Special Issue on Personalized Drug Development Don't miss our August 19 special issue of the NCI Cancer Bulletin, which will focus on how the process of drug development is changing to accommodate new research about targets for cancer therapy, as well as the advent of personalized medicine. NCI Cancer Bulletin special issues are some of the most popular among our readership. Past special issues have focused on cancer prevention, NCI-Frederick, and childhood cancer.

Panel Recommends Against PSA Testing in Men 75 or Older

In updated recommendations released today, the U.S. Preventive Services Task Force (USPSTF) is advising against the routine use of prostate-specific antigen (PSA) testing to screen for prostate cancer in men age 75 and older. Published in Annals of Internal Medicine, the recommendations state that the potential harms of PSA testing for men in this age group outweigh any benefits, and that there is "adequate evidence that the incremental benefits of treatment for prostate cancer detected by screening are small to none."

For men under 75, the panel concluded that there was inadequate evidence to say whether "treatment for prostate cancer detected by screening improves health outcomes compared with treatment after clinical detection." In its report, the panel added that there is "convincing evidence that treatment for prostate cancer detected by screening causes moderate-to-substantial harms, such as erectile dysfunction, urinary incontinence, bowel dysfunction, and death. These harms are especially important because some men with prostate cancer who are treated would never have developed symptoms related to cancer during their lifetime."

The USPSTF is a panel of independent experts convened by the U.S. Agency for Healthcare Research and Quality. Opinions on this issue among urologists and prostate cancer researchers run the gamut, with some arguing that PSA testing in men 75 and older does indeed save lives.

Dr. Howard Parnes, chief of the Prostate and Urologic Cancer Research Group in NCI's Division of Cancer Prevention, notes that the potential harms of screening are well documented, while there is no evidence of a mortality benefit from routine PSA screening in men 75 or older, or in any age group.

The available evidence, he notes, "indicates that the benefit from treatment of a PSA-detected cancer is not likely to be seen for 10 to 15 years. But the potential harms of being treated now are immediate."

Even so, Dr. Parnes stresses, the recommendation is not an absolute. Clinicians and their patients may decide that PSA testing is the best course of action. "Every physician should still individualize care and shouldn't discriminate on the basis of age," he says.

Investigators from NCI's Laboratory of Molecular Pharmacology report that in a mouse model of breast cancer, the small-molecule inhibitor lapatinib (Tykerb) can cross the blood-brain barrier and prevent approximately 50 percent of large HER2-positive brain metastases. Their study appeared online July 29 in the Journal of the National Cancer Institute.

The drug trastuzumab (Herceptin) targets cancer cells that overexpress the protein HER2. These cells have shown a greater potential to spread (metastasize) to the brain, but trastuzumab, a large antibody molecule, cannot cross the blood-brain barrier to reach these metastatic cells.

Lapatinib, which is approved for the treatment of metastatic breast cancer, is a much smaller molecule that is capable of permeating the blood-brain barrier. Its effectiveness in clinical trials treating large secondary tumors in the brain has been limited, so the researchers wanted to see if it might be better at preventing the growth of these tumors when they are still small.

They injected mice with a breast-cancer cell line engineered to overexpress HER2. The mice received a low or a high dose of lapatinib, or a control solution, twice daily for 24 days. Those that received lapatinib in either dose developed half as many large metastases as those that received the control solution.

"What our model system shows is that lapatinib might prevent micrometastases from growing into life-threatening macrometastases," explained Dr. Patricia Steeg, senior author of the study. In the future, stated the authors, preventative therapy to suppress the growth of micrometastases could possibly be combined with standard treatments for large brain metastases, such as neurosurgery or radiation therapy.

Eliminating a Common Bacterium Reduces Risk of Second Gastric Cancer

Researchers in Japan have shown that when the bacterium Helicobacter pylori is eliminated in patients who are treated for early stage gastric cancer, the risk of developing a second gastric cancer decreases by two-thirds. Their report appeared August 2 in The Lancet.

H. pylori infects the stomachs of approximately half the people in the world and has been clearly linked to stomach problems, including peptic ulcers and cancer. Previous studies in animals have shown a preventive effect when the bacterium is eliminated, but results in human studies have been inconclusive.

The latest report, published by the Japan Gast Study Group, comes from an open-label study that included 544 patients aged 20-79 who were either newly diagnosed with gastric cancer and planning to undergo endoscopic surgery, or who had recently undergone surgery for gastric cancer. All patients had confirmed H. pylori infection. Those randomized into the test group received a combination of the antibiotics lansoprazole, amoxicillin, and clarithromycin twice a day for a week to prevent cancer recurrence, while those in the control group received standard care but no antibiotics.

The bacterium was eliminated from approximately 75 percent of patients who received the antibiotic regimen, and approximately 5 percent of patients from the control group. The only adverse effects of the antibiotic group with notable occurrence were soft stools and diarrhea. After 3 years of endoscopic monitoring, second gastric cancers occurred in 9 patients from the treated group and 24 patients from the control group.

