Category Archives: Transhuman News

Scientists from Weill Cornell Medical College and Houston Methodist have found that a gene previously unassociated with breast cancer plays a pivotal role in the growth and progression of the triple negative form of the disease, a particularly deadly strain that often has few treatment options. Their research, published in this week's Nature, suggests that targeting the gene may be a new approach to treating the disease.

About 42,000 new cases of triple negative breast cancer (TNBC) are diagnosed in the United States each year, about 20 percent of all breast cancer diagnoses. Patients typically relapse within one to three years of being treated.

Senior author Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College, wanted to know whether the gene -- already understood from her prior work to be a critical regulator of immune and metabolic functions -- was important to cancer's ability to adapt and thrive in the oxygen- and nutrient-deprived environments inside of tumors. Using cells taken from patients' tumors and transplanted into mice, Dr. Glimcher's team found that the gene, XBP1, is especially active in triple negative breast cancer, particularly in the progression of malignant cells and their resurgence after treatment.

"Patients with the triple negative form of breast cancer are those who most desperately need new approaches to treat their disease," said Dr. Glimcher, who is also a professor of medicine at Weill Cornell. "This pathway was activated in about two-thirds of patients with this type of breast cancer. Now that we better understand how this gene helps tumors proliferate and then return after a patient's initial treatment, we believe we can develop more effective therapies to shrink their growth and delay relapse."

The group, which included investigators from nine institutions, examined several types of breast cancer cell lines. They found that XBP1 was particularly active in basal- like breast cancer cells cultivated in the lab and in triple negative breast cancer cells from patients. When they suppressed the activity of the gene in laboratory cell cultures and animal models, however, the researchers were able to dramatically reduce the size of tumors and the likelihood of relapse, especially when these approaches were used in conjunction with the chemotherapy drugs doxorubicin or paclitexel. The finding suggests that XBP1 controls behaviors associated with tumor-initiating cells that have been implicated as the originators of tumors in a number of cancers, including that of the breast, supporting the hypothesis that combination therapy could be an effective treatment for triple negative breast cancer.

The scientists also found that interactions between XBP1 and another transcriptional regulator, HIF1-alpha, spurs the cancer-driving proteins. Silencing XBP1 in the TNBC cell lines reduced the tumor cells' growth and other behaviors typical of metastasis.

"This starts to demonstrate how cancer cells co-opt the endoplasmic reticulum stress response pathway to allow tumors to grow and survive when they are deprived of nutrients and oxygen," said lead author Dr. Xi Chen, a postdoctoral associate at Weill Cornell, referring to the process by which healthy cells maintain their function. "It shows the interaction between two critical pathways to make the cells better able to deal with a hostile microenvironment, and in that way offers new strategies to target triple negative breast cancer."

Scientists still need to study how those strategies would help women with the disease.

"Obviously we need to know now whether what our group saw in models is what we'll see in patients," said coauthor Dr. Jenny Chang, professor of medicine at Weill Cornell and director of the Houston Methodist Cancer Center. "We are very excited about the prospect of moving this research forward as soon as possible for the benefit of patients."

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Gene implicated in progression, relapse of deadly breast cancer finding points to potential Achilles' heel in triple ...

PUBLIC RELEASE DATE:

24-Mar-2014

Contact: Jen Gundersen jeg2034@med.cornell.edu 646-317-7402 Weill Cornell Medical College

NEW YORK (March 24, 2014) Scientists from Weill Cornell Medical College and Houston Methodist have found that a gene previously unassociated with breast cancer plays a pivotal role in the growth and progression of the triple negative form of the disease, a particularly deadly strain that often has few treatment options. Their research, published in this week's Nature, suggests that targeting the gene may be a new approach to treating the disease.

About 42,000 new cases of triple negative breast cancer (TNBC) are diagnosed in the United States each year, about 20 percent of all breast cancer diagnoses. Patients typically relapse within one to three years of being treated.

