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The Academy: November 2007

OBTN, November 2007, Volume 1, Issue 9

The Academy delivers the latest news on biotech and 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: 1) Paterson Institute at the University of Manchester, UK: New Drug Shows Promise for Childhood Cancers 2) University of Michigan Comprehensive Cancer Center: African-American Women Suffer Worse From Breast Cancer 3) University of Montreal: Nomogram Predicts Prostate Cancer Life Expectancy 4) Johns Hopkins Medicine: Research Shows How Vitamin C Fights Cancer 5) University of Texas M. D. Anderson Cancer Center: Virus Designed to Kill Brain Tumor Stem Cells Genomic Tests for Breast Cancer Decisions

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â–º Paterson Institute at the University of Manchester, UK

New Drug Shows Promise for Childhood Cancers

Results of a preclinical study show that the new drug RH1 could be a potential tool against three types of childhood cancer. Researchers at Cancer Research UK’s Paterson Institute at the University of Manchester found that RH1 could kill tumor cells from neuroblastoma, osteosarcoma, and Ewing’s sarcoma (Figures). These tumors are often resistant to current chemotherapy treatment and can be fatal.

In cancer cells, apoptosis—the natural mechanism for cellsuicide—shuts offor functions improperly. RH1 works by increasing apoptosis. In laboratory tests on children’s tumors, the researchers led by Dr. Guy Makin, pediatric oncologist at the Paterson Institute, found that even at low doses, RH1 increased cancer cell death by 50% compared with untreated cells.

The bioreductive drug RH1 is activated by the enzyme DT-diaphorase (DTD), which is over-expressed in adult tumors, especially those in the lungs, breasts and liver. The drug was a nominated compound for advancement in the National Cancer Institute’s Developmental Therapeutics Program.

The Paterson Institute researchers recently completed a Phase I clinical trial of RH1 on adult cancer patients and presented their results at the 2007 American Society of Clinical Oncology meeting. Based on the promising Phase I adult trial and the more recent laboratory results on children’s tumors, the researchers are planning a Phase I trial of the drug on children with cancer. Dr. Bruce Morland, chairman of the Children’s Cancer and Leukemia Group said, “survival rates for children with cancer are already high at 75%. But in many cases, patients become resistant to their drugs and need new options.”

â–º University of Michigan Comprehensive Cancer Center

African-American Women Suffer Worse From Breast Cancer

A new study has confirmed that breast cancer is worse in African-American women—they are more likely than white women to have breast cancer at a younger age, to succumb to their disease, and to have ER-negative breast cancer. Researchers from the University of Michigan Cancer Center in Ann Arbor, Michigan reported these findings at the 2007 Breast Cancer Symposium in San Francisco on September 6.

The findings of the study did not change when income, education or insurance coverage were taken into account, said Catherine Lee, MD, a clinical lecturer in the department of surgery at the University of Michigan Cancer Center.

Dr. Lee and her colleagues studied the records of 170,079 women with breast cancer. Ninety percent of these women were white and nearly 10% were African American. Of the African-American women, 39% had ER-negative tumors as opposed to 22% of the white women. The average age of diagnosis was 57 years for African-American women whereas it was 62 for white women. Still, African-American women had more advanced cancer—29% of the women had stage I tumors compared with 42% of white women.

The study results support past research that has shown that there are biological differences in breast cancer tumors depending on race, likely because of genetic differences. “Differences in tumor biology have a signifi- cant impact on survival,” Dr. Lee said. Since breast cancers in black women are more aggressive biologically, we need to focus more of our research energy on developing better treatments targeting ER-negative tumors, she added. In addition, she said, “these findings point to a need for improved cancer education and screening in black women, particularly those in younger age groups.”

â–º University of Montreal

Nomogram Predicts Prostate Cancer Life Expectancy

Researchers at the University of Montreal in Canada have found that a simple nomogram using age and comorbidity predicts the 10- year life expectancy of prostate cancer patients who are considering radical prostatectomy or radiotherapy.

Journal of Clinical Oncology

Prostate cancer patients should have an expectancy of at least 10 years if doctors are considering them as candidates for definitive therapy. Judging life expectancy is diffi- cult, said the researchers in a report in the August 20 issue of the . An accurate estimate of life expectancy will help doctors decide the most beneficial course of treatment for a patient.