An accompanying editorial discusses the benefits and drawbacks of widespread H. pylori screening and treatment, concluding, "Worldwide, gastric cancer kills more people [than colorectal cancer], and there is better evidence that H. pylori eradication can prevent mortality than there is for colonoscopy screening. Preventing gastric cancer by eradicating H. pylori in high-risk regions should be a priority."

Metastatic Process Disrupted by Targeting Tumor Cells' Cytoskeleton

Some tumor cells that travel to distant sites in the body and lay dormant for long periods require help from factors in their immediate environment to eventually develop into metastases, researchers reported in the August 1 Cancer Research. This conversion from hibernation to active growth, they found, is initiated by a reorganization of the dormant cells' interior cytoskeletal architecture, induced by signaling molecules immediately outside the cell in the extracellular matrix (ECM), and could be disrupted by targeting a molecular pathway that regulates the cytoskeleton.

Led by Dr. Dalit Barkan from NCI 's Laboratory of Cancer Biology and Genetics, the study used mouse models and a three-dimensional (3-D) culture system, in which signaling factors typically found in the tumor microenvironment could be introduced.

"We show that the switch from quiescence to proliferative metastatic growth is strongly influenced by interactions with the ECM," they wrote. The ECM surrounds cells and contains proteins, often signaling molecules, that other cells secrete.

Using cellular imaging techniques, the researchers showed that one protein component of the ECM, fibronectin, initiated reorganization of the dormant cells' interior cytoskeleton. This reorganization set the stage for the switch from quiescence to metastatic growth and was mediated by an enzyme called MLC kinase. In both the mouse models and the 3-D culture system, metastatic growth could be tamped down by interfering with MLC kinase activity.

"Our results suggest that targeting pathways affecting the cytoskeleton…may provide an important means of inhibiting the switch from tumor cell dormancy to clinical metastatic disease," the authors concluded. "This approach, perhaps in combination with immunotherapeutic strategies, may reduce the incidence of tumor recurrence from disseminated, dormant tumor cells."

Agent Safe, Active in Hormone-Refractory Prostate Cancer

An investigative agent that blocks the production of testosterone in tissue is a safe treatment for men with hormone-refractory prostate cancer and shows promising signs of clinical activity, British researchers report.

Published online July 21 in the Journal of Clinical Oncology, results from a 21-patient phase I trial involving the drug abiraterone acetate showed that it was safe and led to reductions in prostate-specific antigen (PSA) levels by as much as 90 percent in some patients. A majority of patients given the drug also had reductions in tumor size, both in the primary tumor and in metastatic tumors.

The trial, led by Dr. Johann de Bono from the Institute of Cancer Research, where the drug was developed, involved men with advanced, hormone-refractory (also called castrate-resistant) prostate cancer.

Some study participants have been taking the drug for as long as 2.5 years, "and with continued use of abiraterone they were able to control their disease with few side effects," Dr. de Bono explained in a news release. "A number of patients were able to stop taking morphine for the relief of bone pain."

Abiraterone - which has been licensed to the company that funded the trial, Los Angeles-based Cougar Biotechnologies - works by blocking the activity of CYP17, a key enzyme that helps cells produce androgen and estrogen. It's being tested in phase II and III studies of this same patient population.

While the findings have received a significant amount of media attention, particularly in the British press, some U.S. researchers urge caution. "A PSA decline or tumor shrinkage are only evidence of activity, and activity only means there's a need for a good randomized trial," said American Cancer Society Chief Medical Officer Dr. Otis Brawley. "The bottom line for patients and the public is we need a randomized trial showing longer survival time or improved quality of life as the endpoint."

Gene Signatures May Help Predict Lung Cancer Survival

A new study provides perhaps the strongest evidence yet that profiling the activity of genes in lung tumors yields information that can help physicians and patients make treatment decisions. Yet the researchers caution that lung tumors are genetically diverse and it may be difficult to develop a single gene signature that could reliably classify all patients. The findings appeared online in Nature Medicine July 20.

The NCI Director's Challenge Consortium for the Molecular Classification of Lung Adenocarcinoma analyzed 442 lung tumors from patients with known health outcomes. Previous research suggested that lung tumor signatures may provide information such as whether patients may benefit from aggressive treatments, but the signatures and the results often varied from study to study.

The Consortium developed new gene signatures, and their prediction models produced risk scores that correlated with the actual outcomes of patients. Most models performed better with clinical data, leading the researchers to conclude that prognostic models for early stage lung cancer should include both molecular and clinical information, as has been done in prostate and breast cancers.

Drs. David Beer of the University of Michigan Comprehensive Cancer Center and James Jacobson of NCI's Cancer Diagnosis Program led the study, which included a blinded validation step to assess the performance of new gene signatures.

"We put the Consortium together and initiated the study both to explore the challenges involved in carrying out these large confirmation studies for molecular signatures and to identify strategies that could be used to overcome these challenges," said Dr. Jacobson. "I think this work will be a reference point for how these studies should be carried out."

In addition to NCI and the University of Michigan, the Consortium includes researchers from the H. Lee Moffitt Cancer Center, Memorial Sloan-Kettering Cancer Center, Dana-Farber Cancer Institute, and the Ontario Cancer Institute.