National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
January 8, 2013 • Volume 10 / Number 1

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Cancer Research Highlights

Following Up on Genetic Study, Researchers Identify Potential Therapy for Bladder Cancer

In a recent study of bladder cancer, NCI researchers identified a genetic variant associated with a modest increase in risk of the disease. But, after investigating the biologic effects of the variant on cells, the researchers now believe that the variant could be a marker for identifying patients who may respond to an experimental therapy being tested in other cancers.

Up to 75 percent of patients of European descent with bladder cancer may have inherited the variant and could be candidates for the experimental treatment, the researchers reported last week in the Journal of the National Cancer Institute.

The variant occurs in a gene that encodes a protein found on the surface of cells. Many pancreatic and prostate tumors also highly express the protein, called the prostate stem cell antigen (PSCA). A monoclonal antibody called AGS-1C4D4 was developed to target the protein, and results from early-stage clinical trials in prostate cancer (here and here) have been reported.

"We believe the protein is also a promising potential therapeutic target for bladder cancer," said Dr. Ludmila Prokunina-Olsson of NCI's Division of Cancer Epidemiology and Genetics, who led the study. Whether the protein has a direct role in the disease is not yet clear, she added.

The variant (known as rs2294008) was identified during a genome-wide association study (GWAS) of bladder cancer in 2010. To follow up on this lead, the researchers created synthetic versions of the gene with and without the variant. Cells with the variant produced high levels of PSCA, whereas cells without the variant did not produce the protein. The researchers also observed this pattern in normal bladder and tumor tissues from patients.

The new results suggest that patients with bladder cancer who lack the variant would not benefit from therapy such as AGS-1C4D4 because their cells do not produce PSCA. Based on the findings, clinical trials are warranted to validate PSCA as a therapeutic target in bladder cancer and the variant as a predictive marker for treatment response, the study authors concluded.

The study provides "a good lesson that researchers need to understand more about the biology of the variants identified by GWAS," Dr. Prokunina-Olsson said. In this case, the variant was not strongly associated with bladder cancer risk, but further study revealed that it had strong biologic effects on expression of the protein.

"This is one of the first studies to show direct clinical implications of a genetic variant identified through genome-wide association studies for common cancers," Dr. Stephen Chanock, acting co-director for the NCI Center for Cancer Genomics, said in a statement.

Drug Combination Could Help Treat Deadly Form of Thyroid Cancer

New findings from cell and animal studies suggest that combination therapy with two anticancer drugs, paclitaxel and pazopanib, may help treat anaplastic thyroid cancer (ATC), a rare and deadly form of thyroid cancer. The preclinical study results, published January 2 in Science Translational Medicine, also point to a possible new treatment target for ATC.

"[This] seems like a potentially exciting combination for treating an incurable, aggressive malignancy … but human studies need to be done to see if it's effective," said Dr. Ann Gramza of NCI's Center for Cancer Research, who investigates new therapies for ATC but was not involved in the study. The median survival for ATC patients is only about 3 to 5 months, so "any treatment that has the potential to improve outcomes is welcome," Dr. Gramza added.

In a search for drug combinations that might be effective in treating ATC, Dr. Keith Bible of the Mayo Clinic in Rochester, MN, and his colleagues treated laboratory-grown ATC cells with paclitaxel alone and in combination with pazopanib.

"With combination treatment, we found that there was a delay in the process of cell division, which was associated with an enhancement of cell death. Cells treated with the combination could not successfully divide, and instead died," explained Dr. Bible. The drug combination also led to greater shrinkage of tumors formed by implanting ATC cells in mice than did either drug alone.

Further experiments showed that the combined effects of the two drugs are due at least in part to pazopanib's ability to block the activity of a regulatory protein called aurora A kinase, which is critical for cell division. This kinase appears to be a previously unrecognized target of pazopanib. The researchers also found that aurora A kinase messenger RNA and protein levels were significantly higher in tumor tissue from ATC patients than in normal thyroid tissue samples.

Thus, "aurora A looks to be an attractive candidate molecular target in ATC, especially when combined with drugs such as paclitaxel," Dr. Bible noted.

He and his colleagues have begun safety studies in patients with ATC in preparation for a randomized clinical trial to test whether paclitaxel plus pazopanib is more effective than paclitaxel alone when given with radiation therapy.

Although physicians view the prognosis for ATC patients as dire, "promising clinical and preclinical results are emerging that seem to be improving outcomes of patients with ATC," concluded Dr. Bible. "It is gratifying to see increasing efforts to try to improve therapy for these patients. Our ongoing clinical trial and this work represent but one such initiative."

Test May Inform Care of Women Infected with HPV

A new study has shown that women who test positive for human papilloma virus (HPV) but negative for the biomarker p16 do not need an immediate follow-up examination and can be safely rescreened for cervical cancer after 2 to 3 years. Dr. Guglielmo Ronco of the Centro per la Prevenzione Oncologica in Italy and his colleagues reported 3-year follow-up results of a substudy of the New Technologies for Cervical Cancer (NTCC) screening trial December 21 in Lancet Oncology.

Infection with high-risk HPV is the cause of almost all cervical cancers. Cervical cancer can be effectively prevented by treating precancerous cervical changes caused by HPV. Most infections with HPV resolve on their own within a few months or years, whereas cervical cancer can take 10 years or more to develop. Researchers are interested in finding screening tests to reduce unnecessary follow-up testing for women who would otherwise eventually clear the infection.

A group of women participating in the NTCC trial received HPV DNA tests; those who tested positive for high-risk HPV were referred for colposcopy, a procedure for detecting cervical precancer. They were also tested for the biomarker p16. A positive p16 test can indicate that cellular changes caused by HPV infection have occurred.