Senior author Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College, wanted to know whether the gene already understood from her prior work to be a critical regulator of immune and metabolic functions was important to cancer's ability to adapt and thrive in the oxygen- and nutrient-deprived environments inside of tumors. Using cells taken from patients' tumors and transplanted into mice, Dr. Glimcher's team found that the gene, XBP1, is especially active in triple negative breast cancer, particularly in the progression of malignant cells and their resurgence after treatment.

"Patients with the triple negative form of breast cancer are those who most desperately need new approaches to treat their disease," said Dr. Glimcher, who is also a professor of medicine at Weill Cornell. "This pathway was activated in about two-thirds of patients with this type of breast cancer. Now that we better understand how this gene helps tumors proliferate and then return after a patient's initial treatment, we believe we can develop more effective therapies to shrink their growth and delay relapse."

The group, which included investigators from nine institutions, examined several types of breast cancer cell lines. They found that XBP1 was particularly active in basal-like breast cancer cells cultivated in the lab and in triple negative breast cancer cells from patients. When they suppressed the activity of the gene in laboratory cell cultures and animal models, however, the researchers were able to dramatically reduce the size of tumors and the likelihood of relapse, especially when these approaches were used in conjunction with the chemotherapy drugs doxorubicin or paclitexel. The finding suggests that XBP1 controls behaviors associated with tumor-initiating cells that have been implicated as the originators of tumors in a number of cancers, including that of the breast, supporting the hypothesis that combination therapy could be an effective treatment for triple negative breast cancer.

The scientists also found that interactions between XBP1 and another transcriptional regulator, HIF1-alpha, spurs the cancer-driving proteins. Silencing XBP1 in the TNBC cell lines reduced the tumor cells' growth and other behaviors typical of metastasis.

"This starts to demonstrate how cancer cells co-opt the endoplasmic reticulum stress response pathway to allow tumors to grow and survive when they are deprived of nutrients and oxygen," said lead author Dr. Xi Chen, a postdoctoral associate at Weill Cornell, referring to the process by which healthy cells maintain their function. "It shows the interaction between two critical pathways to make the cells better able to deal with a hostile microenvironment, and in that way offers new strategies to target triple negative breast cancer."

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One in a thousand children in the United States is deaf, and one in three adults will experience significant hearing loss after the age of 65. Whether the result of genetic or environmental factors, hearing loss costs billions of dollars in healthcare expenses every year, making the search for a cure critical.

Now a team of researchers led by Karen B. Avraham of the Department of Human Molecular Genetics and Biochemistry at Tel Aviv University's Sackler Faculty of Medicine and Yehoash Raphael of the Department of Otolaryngology-Head and Neck Surgery at University of Michigan's Kresge Hearing Research Institute have discovered that using DNA as a drug -- commonly called gene therapy -- in laboratory mice may protect the inner ear nerve cells of humans suffering from certain types of progressive hearing loss.

In the study, doctoral student Shaked Shivatzki created a mouse population possessing the gene that produces the most prevalent form of hearing loss in humans: the mutated connexin 26 gene. Some 30 percent of American children born deaf have this form of the gene. Because of its prevalence and the inexpensive tests available to identify it, there is a great desire to find a cure or therapy to treat it.

"Regenerating" neurons

Prof. Avraham's team set out to prove that gene therapy could be used to preserve the inner ear nerve cells of the mice. Mice with the mutated connexin 26 gene exhibit deterioration of the nerve cells that send a sound signal to the brain. The researchers found that a protein growth factor used to protect and maintain neurons, otherwise known as brain-derived neurotrophic factor (BDNF), could be used to block this degeneration. They then engineered a virus that could be tolerated by the body without causing disease, and inserted the growth factor into the virus. Finally, they surgically injected the virus into the ears of the mice. This factor was able to "rescue" the neurons in the inner ear by blocking their degeneration.

"A wide spectrum of people are affected by hearing loss, and the way each person deals with it is highly variable," said Prof. Avraham. "That said, there is an almost unanimous interest in finding the genes responsible for hearing loss. We tried to figure out why the mouse was losing cells that enable it to hear. Why did it lose its hearing? The collaborative work allowed us to provide gene therapy to reverse the loss of nerve cells in the ears of these deaf mice."

