The Academy: September 2007

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â–º UNIVERSITY OF MICHIGAN COMPREHENSIVE CANCER CENTER

Gene Fusions Switch on Prostate Cancer

Nature

Researchers at the University of Michigan Comprehensive Cancer Center in Ann Arbor have found a family of gene fusions that can cause prostate cancer. Knowing which gene fusion is involved in a patient’s prostate cancer could make it easier to tailor treatment, according to Arul Chinnaiyan, MD, PhD, Director of the Michigan Center for Translational Pathology, and lead author of the new study presented in the August 2 issue of .

Dr. Chinnaiyan and his colleagues have discovered that pieces of two chromosomes can trade places with each other, causing two genes to fuse. The composite gene overrides the switch that controls cells from growing uncontrollably and causing prostate cancer.

From tests in mice and cell cultures, the researchers found that five genes from the same family can become scrambled and fuse with either ERG or ETV1, two genes that are known to be involved in different types of cancer. The researchers found such abnormal gene fusions in 60% to 70% of the prostate cancer cell lines that they studied.

Oncology and Biotech News

The five genes are regulated differently, the research team found. Some genes are regulated by androgen, some are repressed by androgen, and some do not respond to the hormone. “This suggests that there are different types of prostate cancer,” Dr. Chinnaiyan told . “Some may benefit from antiandrogen therapy, but some may get worse with antiandrogen treatment and some may not get affected at all.”

Fused genes are known to play a role in cancers such as leukemia, lymphoma, and Ewing’s sarcoma. In 2005, Dr. Chinnaiyan and others were the first to show that gene fusions were the causative agents in solid prostate tumors. Just as the drug Gleevec (imatinib mesylate) targets a fused gene that plays a role in chronic myeloid leukemia, knowledge about prostate gene fusions could lead to treatments for prostate cancer, Dr. Chinnaiyan believes. “These gene fusions will be useful biomarkers for the presence of prostate cancer,” he said.

The researchers are now developing processes to detect the gene fusions by testing patients’ urine. This would be helpful for doctors to determine what kind of gene fusion is causing a patient’s prostate cancer so that they can tailor the androgen-based treatment. “This is still in the future,” Dr. Chinnaiyan said, “but somebody could get a biopsy and their gene fusion subtype could be detected and that could be used to guide their treatment.” Ultimately, he said, the goal is to target the gene fusions directly, just as Gleevec does in chronic myeloid leukemia.

â–º DANA-FARBER CANCER INSTITUTE New, Powerful Lung Tumor Suppressor Gene Found

Nature

Researchers have found a new lung tumor suppressor gene for non—small-cell lung cancer in mice. The gene, called LKB1, may be more powerful than other, better-known tumor suppressors, the researchers report in an August 5 paper.

In mice, the researchers found that mutations in this gene led to more aggressive tumors that are more likely to spread. If LKB1 is found to have a tumor-suppressing effect in human lung cells, it could influence the way lung cancer is diagnosed and treated, according to the study’s senior author Kwok- Kin Wong, MD, PhD, a physician—researcher at the Dana-Farber Cancer Institute in Boston, Massachusetts.

People born with mutations in LKB1 often develop Peutz—Jeghers syndrome, which increases the risk for certain cancers, and non-inherited LKB1 mutations have been found in some lung cancers.

The researchers studied lung cancer development in mice with abnormal LKB1, and compared it with disease development in animals with mutations in two other wellknown tumor suppressor genes, p53 and Ink4a/Arf. The animals had a defective Kras gene, which leads to the formation and growth of lung cancer. The researchers found that the defective Kras gene worked more strongly with the mutated LKB1 than with the other genes.

“The LKB1-deficient tumors grew more rapidly and spread more frequently than the others, and comprised all three types of non—small-cell lung cancer—squamous cell carcinoma, largecell carcinoma, and adenocarcinoma—rather than just one or two,” Wong said.

The researchers also examined 144 human non-small cell lung cancer tissue samples and found that about 34% of lung adenocarcinomas and 19% of the squamous cell carcinomas contained abnormal versions of the gene.

â–º DUKE COMPREHENSIVE CANCER CENTER Two-Drug Combo for Kidney Cancer

A combination of two drugs might be a potent tool against kidney cancer, according to a new study by researchers at the Duke Comprehensive Cancer Center, Durham, North Carolina. The researchers found that interferon alpha, a drug that boosts the body’s ability to fight offtumors and infections, and Nexavar (sorafenib), a drug that cuts offa tumor’s blood supply, together lead to tumor shrinkage in 33% of patients in a pilot study. They also found that the combination doubled the time before tumors began to grow again.

