Cancer Frontline

Arrested development: Suffocating cancer cells cheat death with immature miRNA

2013-05-23T22:34:41Z

The epidermal growth factor receptor (EGFR) often goes haywire in cancer, sending constant, urgent signals into a cell, telling it to grow and divide.

But in oxygen-starved conditions, EGFR also stifles production of tumor-suppressing microRNAs, a team of scientists led by MD Anderson researchers reported online at the journal Nature.

"When hypoxia stresses a cell, signaling by EGFR prevents immature miRNAs from growing up to fight cancer," said senior author Mien-Chie Hung, Ph.D., professor and chair of MD Anderson's Department of Molecular and Cellular Oncology and holder of the Ruth Legett Jones Distinguished Chair.

While most cancer cells die when drugs are administered under oxygen-starved conditions, those that survive are highly resistant to subsequent treatment.

Hung said most of the miRNAs left stuck in adolescence by EGFR under hypoxia have previously been reported to have tumor-suppressing characteristics.

]]> EGFR stifling of AGO2 associated with shorter patient survival

Hung and colleagues found that EGFR attaches phosphate groups to the protein argonaute 2 (AGO2), a crucial component of a three-protein complex that converts precursors into mature miRNAs capable of regulating gene expression. This phosphorylation keeps AGO2 from connecting properly with other proteins to form that miRNA-maturation machinery.

The scientists established the EGFR-AGO2 effect in cell line experiments, confirmed it in a mouse model and human breast cancer samples, then found that it reduced breast cancer patient survival.

The hypoxia-EGFR-AGO2 connection was strong in tumor samples from 128 breast cancer patients, but it was low or absent in normal breast tissue.

In 125 breast cancer cases analyzed by the team, half of 62 patients with high levels of phosphorylated AGO2 survived to 48 months and beyond. Median survival had not been reached for the 63 patients in the low-level group, but 78 percent had survived to 48 months.

A first: growth factor signaling regulates miRNA

The group's findings point to a potential new prognostic marker for breast cancer, Hung noted, but also provide the first evidence of a growth factor signaling pathway regulating miRNA maturation.

The two process have been separate, as if one "spoke Chinese and the other English," Hung said. "This is the first paper to show how they communicate." It's likely, Hung said, that other growth factors such as platelet-derived growth factor or insulin-like growth factor might also regulate miRNA processing.

Interestingly, this EGFR signaling occurs right up to the brink of the receptor's destruction by cellular processes triggered by oxygen-starved conditions. EGFR is pulled from its position sticking out of the cell's outer membrane and dragged into cavities called vesicles, from which it is shifted to membrane-bound lysosomes that dissolve proteins.

EGFR is known to continue signaling from the vesicles, so its capture prolongs its activity in hypoxic conditions.

Additional information

MD Anderson news release

Nature paper

Fast food restaurants contribute to African-Americans tipping the scale

2013-05-17T23:57:31Z

The U.S. Centers for Disease Control and Prevention estimates obesity to be a contributing factor to millions of dollars in health care costs and anywhere from 100,000 to 400,000 deaths a year. Easy access to less healthy foods such as fast food has helped widen the gap between ethnic groups when it comes to body mass index (BMI), according to researchers at The University of Texas MD Anderson Cancer Center.

A study, published this week in the American Journal of Public Health, found African-American adults living close to a fast food restaurant are more likely to have a higher BMI than those living farther away. The study also found that those living within 2 miles of a fast food restaurant with income of $40,000 or less were strongly associated with having a higher BMI.

A person is considered overweight with a BMI between 25 and 29, and considered obese with a measurement of 30 and over. Current research shows that African-Americans experience the highest rate of obesity with 38.8 percent of black men being obese and 58.5 percent of black women being obese.

"In fact, African-American women have the highest rates of obesity compared to Caucasians and Hispanics in the U.S.," said Lorraine Reitzel, Ph.D., assistant professor in MD Anderson's Department of Health Disparities Research and lead investigator on the study.

]]> The study examined associations of fast food restaurant density around the home and the proximity to the home of 1,467 participants from the Project CHURCH study - MD Anderson's collaborative project with Windsor Village United Methodist Church in Houston.

Most fast foods tend to be high in calories and fat, and cause weight gain, especially if a person is not burning the calories with physical activity. "People are looking for convenience on a low budget," Reitzel said. "Fast food is affordable and easily accessible to those living in low-income environments."

The study found that every additional mile participants lived from the closest fast food restaurant was associated with a 2.4% lower BMI.

Reitzel said further research is needed. "Longitudinal studies of where people are eating, what they are eating and how many times a week they are eating at fast food restaurants would be beneficial to helping us understand the behaviors and how to develop interventions to deal with this problem."