Previous results showed that a positive p16 test was sensitive and specific for patients with high-grade cervical intraepithelial neoplasia (CIN; classified as CIN2, CIN3, or higher), suggesting that women with a positive p16 test should be referred for colposcopy. But there were no prospective data that indicated how to manage women with a negative p16 test.

The researchers followed the study participants for 3 years after their initial screening to determine whether the screening interval for patients who were HPV positive but p16 negative could be safely extended. During the 3-year follow-up period, 9.7 percent of p16-positive women but only 1.7 percent of p16-negative women were found to have changes classified as CIN3 or higher. The relative risk of precancerous changes was also higher for p16-positive women between the ages of 35 and 60 compared with those aged 25 to 34 years.

The researchers suggested that using the p16 test to triage HPV-positive women can safely delay additional screening for p16-negative women for 2 to 3 years.

"Variations in health care settings and the availability of resources will also play a factor in determining screening intervals and how these tests may be used for HPV-positive women," said Dr. Nicolas Wentzensen of NCI's Division of Cancer Epidemiology and Genetics and the author of a commentary on the report. He noted that the study showed promising results, warranting further evaluation of p16 for triage of these women.

Other biomarkers for triage of HPV-positive women are being evaluated, but the study by Dr. Ronco and his colleagues is the first to look at 3-year follow-up data in a screening population.

Genetic Mutations Alone Do Not Dictate Cancer Cell Behavior

In laboratory experiments, researchers have found that colorectal tumor cells grown from a single cell behaved very differently, even though the cells were genetically identical. These findings, published last month in Science, suggest that cancer treatments may fail to eradicate tumors for reasons other than the standard rationale that cancer cells acquire more genetic changes as they multiply.

The researchers, led by Drs. Antonija Kreso and Catherine O'Brien of the University of Toronto, began by isolating single cells from 10 human colorectal cancers. They then transplanted each of these single cells into mice, where the single cells grew into tumors. The genomes of these tumor cells—including the mutations—were identical to that of the original founder cell. When the researchers transplanted cells from these tumors from one mouse to another, the genomes remained stable and did not acquire many new mutations, even when transplanted sequentially up to 5 times.

Despite having identical genomes, the cells within the new tumors behaved in different ways. Some cells reproduced consistently when transplanted from one mouse to another, while others lost their ability to reproduce over the course of one or several transplantations. And some cells seemed to regain their ability to reproduce after a period of dormancy—that is, they were not detected in the initial transplant but were detected in subsequent serial transplants, or they were detected in the initial transplant but not in one or more subsequent transplants and then became detectable again in later transplants. Genetic tests showed that the cells had not mutated enough to explain these different behaviors.

The researchers then tested whether the cells that behaved differently also responded differently to treatment with oxaliplatin (Eloxatin). Cancer cells from mice treated with the drug, when transplanted into new animals, produced tumors with a lower proportion of cells that had previously reproduced consistently and a higher proportion of cells that reproduced after a period of dormancy.

This finding suggests that "resting or slowly proliferating [colorectal cancer] cells can endure oxaliplatin treatment and reinitiate tumor growth," explained the authors.

"Our findings reveal another layer of complexity, beyond genetic diversity, that drives intratumoral heterogeneity of [colorectal cancer]," they added. The authors wrote that mechanisms underlying this nongenetic behavioral diversity could include interactions between tumor cells and their microenvironment, complex intracellular signaling networks, and epigenetic changes. Understanding how genetic changes and these nongenetic factors interact to confer treatment resistance should be a focus of future research, they concluded.

Also in the Journals: Substitute for Drug in Short Supply Found to Be Inferior

Several members of the Pediatric Hodgkin Lymphoma Consortium recently reported poorer outcomes among patients whose treatment regimens had been modified because of drug shortages. Since 2006, the group had been treating intermediate- and high-risk Hodgkin lymphoma patients with the Stanford V regimen, a combination of 7 drugs. When one of these drugs, mechlorethamine (Mustargen), became unavailable, the group substituted another drug, cyclophosphamide. Based on the available literature, the researchers believed the two drugs would be equally effective. The findings were reported last month in the New England Journal of Medicine.

But the researchers discovered that only 75 percent of patients who received cyclophosphamide were event-free after 2 years compared with 88 percent of those receiving mechlorethamine. Although no patients in the study have died, those who relapsed underwent treatments that carry greater risks of infertility and long-term toxic effects.

"Our results suggest that even promising substitute regimens should be examined carefully before adoption; what might appear to be a suitable alternative regimen may result in an inferior outcome—an intolerable situation for young people with curable disease," the authors concluded.

Further reading:

Also in the Journals: Video Explains Realities of CPR for Patients with Advanced Cancer

Cardiopulmonary resuscitation (CPR) does not revive most people with advanced cancer, and those who do survive often experience medical complications. A new study suggests that an educational video may help physicians communicate this information to patients in a meaningful way.

In the study, substantially more patients who watched a video depicting the realities of CPR were dissuaded from choosing the procedure than were patients who listened to a verbal explanation about the procedure's potential risks. The findings appeared last month in the Journal of Clinical Oncology.

The randomized trial included 150 patients with advanced cancer. Twenty percent of patients who watched the video wanted CPR compared with 48 percent of patients who received a verbal explanation. For patients still alive 6 and 8 weeks later, the percentages who wanted CPR remained about the same. A sample clip from the video can be viewed online.

Further reading: "Video Eases End-of-Life Care Discussions"

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