Journal of Clinical Oncology

When given separately, each drug reduces only 5% to 10% of tumors. Also, most tumors start to grow again after five to six months, according to Jared Gollob, MD, professor of medicine at the Duke Comprehensive Cancer Center who led the study published in the August 1 issue of the .

For the study, Dr. Gollob and his colleagues gave 40 patients a sorafenib pill twice daily and interferon alpha injections three times a week for eight weeks. If the patient’s tumor stopped growing or reduced in size, the researchers repeated the drug-combination regime after a two-week break until the tumor disappeared or the cancer get worse. A third of the patients’ tumors shrank significantly, and the treatment completely destroyed the tumors in two of the 40 patients.

â–º UNIVERSITY OF CALIFORNIA, LOS ANGELES COX-2 Inhibitors Delay Pancreatic Cancer Precursors

Cancer Research

The cyclooxygenase-2 (COX-2) inhibitor nimesulide delays the progression of pancreatic cancer precursor lesions in mice, according to new research published in the August issue of .

Oncology and Biotech News

“This study implies that COX-2 is an important molecule for pancreatic cancer development and that inhibition of COX-2 by selective inhibitors may prevent the development of pancreatic cancers in humans,” lead author Guido Eibl, MD, Scientific Director of the Hirshberg Laboratory of Pancreatic Cancer Research and adjunct assistant professor at the University of California Los Angeles told .

Cyclooxygenase-2, an enzyme that causes inflammation and pain, is linked to the development and growth of breast, colon, and pancreatic cancer tumors. There is evidence that COX-2 inhibitors can help prevent cancer, but the drugs have also been mired in controversy because trials have found that the drugs can increase the risk of heart attacks and strokes.

The UCLA researchers studied the effects of COX-2 on the progression of pancreatic intraepithelial neoplasias (PanINs)—abnormal pancreatic lesions that are believed to lead to cancer. They used the KrasG12D mouse model, which mimics early stages of pancreatic cancer. Early-stage PanINs, stages I and II, start to appear in the animal at one month, and late-stage, or stage III PanINs start at six months. Stage III PanINs are believed to be direct precursors to pancreatic tumors in humans and mice, according to Dr. Eibl. The majority of the mice in the study develop tumors between 12 and 15 months.

Dr. Eibl and his colleagues divided the mice into two groups. For 10 months, one group received a nimesulideenriched diet, while the other got regular food. The researchers found that the nimesulide diet reduced the number of late-stage PanINs—10% of the pancreatic ducts in the nimesulide-fed mice had stages II or III PanINs, as compared with 40% of the pancreatic ducts in the mice on a regular diet.

Right now, the researchers have analyzed the pancreases of the mice at 10 months, before the typical appearance of pancreatic tumors. They plan to conduct more studies to study the long-term effects of nimesulide and other COX-2 inhibitors and determine whether they can delay the onset of or prevent pancreatic cancer.

Given the cardiovascular risk associated with COX-2 inhibitors, in the future, studies will also be needed to verify the safety of the drugs and to determine a target patient population. “There are numerous other studies necessary to clearly define the population that may benefit from these inhibitors, especially with regard to their cardiovascular risk profile, or to develop other, safer inhibitors,” Dr. Eibl said.

â–º JAMES GRAHAM BROWN CANCER CENTER Gardasil Developers Working on Affordable HPV Vaccine

An international team of researchers is trying to develop a low-cost human papillomavirus (HPV) vaccine using tobacco plants. The new vaccine would cost $3 for three doses. In contrast, the current standard, Merck’s Gardasil, costs $360.

The researchers who are working on the new vaccine include A. Bennett Jenson, MD and Shin-je Ghim, PhD, researchers at the University of Louisville’s James Graham Brown Cancer Center in Louisville, Kentucky who helped develop Gardasil. Other members on the team are from the Owensboro Cancer Research Program in Owensboro, Kentucky and the Chittaranjan National Cancer Institute in Kolkata, India.

The new vaccine’s target is the L-2 protein found in HPV. The researchers make the vaccine by creating a synthetic gene that expresses the same protein in plants. They insert this gene into a tobacco virus, which they use to infect tobacco plants and grow the vaccine. Six to 10 days later, they juice the tobacco parts and then purify the liquid to remove tobacco parts until they have the pure protein. The protein induces antibodies to protect the body against at least 13 HPV strains that are known to cause cervical cancer.

