Monthly Archives: February 2015

Cancer researchers at Indiana University report that about 15 percent of people with pancreatic cancer may benefit from therapy targeting a newly identified gene signature.

Using data from the Cancer Genome Atlas, Murray Korc, M.D., the Myles Brand Professor of Cancer Research at the Indiana University School of Medicine and a researcher at the Indiana University Melvin and Bren Simon Cancer Center, and colleagues found that a sub-group of pancreatic cancer patients who possess a strong angiogenic gene signature could benefit from personalized therapies that cut off the pathways that feed the cancer's growth.

This particular gene signature enables abnormal blood vessels to form in tumors, which feeds the tumor's growth.

The finding, published online Feb. 25 in the journal Oncotarget, is new because the prevalence of this signature was not previously known. The authors also demonstrated for the first time that endothelial cells, the main type of cell found in the inside lining of blood vessels, can produce molecules that directly stimulate the growth of pancreatic cancer cells.

"We showed that endothelial cells can stimulate the growth of pancreatic cancer cells and that by silencing or inhibiting certain pathways -- JAK1-2 and STAT3 -- we can alter that effect," Dr. Korc explained. "We demonstrated that it is possible to target these pathways and prolong the survival of genetically modified mice whose pancreatic cancers also have a strong pro-angiogenic gene signature."

Thus, for people with a strong pro-angiogenic gene signature, the finding suggests that they may benefit from targeted therapy that is directed against one of these pathways.

An important feature of the study was to demonstrate that it is possible to implant in mice small biopsy samples obtained from patients undergoing endoscopic procedures and to generate human tumors in these mice. When the original human tumor had evidence for angiogenesis, the implanted human tumor also exhibited angiogenesis in the mouse. Additional studies are necessary to confirm that these approaches could guide the design of precision medicine using targeted therapies, Dr. Korc said.

The need for new therapies for pancreatic cancer patients is great as only 7 percent of people with the disease survive more than five years after diagnosis. According to the American Cancer Society, there will be an estimated 48,960 new cases of pancreatic cancer and 40,560 deaths from the disease in 2015.

Co-authors of the study were Jesse Gore, Ph.D.; Stuart Sherman, M.D.; Harvey Cramer, M.D.; Hai Nguyen, M.D.; Kelly Craven, Monica Cheng, and Julie Wilson, all of IU School of Medicine, and Gregory Cote M.D. M.S., formerly of IU School of Medicine and now at the Medical University of South Carolina.

The study was made possible, in part, by grant CA-075059 awarded by the National Cancer Institute of the National Institutes of Health.

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Pancreatic cancer patients who benefit from personalized treatment identified

CHOP study of common variable immunodeficiency finds gene crucial to immune defense

IMAGE:Dr. Hakon Hakonarson is the director of the Center for Applied Genomics of The Children's Hospital of Philadelphia. view more

Credit: The Children's Hospital of Philadelphia

Genomics researchers analyzing a rare, serious immunodeficiency disease in children have discovered links to a gene crucial to the body's defense against infections. The finding may represent an inviting target for drugs to treat common variable immunodeficiency (CVID).

A team led by Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children's Hospital of Philadelphia (CHOP), reported their findings online Feb. 10 in the Journal of Allergy and Clinical Immunology.

The researchers found 11 single nucleotide polymorphisms (SNPs) on the 16p11.2 locus of chromosome 16. SNPs are changes in one letter of DNA, compared to the more typical sequence at a given location. Of particular interest, the study team found variants in the gene ITGAM, carrying codes for an integrin protein, which regulates cellular contact and adhesion.

"This association is of high biological relevance, because ITGAM plays an important role in normal immune responses," said Hakonarson. "Other researchers have shown that mice in which this gene has been knocked out have immune deficiencies." He added that his team's findings may have broader implications for patients who do not have these specific rare variants, because the integrin protein affects many important pathways in immune function.

A child with CVID has a low level of antibodies, reducing the body's ability to fight disease, and leaving the child vulnerable to recurrent infections. CVID can first occur early or later in life, and the symptoms are highly variable. Frequent respiratory infections may lead to permanent lung damage. Patients may also suffer joint inflammation, stomach and bowel disorders, and a higher risk of cancers.

The great variability of the disease and the lack of a clear-cut diagnostic test often mean that CVID goes undiagnosed for years before doctors can begin treatment.

The study team performed an association analysis that focused on immune-related genes in a cohort of 360 CVID patients and 21,610 healthy controls. They used a genotyping chip specialized to search for gene variants previously implicated in autoimmune and inflammatory diseases, to pinpoint SNPs associated with CVID.

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Novel gene variants found in a difficult childhood immune disorder

Genomics researchers analyzing a rare, serious immunodeficiency disease in children have discovered links to a gene crucial to the body's defense against infections. The finding may represent an inviting target for drugs to treat common variable immunodeficiency (CVID).

A team led by Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children's Hospital of Philadelphia (CHOP), reported their findings online Feb. 10 in the Journal of Allergy and Clinical Immunology.

The researchers found 11 single nucleotide polymorphisms (SNPs) on the 16p11.2 locus of chromosome 16. SNPs are changes in one letter of DNA, compared to the more typical sequence at a given location. Of particular interest, the study team found variants in the gene ITGAM, carrying codes for an integrin protein, which regulates cellular contact and adhesion.

"This association is of high biological relevance, because ITGAM plays an important role in normal immune responses," said Hakonarson. "Other researchers have shown that mice in which this gene has been knocked out have immune deficiencies." He added that his team's findings may have broader implications for patients who do not have these specific rare variants, because the integrin protein affects many important pathways in immune function.

A child with CVID has a low level of antibodies, reducing the body's ability to fight disease, and leaving the child vulnerable to recurrent infections. CVID can first occur early or later in life, and the symptoms are highly variable. Frequent respiratory infections may lead to permanent lung damage. Patients may also suffer joint inflammation, stomach and bowel disorders, and a higher risk of cancers.

The great variability of the disease and the lack of a clear-cut diagnostic test often mean that CVID goes undiagnosed for years before doctors can begin treatment.

The study team performed an association analysis that focused on immune-related genes in a cohort of 360 CVID patients and 21,610 healthy controls. They used a genotyping chip specialized to search for gene variants previously implicated in autoimmune and inflammatory diseases, to pinpoint SNPs associated with CVID.

"Our studies identified ITGAM as an exciting candidate gene for further research," said Hakonarson. "Better understanding of its functional role may reveal opportunities for highly targeted therapies that could improve future treatment for patients with this challenging, complicated disease. This discovery fits well with the 'precision medicine' concept that is currently in its infancy but represents the future of genomic medicine."

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The above story is based on materials provided by Children's Hospital of Philadelphia. Note: Materials may be edited for content and length.

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Novel gene variants discovered in a difficult childhood immune disorder