese individuals and may be negatively regulating breast cancer growth, Dr. Cleary and colleagues analyzed five breast cancer cell lines, MDA-MB-231, MDA-MB-361, MCF-7, T47D, and SK-BR-3, and determined that all lines that were examined expressed one or both of the Acrp30 receptors. In addition, researchers found that the addition of Acrp30 to MCF-7, T47D, and SK-BR-3 cell lines inhibited growth.

in vivo

Researchers also determined that estrogen receptor (ER)—positive MCF-7 and T47D cells were inhibited at lower Acrp30 concentrations than ER–negative SK-BR-3 cells. Growth inhibition, according to researchers, may be related to apoptosis since PARP cleavage was increased by Acrp30 in the ER-positive cell lines. To investigate the role of ER in the response of breast cancer cells to Acrp30, researchers established the MDA-ERα7 cell line by insertion of ER-α into ER-α-negative MDA-MB-231 cells. This line readily formed tumors in athymic mice and was responsive to oestradiol .

In vitro

, MDA-ERα7 cells were growth inhibited by globular Acrp30 while the parental cells were not. This inhibition appeared to be caused by blockage of JNK2 signaling.

The results, asserted the study team, are significant in that they provide information on how obesity may influence breast cancer cell proliferation and establish a new model to examine interactions between ER and Acrp30.

“We found that adiponectin plays a dual role,” stated Dr. Cleary, “Lower blood levels of this protein are associated with higher amounts of body fat. In this case, low adiponectin may help trigger the growth and spread of breast cancer.”

By comparison, Dr. Cleary explained: “Higher levels of this hormone protein exist in relationship to normal body weight and body fat levels. In this case, adiponectin may be a protective factor against the development of estrogen receptor— positive tumors because it can stop or reduce the cancerous cells from growing and spreading.”

Dr. Cleary says the message of her finding for postmenopausal women is: “Maintaining your proper weight may possibly help you reduce your chances of breast cancer.” She adds that the levels of adiponectin may be increased with weight loss through diet or surgery.

In her article about this study, Dr. Cleary wrote: “The number of women in the United States who are obese has doubled in the past 25 years. As the average body mass index climbs, the overall levels of adiponectin will decline, making this area of research progressively more important.”

Approximately 40% of the 45 million women in the United States between the ages of 45 and 75 are obese.

Other research has implicated adiponectin in other diseases related to diet, including type 2 diabetes and coronary artery disease.