Recently by Scott Merville

A pivotal protein leads to autoimmune inflammation of the central nervous system in a mouse model of multiple sclerosis (MS) and potentially captures a key element of the human disease.

Researchers found that Peli1 plays a central signaling role in experimental autoimmune encephalomyelitis (EAE) and reported their findings in an advance online publication at Nature Medicine.

"The major implication of discovering a signaling role for Peli1 in this animal model is that it might also be significant in the pathogenesis of MS," said senior author Shao-Cong Sun, Ph.D., professor in MD Anderson's Department of Immunology.

Microglia cells involved in multiple sclerosis

Peli1 activates immune cells called microglia that promote inflammation in the central nervous system in response to tissue damage or invasion by microbes, directing a T cell attack. Sun and colleagues found that Peli1 is heavily expressed in microglial cells and is central to an abnormal, damaging autoimmune response.

Microglia are known to be crucial to the initiation of MS, an immune system assault on nerve fibers called axons and on myelin, the protective sheath around the axons.

Peli1 also initiates the destruction of a protein that otherwise would inhibit inflammation.

The researchers show that Peli1 tells another molecule to mark the protective Traf3 protein for destruction by the cell's proteasome. Traf3 restrains the MAPK molecular pathway, which activates a variety of genes involved in inflammation and T cell response.

With Traf3 degraded in the microglia, MAPK is unleashed.

Sun said the team is studying the pathway in human multiple sclerosis to replicate their findings and explore the possibilities for potentially treating MS.

Additional information

 

MD Anderson news release

Nature Medicine paper

"Cancer is a complex and heterogeneous disease driven by gene mutations. As we enter the era of personalized medicine, the characterization of the cancer genome has begun and will continue to influence diagnostic and therapeutic decisions in the clinic."

 

So begins Timothy Heffernan, Ph.D., associate director of target discovery at the Institute for Applied Cancer Science (IACS), in an article discussing how cancer genome discoveries have led to recent successes in oncology drug development through the identification of genetic alterations known as driver mutations.

 

"The translation of genomic data into drug development endpoints requires coordinated integration across multiple scientific disciplines. Genomic technologies provide comprehensive lists of genes that are altered in human cancer. Sophisticated computational models and powerful data analytics prioritize genes with the strongest weight of genomic evidence," he notes.

 

"Subsequent functional studies in relevant disease models provide biological significance by identifying genes that confer a proliferative and/or survival advantage to cancer cells.  Lastly, deep biological exploration is required to provide a mechanistic understanding of the gene's cancer-relevant activity," Heffernan writes.

 

Systematic approaches to apply genomic data

 

Heffernan's article in the current issue of the Insights and Developments newsletter discusses the systematic approaches implemented at IACS to functionalize genomic data and identify novel therapeutic targets.

 

  MD Anderson scientists Jim Allison and Hagop Kantarjian, at left, and Guillermina Lozano and Gabriel Hortobagyi, at right, won four of 14 individual awards for senior scientists at the AAACR Annual Meeting 2013 in Washington, D.C.

Highlights

Scientists and clinicians from across MD Anderson presented their latest research findings at the AACR Annual Meeting 2013 in Washington, D.C. 

A record six scientists, from post-doctoral fellows to junior faculty to senior investigators, won awards at the meeting run by the American Association for Cancer Research, the oldest and largest organization dedicated to cancer research in the world.

By the numbers, MD Anderson faculty members, post-docs and graduate students presented (follow link to Advanced Search, type MD Anderson in institution box):

• 160 research posters in 152 poster sessions.
• 25 oral presentations or invited talks
• 10 educational sessions
• 4 lectures tied to major awards.

Highlighted work included research by Xifeng Wu, M.D., Ph.D., professor and chair of the Department of Epidemiology, showing that low bilirubin levels in the blood are a sign of high risk for lung cancer among male smokers.

Elsa Flores, Ph.D., associate professor in the Department of Biochemistry and Molecular Biology, Her presentations included one that shows p63 and p73 can provide back-up tumor suppression when their more famous sibling, p53, is inactivated.  However, they also need to be protected from themselves or they might shut down all three tumor-blocking genes.

Ellen Gritz, Ph.D., chair and professor of the Department of Behavioral Sciences, co-authored a new AACR statement urging physicians to more closely monitor their patients' tobacco use and to provide smoking cessation information during clinical visits. 

