United States, Latin America Partner on Cancer Research

The National Cancer Institute formalized bilateral partnerships last month with the governments of Argentina, Brazil, Mexico, and Uruguay, to accelerate progress against cancer in Hispanic populations in the United States and Latin America, and improve cancer research. Dr John Niederhuber, NCI director, representing the U.S. Department of Health and Human Services, signed formal letters of intent to collaborate in cancer research efforts. These countries, along with Chile, which signed a letter of intent in June, and the United States, comprise the United States-Latin America Cancer Research Network. The Network is committed to developing a comprehensive understanding of the cancer burden among Hispanic populations in Latin America and the United States, and to enhance the cancer research and care infrastructures in both regions of the hemisphere.

Spearheaded by NCI’s Office of Latin American Cancer Program Development, this partnership will support the co-development of programs in three broad scientific areas: cancer research and clinical trials; multinational and multidisciplinary training programs; and technology and capacity building. The Latin American countries and the United States will link their research efforts through the cancer Biomedical Informatics Grid, an information network enabling the US-LACRN members to share data and knowledge. The network participants will also initiate pilot projects to expand research efforts and improve the delivery of cutting-edge cancer treatments to patients in the United States and Latin America.

In Latin America, cancer is among the top three deadliest diseases, and its incidence in these countries continues to rise. Cancer also takes a large toll on Hispanic/ Latino populations in the United States. It is estimated that the U.S. Hispanic population will climb to nearly 60 million, and represent approximately 19% of the U.S. population by 2020. Reducing the burden of cancer in the United States and abroad will depend heavily on understanding and controlling cancer in this population.

For the first pilot project of this collaboration, the countries identified research concepts that are intended to improve breast cancer management in Latin America. At the same time, they will provide an opportunity to enhance research training, capacity building, and establishment of a sustainable clinical research infrastructure for future projects. The effort builds on collaborative resources among the countries as well as cosponsorships of workshops and conferences with domestic and international foundations and organizations to support cancer research in Latin America.

Second Copy of Gene Explains Rare Bone Cancer

Scientists have discovered that a familial form of a rare bone cancer called chordoma is explained not by typical types of changes or mutations in the sequence of DNA in a gene, but rather by the presence of a second copy of an entire gene. Inherited large structural changes, known as copy number variations, have been implicated in some hereditary diseases, but have seldom been reported as the underlying basis for a familial cancer. This finding appeared online Oct 4, 2009, in Nature Genetics, and was done by researchers at the National Cancer Institute and their colleagues.

Usual types of gene mutations and gene duplications are permanent changes to the DNA that a person inherits from parents. These changes often alter the expression of the affected gene in ways that lead to cancer and other diseases. The new finding highlights the importance of CNVs, as well as typical specific genetic mutations, in the genetic development of cancer.

Chordoma affects about 1 in every 1 million people in the United States, with about 300 new cases diagnosed each year. Those affected with the disease usually develop a tumor at the base of the skull, or at any point along the spinal column, including the tailbone. The growths are thought to arise from remnants of the notochord, an embryonic precursor to the spinal column. There are few effective treatments and no cure for chordoma; many people with the non-familial form of chordoma die within 10 years of diagnosis.

The researchers based their initial finding on a study of a large family with a history of chordoma that spanned several generations. Because of the familial nature of this cancer, the researchers searched for a genetic alteration that could help explain the increased risk to family members. Initially they considered possible defects on chromosome 7, but no mutation was found that was shared by all affected relatives. The researchers then conducted further linkage studies, which look for patterns that appear in every affected member of a family, and found six new areas in the genome that warranted further study. The area that looked to be the most promising was on chromosome 6, in a region that contained a gene related to notochord development that is called the T gene or brachyury.

The scientists then looked for CNVs in the region on chromosome 6 that included the T gene in DNA from seven families (65 people, including 21 chordoma patients) in which at least two blood relatives had the disease. The scientists found that in four of the families, all of those with the disease had a second copy of the T gene. The duplications were not found in the chordoma patients from the other three families or in 100 healthy normal controls.

Based on their finding that duplications of the T gene cause an increased risk for chordoma in some families, the scientists suggest that future efforts to identify novel genes for familial cancers may benefit from screening for complex genomic rearrangements in addition to using traditional gene-mapping approaches.

Prostate Tumors Can Change Immune Cell Function in Mice

Researchers have discovered that prostate tumors in mice can cause immune cells known as CD8+ T cells to change their function from cells that have antitumor activity to cells that suppress immune responses. This finding by researchers at the National Cancer Institute, has important implications for the design of immune-based therapies for cancer. The new study, available online, appeared in the Oct. 15, 2009, issue of the Journal of Immunology. According to the research team, studying this process in mice may help explain why some cancer patients have an initial response from immune-based therapy but which fails over time.