Nomograms are already used to help assess the risk of failure associated with specific prostate cancer treatments relative to other disease-related factors such as PSA levels and stage of the cancer. These nomograms are typically in the form of look-up tables.

Oncology & Biotech News

The new tool, which has a simple and user-friendly computerized interface, was developed by Pierre Karakiewicz, MD, a urologist oncologist at the University of Montreal Health Center. It predicts the 10-year life expectancy after radical prostatectomy or external beam radiation therapy with an accuracy of 84.3%. This, they said, is about 3% more accurate than its alternatives. “Patients deserve to have the best tools and so do doctors,” Dr. Karakiewicz told .

The researchers used data from a population- based cohort of prostate cancer patients who did not receive secondary treatment. They found that the patients had an overall 10-year survival probability of 81.1% after prostatectomy, and of 30.4% after radiation therapy.

They also found that every 1-year increase in age was associated with a 10% increase in overall mortality during 10 years of follow-up. Each 1-unit increase in the Charlson comorbidity index, on the other hand, was associated with a 40% increase in morbidity. External beam radiation therapy, the researchers found, was associated with a 6.6-fold higher mortality compared with radical prostatectomy.

â–º Johns Hopkins Medicine

Research Shows How Vitamin C Fights Cancer

Cancer Cell

Antioxidants such as vitamin C were conventionally thought to help prevent cancer growth because they combine with oxygen free radical molecules and prevent them from damaging DNA. Now, Johns Hopkins researchers have shown that antioxidants can indeed inhibit the growth of certain tumors, although by a different pathway. In the September 11 issue of , the researchers show that antioxidants destabilize a tumor’s ability to grow under low-oxygen conditions.

The researchers, led by Chi Dang, MD, PhD, professor of medicine and oncology at Johns Hopkins in Baltimore, Maryland, studied mice implanted with human lymphoma and human liver cancer cells. These cancers produce high levels of free radicals that can be suppressed by feeding the mice antioxidant supplements, such as vitamin C or N-acetylcysteine (NAC). However, cancer cells in mice that were not given antioxidants did not show any significant DNA damage.

“We did expect antioxidants to have the antitumor effects, however, we were surprised after we tried very hard but could not link the effects to DNA damage,” Ping Gao, PhD, a researcher at Johns Hopkins who conducted the study along with Dr. Dang.

Dr. Gao and his colleagues then analyzed another mechanism—a protein called hypoxia-induced factor (HIF-1). In an oxygen-starved cell, HIF-1 helps to convert sugar into energy without oxygen and initiates the construction of new blood vessels to bring in fresh oxygen. Since some fast-growing tumors consume all the oxygen in their vicinity, they need HIF-1 to survive, however, HIF-1 can only operate if it has a supply of free radicals. Further, in the vitamin C-treated cells, the protein disappeared, in turn stopping tumor growth.

To test their hypothesis, the researchers created genetically modified cells that constantly expressed HIF-1 whether or not free radicals were present. “We observed that vitamin C or NAC had no effect on tumorigenesis of this mutant cell line,” Dr. Gao said. “These results indicate that antioxidants’ role on HIF degradation is dominant.”

â–º University of Texas M. D. Anderson Cancer Center

Virus Designed to Kill Brain Tumor Stem Cells

Journal of the National Cancer Institute

Researchers have engineered a virus that destroys brain tumor stem cells that lead to aggressive, therapy-resistant brain tumors. Juan Fueyo, MD, associate professor at the University of Texas M. D. Anderson Cancer Center in Houston, Texas, and his colleagues reported their development in the September 18 .

The virus, called Delta-24-RGD, worked successfully against glioblastoma multiforme, a highly invasive and aggressive brain tumor, which is resistant to radiation and chemotherapy.

Dr. Fueyo and his colleagues have designed the virus to take advantage of the abnormal expression of the retinoblastoma (Rb) protein in brain tumors and brain tumor stem cells. When expressed normally in healthy cells, the protein prevents the proliferation of cancerous cells and viral infection. The virus creates its own special protein called E1A to combat the effect of Rb, however, the researchers genetically modified the virus so that it did not produce the E1A protein. As a result, the virus cannot replicate in normal cells but it proliferates in brain tumor cells, which do not have normal levels of Rb to protect themselves.

