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Signaling Molecule Selectively Kills Breast Cancer Cells

Posted Apr 23 2011 10:34pm

Cancer Burden among People Infected with HIV Changing in U.S.

The number of cancers not traditionally associated with AIDS rose sharply between 1991 and 2005 among people living with HIV. Among contributing factors, the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s greatly prolonged survival for people living with HIV. As more of these people reach ages at which cancer risk increases, the number of these cancers is likely to continue to rise, Dr. Meredith Shiels of NCI’s Division of Cancer Epidemiology and Genetics (DCEG) and her colleagues reported online in the Journal of the National Cancer Institute on April 11.

The researchers collected data from the ongoing HIV/AIDS Cancer Match Study , which links 15 U.S. cancer registries and HIV registries, and from the Centers for Disease Control and Prevention (CDC) AIDS registries, which monitor the number of people living with AIDS in all 50 states.

The researchers found that though the number of people living with AIDS rose from 96,179 in 1991 to 413,080 in 2005, the estimated number of “AIDS-defining cancers” (that is, Kaposi sarcoma , non-Hodgkin lymphoma , and cervical cancer ) fell in most age groups, from 34,587 cancers during 1991-1995 to 10,325 cancers during 2001-2005. (A diagnosis of any one of these cancers can mark the point at which HIV infection has progressed to AIDS, which is why doctors call them “AIDS-defining.”)

In contrast, the estimated number of other cancers among the study subjects living with HIV nearly tripled, from 3,193 during 1991-1995 to 10,059 during 2001-2005. New cases of anal, liver, and lung cancers and Hodgkin lymphoma accounted for about half of the increase.

The authors proposed that the growing number of non-AIDS-defining cancers will require greater attention to cancer prevention and early detection among HIV-infected people. In addition, they stated, more research is needed to appropriately tailor cancer treatments to people with HIV. “As the HIV-infected population in the United States continues to grow and age, cancer will emerge as an important public health issue,” concluded the paper’s senior author, Dr. Eric A. Engels of DCEG.

Genetic   Study Yields New Clues to Melanoma

In the largest genetic survey of melanoma tumors to date, researchers have sequenced the genes of 14 untreated patients with advanced disease. The results , published online in Nature Genetics on April 15, point to additional genes and pathways not previously associated with melanoma that may play a role in the disease.

Dr. Yardena Samuels of the National Human Genome Research Institute and her colleagues sequenced the protein-coding genes (also called the exome) of tumor cells and of matched normal cells from the same individuals. The tissue samples came from patients subsequently treated by study co-author Dr. Steven Rosenberg, chief of the Surgery Branch in NCI’s  Center for Cancer Research .

The sequencing revealed alterations in 16 genes that may contribute to the disease. Among these, only the BRAF gene had been linked to melanoma previously. In an unexpected finding, the researchers discovered the same mutation in a gene called TRRAP in six different individuals with melanoma. TRRAP encodes a protein that helps control cell proliferation. The recurrent nature of the mutation at the same amino acid location suggests that it plays a role in the disease, the researchers noted.

Recurrent mutations were also found in a gene called GRIN2A. (The protein product of GRIN2A is a subunit of a type of glutamate receptor.) In a larger analysis of 135 melanoma tumors, the gene was mutated in 25 percent of the samples, making it one of the most highly mutated genes in melanoma identified so far. An analysis of signaling pathways confirmed that the glutamate pathway may play a role in melanoma, as had been reported previously in Nature Genetics.

“This is the most comprehensive view of the melanoma genetic landscape to date,” said Dr. Samuels, noting that many more genomes need to be sequenced to understand the genetic picture of the disease completely. The work builds on an earlier study by the same group that involved sequencing families of genes. A single whole-genome sequence of a patient with melanoma was first reported last year by researchers at the Wellcome Trust Sanger Institute.

“We can derive genetic data from tumors efficiently, and we can do the analysis,” Dr. Samuels said. “But the main challenge will be to find out which of the mutations are important in the disease and apply the findings to patient care.”

Signaling   Molecule Selectively Kills Breast Cancer Cells

Normal breast cells (mammary epithelial cells, or MECs) secrete a signaling molecule that kills breast cancer cells but does not harm healthy cells, researchers have found. The signaling molecule, known as interleukin -25 (IL-25), binds to receptors on the surface of breast cancer cells and triggers cell death. The findings appeared in Science Translational Medicine on April 13.

Dr. Saori Furuta of Lawrence Berkeley National Laboratory (LBNL) and her colleagues used a three-dimensional (3D) cell-culture system to study the growth and development of normal MECs and breast cancer cells. The 3D culture system, which simulates the structure of normal breast tissue, was developed in the laboratory of Dr. Mina Bissell of LBNL. She co-led the study with Dr. Wen-Hwa Lee of the University of California, Irvine.

The researchers identified six molecules produced by normal breast cells grown in 3D culture that either killed breast cancer cells or suppressed their growth. Of those six molecules, IL-25 had the most potent cell-killing (cytotoxic) effects on breast cancer cells grown in the 3D system.

“The cytotoxic activity of IL-25 was restricted to cancer cells that express the receptor IL-25R on the cell surface,” said Dr. Furuta. Additional experiments showed that, when IL-25 binds to its receptor, it sets off a process known as programmed cell death, or apoptosis . The body normally uses this process to eliminate unneeded or abnormal cells.

“IL-25 is naturally produced by healthy breast tissue and thus could be a natural defense mechanism against cancer,” Dr. Furuta noted.

Injecting mice with IL-25 once a day for 1 month dramatically slowed the growth of tumors formed by implanting human breast cancer cells in the mice but did not affect healthy breast tissue or other body tissues that the researchers examined.

The researchers also analyzed 69 human breast cancer biopsy samples and found that 19 percent of those samples were IL-25R-positive. “Importantly, these IL-25R-positive tumors were highly invasive and correlated to poor clinical outcome of patients,” Dr. Furuta said.

“These data suggest strongly that the IL-25/IL-25R signaling pathway may provide novel targets for treating aggressive breast cancers” that express the IL-25 receptor, the study authors conclude.

The researchers have patented their findings and are in the process of transferring the technology to a pharmaceutical company for further development, Dr. Furuta explained.

Also in the News:   ASCO Recommends Tumor Testing for Some Lung Cancer Patients

The American Society of Clinical Oncology (ASCO) has issued a Provisional Clinical Opinion (PCO) recommending that patients with advanced non-small cell lung cancer have their tumors tested for mutations in the gene that encodes epidermal growth factor receptor (EGFR) prior to taking drugs that inhibit signaling from EGFR as a first-line therapy. Patients whose tumors test negative for these mutations may benefit more from chemotherapy than from an EGFR inhibitor, such as erlotinib (Tarceva) or gefitinib (Iressa), according to the April 11 PCO.

“For patients who do not have the [EGFR] mutation, giving erlotinib first is not the right thing to do,” co-author Dr. Giuseppe Giaccone, chief of the Medical Oncology Branch at NCI’s Center for Cancer Research, said in a statement . “It does not work as well for those patients, and we may be losing the opportunity to give chemotherapy, which could be more effective.”

The PCO, which is intended to provide direction to doctors, is based on the results of five phase III clinical trials. At ASCO’s request, NCI’s Physician Data Query (PDQ) Adult Treatment Editorial Board provided a written analysis of the results of one of the trials, the IPASS study .

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