The first of six awards to scientists at The University of Texas MD Anderson Cancer Center at this year's AACR Annual Meeting 2013 went to Guillermina "Gigi" Lozano, Ph.D., chair and professor in the Department of Genetics.

 

LozanoSaturday received the 16^th annual Women in Cancer Research Charlotte Friend Memorial Lectureship awarded by The American Association for Cancer Research (AACR), recognizing her contributions to the field of cancer research and the advancement of women in science.

 

Lozano delivered her award lecture, "Activities of Mutant p53 Proteins in Cancer," Saturday evening.

 

Expert on tumor-suppressor p53

 

Lozano presented her research showing that the chemotherapy drug doxorubicin is more effective against breast cancer with mutant p53 rather than normal p53. 

 

"It is an incredible honor to be in the same company as Dr. Friend, a researcher who has inspired future generations of female scientists looking to excel in their research," said Lozano. "What drives me is the hope that someday my research will translate into novel therapies targeting p53, ultimately impacting clinical care and saving the lives of patients affected by cancer."

For years, scientists have crafted vaccines designed to treat cancer, rather than to prevent it, by priming the immune system to track down and kill tumors.

They identify antigens - distinctive targets - on tumors, combine them with substances (adjuvants) to enhance immune response, and then inject the vaccine to treat a given cancer.

A frustrating pattern emerged, says Willem Overwijk, Ph.D. associate professor in MD Anderson's Department of Melanoma Medical Oncology.  In both mouse experiments and human clinical trials, the vaccines created abundant T cells specialized to find the antigen and destroy cells that have it.

These T cells were easily observed in the bloodstream, yet there was little or no effect on tumors in the vast majority of cases.

Overwijk and colleagues decided to focus their attention on potential problems in the vaccine itself.  What they found, reported this week in Nature Medicine, could profoundly alter vaccine design and effectiveness.

"We discovered that only a few T cells actually get to the tumor, while many more are stuck or double back to the vaccination site," Overwijk says.

 

 A phase 2 clinical trial of a targeted therapy provides evidence that there might, at last, be a treatment that shrinks or stifles the growth of recurrent low-grade serous ovarian cancer.

Women who have low-grade disease tend to be younger and survive longer than those with high-grade ovarian cancer, but when their cancer persists or comes back, it almost always thwarts treatment. Between 2% and 4% of patients respond to chemotherapy.  Hormonal therapies do modestly better, with a 9% response rate.

In the clinical trial of the drug selumetinib published in the February edition of The Lancet Oncology, eight of 52 (15 percent) patients had a complete or objective partial response (tumor shrinkage) and 34 (65 percent) had no disease progression during the two-year course of the study.

"These are remarkably encouraging results for what can ultimately be a devastating disease," says David Gershenson, M.D., professor in MD Anderson's Department of Gynecologic Oncology and Reproductive medicine, the paper's senior author.

Selumetinib hasn't made Doris Elliott's recurrent low-grade ovarian cancer disappear. But it shrank all of her tumors and has arrested their development for five years running. 

For Dotsy Elliott, cancer under control for five years and counting

After her diagnosis in 1997, six rounds of chemotherapy kept  cancer at bay until 2005. Surgery and nine rounds of chemotherapy did little to slow progression. Another clinical trial helped for about 18 months.

A key to the perils of endless injury repair, the molecular path from stress through a cancer-promoting gene to ovarian cancer progression, and signals by endothelial cells that strengthen  colorectal cancer are among recent discoveries by MD Anderson researchers.

By uncovering these new connections, scientists expose new potential targets for fibrosis, the lethal scarring of organs, and cancer.

Endothelial cells make cancer cells tougher, more dangerous 

Blood vessels feeding colorectal cancer tumors are delivering more than oxygen and nutrients. They also flip a molecular switch that sends a signal to nearby cancer cells telling them to convert to colorectal cancer stem cells.

"Cancer stem cells initiate and sustain tumor growth, promote metastasis and resistance to chemotherapy and have a variety of other attributes," says Lee Ellis, M.D., of MD Anderson's Department of Surgical Oncology. The blood vessels cells activate Notch signaling.  Drugs in  clinical trials attack Notch. 

News release and Cancer Cell paper

Stress hormone breaks dam, cancer-promoting flood follows

The hormone noradrenaline turns on the oncogene Src, which promotes ovarian cancer growth and spread through beta-adrenergic (ADRB) receptors expressed on tumor cells.