The researchers have tested the vaccine in five dogs. The vaccine protected the dogs completely against oral canine HPV. The researchers hope to start the first phase of human clinical trials in 2008.

If successful, the team’s efforts will make cervical cancer vaccine affordable to low-income populations in the United States, and also to people in developing countries such as India, where four times as many women get cervical cancer and eight times as many women die from it as in the U.S.. Although Merck has announced that it would sell Gardasil at lower prices in developing countries, the reduced price tag could still be inhibitory to the vaccine’s use by a vast majority of people.

â–º INDIANA UNIVERSITY CANCER CENTER Chemotherapy and Stem Cell Treatment Could Cure Metastatic Testicular Cancer

New England Journal of Medicine

High-dose chemotherapy and a stem cell transplant could be used to cure testicular cancer patients who do not respond to traditional therapy, researchers at the Indiana University School of Medicine reported in the July 26 . The retrospective study, led by Lawrence Einhorn, MD, Professor of Medicine at the Indiana University Cancer Center, demonstrated that testicular cancer is potentially curable with chemotherapy and a stem cell transplant using cells harvested from the patient before the initial chemotherapy treatment.

Right now, first-line testicular cancer therapy involves multiple courses of cisplatin. About 90% of metastatic testicular cancer patients respond to this treatment.

In the new study, Dr. Einhorn and his colleagues analyzed the outcome of 184 patients with testicular cancer who did not respond to initial treatment. The researchers treated the patients with carboplatin chemotherapy at five times the dosage given to men receiving first-line therapy. The high drug dosage decreases blood cells so the researchers gave the men a stem cell transplant to boost the body’s immune system. Then they repeat the process three to four weeks later.

A median follow-up at 48 months showed that 116 of the 184 patients were completely disease-free. The researchers also found that 70% of the patients who received second-line therapy were disease-free, as opposed to 45% of those who got later therapy. Patients also responded well if their tumors were sensitive to cisplatin, if they had a better response to initial chemotherapy, and had a favorable prognosis.

â–º NORTHWESTERN UNIVERSITY Optical Technique Captures Early Signs of Pancreatic Cancer

A new optical technology paired with routine endoscopy could give doctors a minimally invasive method to detect pancreatic cancer in its early stages. The technology, developed by biomedical engineers at Northwestern University in Evanston, Illinois, highlights abnormal changes in the duodenum tissue of patients with pancreatic cancer, showing that early stages of the disease can cause subtle changes in tissue surrounding the pancreas.

Clinical Cancer Research

Right now, pancreatic cancer is detectable only via intensive radiological techniques such as CT scans and MRIs or with a biopsy. Both of these techniques can be risky to asymptomatic pancreatic cancer patients. Besides, by the time a patient starts showing symptoms and the tumor is detectable using MRI or other whole-body imaging techniques, it is generally too late for a treatment to work, according to Vadim Backman, PhD, biomedical engineering professor at Northwestern University, who led the new work published in the August 1 issue of .

“We asked the question: can we detect pancreatic cancer noninvasively, that is, without interrogation of the pancreas,” Dr. Backman told Oncology and Biotech News. This led him and his colleagues to investigate tissue in surrounding organs such as the duodenum, which can be interrogated more easily using endoscopy. According to Dr. Backman, if there are precancerous or cancerous lesions in the pancreas, even tissue that looks normal and is away from the lesion, including that in the duodenum, will have molecular and other kinds of abnormal changes.

The optical techniques that the researchers tested are called four-dimensional elastic light-scattering fingerprinting and low-coherence enhanced backscattering spectroscopy, both packaged into the same instrument. The instrument shines intense white light on tissue samples and uses the two techniques to measure how cellular structures in the tissue refract light—normal tissue refracts light differently than abnormal one does.

The researchers used these techniques to examine duodenum tissue samples from 19 patients diagnosed with cancer and 32 without the disease. They used duodenal mucosa tissue that can be gathered during upper endoscopy. They were able to identify patients with pancreatic cancer with 95% accuracy. More importantly, they identified all 10 patients with surgically removable early-stage tumors, showing that the optical methods might hold promise for early pancreatic cancer detection.

The Northwestern researchers are now testing the technique more extensively in a new study, for which they have recruited 200 patients. Other questions remain unansweredbefore the technique can be submitted for FDA approval, said Dr. Backman. “We will have to figure out if pancreatic benign conditions, such as pancreatitis, will affect the marker,” he said. “Will the marker be different in patients with a family history of the disease?”