In mice and humans, when the immune system encounters a pathogen or other foreign invader, it responds by mounting an immune response. Part of this response involves the recruitment and activation of CD8+ T cells, which are also called cytotoxic T cells or killer T cells, to help destroy the invader. CD8+ T cells also play a role in immune responses against tumor cells. Other T cells, known as CD4+ T regulatory cells, work to suppress CD8+ T cell activity. Immune suppression by these regulatory T cells helps prevent the body from attacking its own cells. A high level of CD4+ T regulatory cells is also associated with poor prognosis of some cancers. Moreover, research in mice has shown that blocking the immune suppressive activity of these regulatory T cells enhances the body’s immunity against tumors, causing tumor growth to slow and improving the antitumor immune responses elicited by cancer vaccines.

Recent evidence in mice has suggested that CD8+ T cells can develop suppressive activities similar to those of CD4+ T regulatory cells. In addition, CD8+ suppressor cells have been found in cancer patients. The presence of these suppressor cells could explain earlier findings by Hurwitz’s team that prostate tumor-specific CD8+ T cells injected into prostate tumor-bearing mice migrate to the tumors but then become unresponsive, or tolerized, to the tumor cells. It remained unclear, however, whether the suppressive CD8+ T cells have suppressor activity before they reach the tumor or whether they are converted into suppressor cells by the tumor.

Researchers found that CD8+ T cells acquire immune suppressive functions after they enter the mouse tumor microenvironment, which encompasses nearby noncancerous cells and immune cells in addition to tumor cells. The researchers found that tumor-specific CD8+ T cells isolated from the tumors were able to suppress the proliferative capacity of nonspecific T cells, whereas tumor-specific CD8+ T cells isolated from lymph nodes of the mice were unable to do so.

This anti-proliferative activity appeared to be caused, in part, by substances secreted by the CD8+ T cells after they had been converted to suppressor cells. One of these substances, TGF-beta, is a protein that controls cell proliferation and differentiation and plays a role in cancer and other diseases. TGF-beta is thought to be involved in the immune-suppressive activity of CD4+ T-regulatory cells.

Next, the team investigated whether the conversion of tumor-specific CD8+ T cells to suppressor cells could be prevented. To do this, they administered tumor-specific CD4+ and CD8+ T cells to prostate tumor-bearing mice. Some CD4+ T cells act as helper cells and enhance the activity of other immune cells, including CD8+ T cells. The researchers found that, under these conditions, CD8+ T cells isolated from the prostate tumors no longer suppressed the proliferation of other T cells. Moreover, these cells produced less TGF-beta than cells that were not exposed to CD4+ T cells.

The researchers propose that activated CD4+ T cells that enter tumors may secrete factors that support the CD8+ T cell antitumor functions, or may help other immune cells located in the tumor block the processes by which CD8+ T cells acquire their suppressive activity. In the future, the researchers plan to focus on defining the mechanisms by which tumor-specific CD8+ T cells gain their suppressive functions upon entering the mouse tumor microenvironment.

Kidney Disease Data Available Sooner Than Expected

Incidence and prevalence data for end-stage kidney disease in the United States will be available online from the U.S. Renal Data System a year earlier than usual, the National Institute of Diabetes and Digestive and Kidney Diseases announced last month. In addition, the data will be updated online every 3 months and will show quarterly counts of patients at www.usrds.org/qtr/qrt_report_table_new.html.

The first of the new tables shows incidence and prevalence counts through December 2008. As the tables are updated quarterly, an additional 3 months of counts will be added. The next update in December 2009 will include patient counts through March 2009. Previously, incidence and prevalence data had been made available only through yearly updates of the USRDS Annual Data Report (www.usrds.org/adr.htm). Because the report includes detailed data from multiple sources, reporting lagged by about 18 months while data were merged and verified. For example, the 2009 report, which became available this month, has complete data only through 2007.

Data from the USRDS is used by researchers, government officials, health program planners, and others to develop research goals, assess public health needs, set program priorities, and inform policymakers and the public.

More than half a million people in the United States have end-stage kidney disease, requiring frequent dialysis treatments or a kidney transplant. People with the disease account for just 1.2% of the Medicare population, but accounted for 7.3% of Medicare costs in 2007. The total cost for the disease was $35.32 billion, including coverage by Medicare and other payers, such as employer group health plans.