"When Src is triggered by stress, it works like a dam letting out water that causes a flood downstream. Src, like the dam, is a master regulator switch that causes a chain reaction in the cells," says Anil Sood, M.D., of the departments of gynecological medical oncology and cancer biology. One implication: beta blockers might work against ovarian cancer.

News release and Nature Communications paper

Protein plays pivotal role in scarring that destroys organs

When the body's wound-healing process gets endlessly turned on, the tissues that provide a scaffold for injury repair can destroy the kidneys, liver and lungs. This process, known as fibrosis, also is tightly tied to cancer.

"Fibrosis is wound-healing that never stops. The body thinks an injury exists when it doesn't, so it just keeps going, producing scars that clog an organ's system and destroy its functional tissue until it fails," says Raghu Kalluri, Ph.D., M.D., chair of the Department of Cancer Biology. Kalluri and colleagues identified the role of HE4 in promoting fibrosis. A test already approved for ovarian cancer detects HE4 levels in the blood.

News release and Nature Medicine paper

When a crucial enzyme is dotted with targets that summon an attack by a cell's protein-destroying complex, another molecule comes to the rescue, blinding the attacker by wiping off the targets. 

The enzyme, called TRAF3,  survives to control a molecular network that's implicated in a variety of immune system-related diseases if left to its own devices.

University of Texas MD Anderson Cancer Center scientists identified TRAF3's savior and demonstrated how it works in a paper published online this week in Nature.

By discovering the role of OTUD7B as TRAF3's protector, Shao-Cong Sun, Ph.D., professor in MD Anderson's Department of Immunology, and colleagues filled an important gap in their understanding of a molecular pathway discovered in Sun's lab.

"Genetic defects or constant degradation of TRAF3 lead to the uncontrolled activity of what we call the non-canonical NF-kB pathway. This in turn, is associated with autoimmune diseases and lymphoid malignancies such as multiple myeloma and B cell lymphomas," Sun said. "Understanding how the degradation of TRAF3 is regulated is extremely important."

Cancer begins when a single cell goes haywire.  Now the keys to understanding that cell's transition to lethal tumor may be found in the unprecedented analysis of single tumor cells.

By isolating, capturing and then analyzing the genome of individual cells, Nicholas Navin, Ph.D., assistant professor in MD Anderson's Department of Genetics, proposes to identify the mutations that allow a primary tumor cell to escape into the bloodstream and then to establish a deadly colony in another organ.

Successfully analyzing differences in active mutations among single cells would help researchers understand, map and eventually block the lethal path to metastasis - the spread of the primary cancer to other organs.  Primary tumors are rarely lethal, Navin notes, but their genetic diversity from cell to cell hinders scientists' ability to understand metastasis.

The Damon Runyon Cancer Research Foundation will give Navin the opportunity to try his unique approach.  He is the Nadia's Gift Foundation Innovator, one of only seven 2013 Damon Runyon-Rachleff Innovation Awards announced earlier this month.

The foundation announcement notes the innovation awards are for "cancer research by exceptionally creative thinkers with "high-risk/high-reward" ideas who lack sufficient preliminary data to obtain traditional funding." Navin's approach "will have myriad clinical applications, which have prognostic value in predicting invasion, metastasis, survival and response to chemotherapy."

 

Patients with chronic myeloid leukemia (CML) or acute lymphoblastic leukemia that carries the Philadelphia chromosome (Ph+ALL) who can't tolerate the targeted drugs that revolutionized care for these leukemias now have three new options.

The U.S. Food and Drug Administration (FDA) has approved  three new drugs in the past few months. Ponatinib (Iclusig) was approved last week, an effective drug for many patients with  treatment-resistant disease. This comes on the heels of approvals of bosutinib (Bosulif) in September and omacetaxine (Synribo) in October.

Patients with both leukemias have enjoyed strong responses to imatinib (Gleevec) and second-generation drugs nilotinib (Tasigna) and dasatinib (Sprycel).  All work by inhibiting proteins called tyrosine kinases on leukemia cells, in particular the aberrant BCR-ABL protein that causes these diseases.

However, 30-40 percent of patients' CML resists imatinib. Nilotinib and dasatinib work for about 40-50 percent of those patients.

"It's important to have as many therapies against cancer as we can, because rarely does one drug or combination succeed for all patients," said Jorge Cortes, M.D., professor in MD Anderson's Department of Leukemia.  "These new drugs cover different gaps in treatment, so they can serve our patients in different ways."