Oncology & Biotech News

The virus forces tumor cells and stem cells to form a membrane around part of their cytoplasm or cell organelle and then digest the contents of the membrane, thus cannibalizing themselves. Cells typically do this to fend offbacterial or viral infection. “Thus the virus attacks both the bulk population of cancer cells and the brain tumor stem cell population,” Dr. Fueyo told .

in vitro

For the present study, the research team derived four brain tumor stem cell lines from different glioblastoma multiforme specimens. Delta- 24-RGD killed all four types of stem cells . Then the researchers grafted the stem cell lines into the brains of mice and injected the virus into the resulting tumors. The mean survival time in untreated mice was 38.5 days, while that in treated mice was 66 days. Two of the eight treated mice survived for 92 days with no neurological symptoms.

The virus treatment seems to be relatively safe. The researchers did not observe any side effects in the mice. Moreover, although toxicity due to virus replication in normal cells is theoretically possible, laboratory and clinical experience with other similar adenoviruses indicate that it is not a major problem, Dr. Fueyo said.

The researchers hope to start a clinical trial as early as this fall. In addition to testing the virus for potential toxicity, said Dr. Fueyo, “we are very interested in ascertaining whether the virus replicates within the tumor, how far the spread of the virus travels from the injection point, how much tumor the virus is able to destroy, and how long the virus effect remains in the tumor.”

â–º University of Texas M. D. Anderson Cancer Center

Genomic Tests for Breast Cancer Decisions

Three genomic tests that independently predict the chances of breast cancer recurrence and sensitivity to therapy could guide physicians in choosing treatment options for their patients. The three tests forecast the likelihood that a patient’s breast cancer will reoccur after surgery without additional treatment, the cancer’s susceptibility to chemotherapy, and its vulnerability to hormone therapy.

Researchers at the University of Texas M. D. Anderson Cancer Center in Houston, Texas have put together the genomic predictors, which were developed and validated separately. The tests can now be assessed from a single microarray analysis of a needle biopsy of a patient’s tumor.

W. Fraser Symmans, MD, professor of pathology, and Lajos Pusztai, MD, PhD, associate professor of breast medical oncology at M. D. Anderson, presented their results at the 2007 Breast Cancer Symposium in San Francisco on September 7—8.

“Existing genomic tests for breast cancer provide information about future risk in general, but not the likely benefit of each treatment option separate from a patient’s overall prognosis if no treatment followed surgery,” Dr. Symmans said. “It is important to independently assess these three variables.”

Of the three tests, two were developed at M. D. Anderson. One is a 30-gene predictor of a patient’s sensitivity to chemotherapy and the other is a 200-gene index that indicates a patient’s response to hormone-suppressing therapy. Researchers at Erasmus University in Rotterdam, Netherlands developed the third test—a 76-gene prognostic test that predicts the risk of cancer recurrence after surgery.

Combining the three gene tests, the M. D. Anderson researchers reported the predictions for two groups of patients with stage 1 or stage 2 breast cancer that had not spread to the lymph nodes and who had not been given chemotherapy or hormone therapy after surgery.

The first group of 55 patients was predicted to be at relatively low risk of cancer recurrence. Of these patients, the tests predicted 21 to have cancer sensitive to chemotherapy and 16 to have cancer vulnerable to hormone therapy. Two patients had cancers susceptible to both therapies.

The second group comprised of 143 patients who were indicated to have high recurrence risk. Of those, 109 were predicted to be unlikely to respond to hormone therapy, 64 to have cancer insensitive to chemotherapy, and 38 to be insensitive to both therapies.

The independent predictors will better guide physicians in deciding the best course of treatment after surgery—whether to follow with chemotherapy, hormone therapy, both or neither. For instance, if the microarray analysis of a patient’s biopsy shows that she is at low cancer recurrence risk and has cancer insensitive to both hormone therapy and chemotherapy, the best option would be surgery alone, said Dr. Pusztai. Similarly, a patient with chemotherapy-resistant but highly hormone-sensitive cancer could avoid potentially toxic chemotherapy. However it is important to know the cancer’s sensitivity to therapy independent of the risk of recurrence alone. “For example, a person even with low risk for cancer recurrence might elect to receive further therapy if her cancer is known to be highly susceptible to treatment,” he said.