Drug Targets Large Brain Tumors in Mice

The drug vorinostat is able to cross the blood-brain barrier and reduce the development of large metastatic tumors in mice brains by 62% when compared to mice that did not receive the drug, according to a new study. In humans, the drug has been approved by the Food and Drug Administration for the treatment of a cancer called cutaneous T-cell lymphoma, but can be used experimentally to study its effectiveness against other cancers. This research, by investigators at the National Cancer Institute and their collaborators, appeared online Sept. 29, 2009, in Clinical Cancer Research.

For people, while various therapies are improving the survival of breast cancer patients, the incidence of breast cancer spreading to the brain is increasing. Brain metastases of breast cancer have proven to be largely untreatable because the blood-brain barrier, which arises from the specialized structure of blood capillaries in the brain, severely limits drug access, and many drugs are actively transported out of brain at this barrier. Consequently, the one-year survival estimate for breast cancer patients after a diagnosis of brain metastasis is only about 20%.

Vorinostat has been found to slow the growth of primary tumors of several different types of cancer in mice. Previous studies have suggested that the drug can be taken up by the brain, although little was known about its effects on metastatic tumors. Therefore, to study the effect of vorinostat on the formation of brain metastases, scientists used a mouse model of human breast cancer. Human breast cells were cultured in the laboratory, and were injected into mice with compromised immune systems. The breast cancer cells then migrated to the brain, forming metastases.

The researchers found that vorinostat was absorbed readily into normal mouse brains, and accumulation of the drug was up to three-fold higher in some metastases treated with this drug when compared to surrounding brain tissue. Vorinostat also reduced the development of tiny tumors (micrometastases) in mice by 28% when compared with mice that did not receive this therapy.

The ability of vorinostat to reduce metastatic lesions in the brain was linked to a novel double-barreled mechanism — the drug can cause breaks in both strands of a DNA helix and can also lower the activity of a DNA repair gene called Rad52. The researchers hypothesize that the inability of the cancer cells to repair DNA damage would then slow the rate of tumor cell metastasis.

In June of this year, several researchers affiliated with this study published a paper in Molecular Cancer Therapeutics showing that vorinostat could enhance the effect of radiation therapy in mice with brain cancer metastasis. Mice that received implants of human breast tumors in their brains lived the longest after treatment with both vorinostat and radiation, demonstrating that the drug enhances the sensitivity of cancer cells to radiation therapy. The researchers believe that this finding combined with the new study establish a preclinical basis for testing the drug in clinical trials in humans.

NIDCR Launches On Targeting Facial Defects Research

Although about half of all birth defects involve the face and skull, scientists remain unclear about why most occur. In an attempt to integrate available clinical information on facial birth defects, the National Institute of Dental and Craniofacial Research (NIDCR) issued the first 11 research and technology grants of its new FaceBase Consortium last month. The five-year initiative will systematically compile the biological instructions to construct the middle region of the human face and precisely define the genetics underlying its common developmental disorders, such as cleft lip and palate. The mid-face includes the nose, upper lip, and the palate, or roof of the mouth.

As a key part of the initiative, a one-stop, encyclopedic database of head and skull, or craniofacial, development will be created and maintained to allow scientists to mine the riches of the information enabling them to more rapidly and effectively generate hypotheses and accelerate the pace of their research. The database, called FaceBase, will be free and publicly accessible to the scientific community. Its organizers anticipate that FaceBase will have a prototype ready within the next year and a fully functioning database soon after.

The NIDCR began organizing FaceBase 2 years ago. The initiative builds on two broad organizing principles. The first is to encourage the formation of multidisciplinary research teams and then a higher level of integration into a consortium with the idea being that not every research problem will be or even can be solved with a single approach. Most will require a range of tools and expertise, allowing a more powerful research synergy to peel away the many layers of biological complexity and reach the essence of the question. The 11 grants announced today will support the FaceBase Consortium, a collection of collaborative research teams at various sites around the country.

The second is for each team to target its efforts at one specific aspect, or theme, of craniofacial development. This will allow the initiative to cast a more comprehensive research net that avoids duplication of effort. The research teams will coordinate their efforts through a designated FaceBase hub that manages data integration, data sharing and organizational needs.

Another essential aspect of the initiative is the FaceBase database, which will build on the lessons learned of other biology-focused databases but mold its content to the specific interests and needs of craniofacial researchers. That includes learning how best to house data on biochemical, molecular, genetic and imaging studies. It also includes learning how best to display thousands of visual images of tissue morphology, or shape, after a specific gene has been disrupted in zebrafish, mice, and other organisms, a standard approach to determine a gene’s function. These images then will be linked to molecular data from other studies and these datasets will be made available to the scientific community.

back to October articles