Although this approach is short of improving hearing in these mice, it has important implications for the enhancement of sound perception with a cochlear implant, used by many people whose connexin 26 mutation has led to impaired hearing.

Embryonic hearing?

Inner ear nerve cells facilitate the optimal functioning of cochlear implants. Prof. Avraham's research suggests a possible new strategy for improving implant function, particularly in people whose hearing loss gets progressively worse with time, such as those with profound hearing loss as well as those with the connexin gene mutation. Combining gene therapy with the implant could help to protect vital nerve cells, thus preserving and improving the performance of the implant.

More research remains. "Safety is the main question. And what about timing? Although over 80 percent of human and mouse genes are similar, which makes mice the perfect lab model for human hearing, there's still a big difference. Humans start hearing as embryos, but mice don't start to hear until two weeks after birth. So we wondered, do we need to start the corrective process in utero, in infants, or later in life?" said Prof. Avraham.

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From mouse ears to human's? Gene therapy to address progressive hearing loss

PUBLIC RELEASE DATE:

24-Mar-2014

Contact: Andrea Grossman 617-636-3728 Tufts University, Health Sciences Campus

Boston, MA [March 24, 2014, 3:00 p.m. EDT] A single gene appears to play a crucial role in coordinating the immune system and metabolism, and deleting the gene in mice reduces body fat and extends lifespan, according to new research by scientists at the Jean Mayer USDA Human Nutrition Research Center (USDA HNRCA) on Aging at Tufts University and Yale University School of Medicine. Their results are reported online today in the Proceedings of the National Academy of Sciences.

Based on gene expression studies of fat tissue conducted at the USDA HNRCA, the Tufts University researchers initiated studies of the role of FAT10 in adipose tissue and metabolism. "No one really knew what the FAT10 gene did, other than it was 'turned on' by inflammation and that it seemed to be increased in gynecological and gastrointestinal cancers." said co-author Martin S. Obin, Ph.D., an adjunct scientist in the Functional Genomics Core Unit at the USDA HNRCA at Tufts University. "Turning off the FAT10 gene produces a variety of beneficial effects in the mice, including reduced body fat, which slows down aging and extends lifespan by 20 percent."

Typically, mice gain fat as they age. The authors observed that activation of the FAT10 gene in normal mice increases in fat tissue with age. Mice lacking FAT10 consume more food, but burn fat at an accelerated rate. As a result, they have less than half of the fat tissue found in normal, aged mice. At the same time their skeletal muscle ramps up production of an immune molecule that increases their response to insulin, resulting in reduced circulating insulin levels, protection against type 2 diabetes and longer lifespan.

The authors note that eliminating FAT10 will not fully address the dilemma of aging and weight gain. "Laboratory mice live in a lab under ideal, germ-free conditions," said Obin, who is also an associate professor at the Friedman School of Nutrition Science and Policy at Tufts University. "Fighting infection requires energy, which can be provided by stored fat. Mice without the FAT10 gene might be too lean to fight infection effectively outside of the laboratory setting. More research is needed to know how to achieve that balance in mice and then hopefully, at some point, people."

The possibilities for future research of FAT10 are exciting. Recent high-profile studies reported that FAT10 interacts with hundreds of other proteins in cells. Now the Tufts and Yale researchers have demonstrated that it impacts immune response, lipid and glucose metabolism, and mitochondrial function.

"Now there is dramatic road map for researchers looking at all of the proteins that FAT10 gets involved with," said co-first and corresponding author Allon Canaan, Ph.D., an associate scientist in the Department of Genetics at Yale. "Blocking what FAT10 does to coordinate immunity and metabolism could lead to new therapies for metabolic disease, metabolic syndrome, cancer and healthy aging, because when we knock it out the net result is mice live longer."

Canaan and colleagues initially developed the FAT10-deficient mouse to study the role of FAT10 in sepsis. In an attempt to increase sensitivity for sepsis, Canaan aged the FAT10 knockout mice and made the discovery that mice lacking the gene were lean and aged more slowly. The mice appear younger and more robust than comparably-aged normal mice, have better muscle tone, and do not develop age-related tumors.

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Deletion of FAT10 gene reduces body fat, slows down aging in mice