Additional information

MD Anderson news release

AJPH paper

Key protein fires up central nervous system inflammation

2013-05-01T23:06:32Z

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

Challenges and opportunities in drug discovery and development

2013-04-29T14:16:53Z

"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.

]]> In a separate article Philip Jones, Ph.D., head of drug discovery at IACS continues his discussion, the second article of a three-part series, of key components in a successful drug discovery and development program, as well as the strategies that IACS has implemented to speed the delivery of innovative targeted therapies to patients.

In the inaugural issue of the newsletter Jones discussed the inherent challenges in translating scientific discoveries into effective therapies. Here he covers the critical role that target selection and validation contribute to program success.

Jones describes the rigorous target selection process that IACS employs, which considers, "(1) biologic relevance to tumorigenesis and general physiology; (2) tractability/technical feasibility of a drug discovery program; (3) clinical translatability (how a novel therapy would be used clinically); and (4) issues including competition, toxicity, freedom to operate and decision points."

Patient-centered drug discovery

Once a program is launched, an iterative workflow involving multiple disciplines commences. Because IACS is committed to delivering clinical candidates and not just tool compounds, Jones notes potential drugs must be "simultaneously optimized for multiple properties," including potency, pharmacokinetics and potential side effects.

IACS' approach is focused around three key tenets, which are: right target, right drug and right patients. In the final installment of this series, due out in June, Jones will address key aspects of translational research and clinical development. By connecting these three pillars, IACS and the broader MD Anderson community hope to address the critical need of patients for targeted and effective treatments.

Additional information

IACS website

Read about IACS projects to target resistant cancers and to develop immunotherapies in the latest issue of Conquest Magazine.

MD Anderson cancer research revealed, honored at AACR annual meeting

2013-04-10T21:36:13Z

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.

]]> Awards

Guillermina Lozano, Ph.D., professor and chair of the Department of Genetics, was awarded the 16th Annual AACR-Women in Cancer Research Charlotte Friend Memorial Lectureship.

Gabriel Hortobagyi, M.D., professor of Breast Medical Oncology, was honored with the 8^th Annual AACR-Minorities in Cancer Research Jane Cooke Wright Lectureship.

Hagop Kantarjian, M.D., chair and professor of the Department of Leukemia, won the AACR Joseph H. Burchenal Memorial Award for Outstanding Achievement in Clinical Research.

James Allison, Ph.D., chair and professor of the Department of Immunology, earned the First AACR-CRI Lloyd J. Old Award in Cancer Immunology.

Kenneth Tsai, M.D., Ph.D., assistant professor in the Departments of Dermatology and Immunology, won the Sixth Annual Landon Foundation-AACR INNOVATOR Award for Cancer Prevention Research, the second year in a row an MD Anderson scientist has won the honor..

Postdoctoral fellow Maria Pia Morelli, M.D., Ph.D., was awarded the 2013 Fight Colorectal Cancer-AACR Fellowship in Memory of Lisa Dubow.

Also, Anirban Maitra, M.B.B.S., who will soon join MD Anderson as scientific director and co-director of the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, was part of the Johns-Hopkins pancreatic cancer genetics group that won the AACR's team science award.

AACR Academy

Five scientists also were among the first appointed to the newly created AACR Academy.

· Isaiah Fidler, Ph.D., D.V.M., professor, Cancer Biology

· Waun Ki Hong, M.D., vice provost, Clinical Research; head, Cancer Medicine

· Margaret Kripke, Ph.D., professor emerita, Immunology

· John Mendelsohn, M.D., co-director, Khalifa Institute for Personalized Cancer Therapy; professor, Experimental Therapeutics

· Louise Strong, Ph.D., professor, Genetics

MD Anderson genetics chair Guillermina Lozano wins AACR lectureship

2013-04-07T13:49:18Z

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."

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Lozano's lab at MD Anderson was the first to establish p53 as a transcriptional activator of other genes. Their landmark study published in Science in 1989 identified a p53 transactivation domain and showed that p53 mutants failed to activate transcription, paving the way for important discoveries regarding its mechanism in the development of numerous cancers including breast, colon, lung and ovarian cancer.

Her subsequent research provided the necessary mouse models to validate the critical gatekeeper role the protein Mdm2 plays in regulating p53 activity, as well as establishing the importance of dual functions of p53 in preventing tumor development where it not only forces cell death, but also halts a defective cell's ability to reproduce and helps maintain genomic stability. Most recently she has explored how mutant p53 proteins contribute to cancer development and treatment outcomes.

Lozano celebrates her 25th anniversary at MD Anderson this year. Over the course of her career, she has published 179 peer-reviewed articles in prestigious scientific journals, reviews and book chapters . She has devoted extensive efforts to teaching young scientists, an aspect of her work that she finds exceptionally rewarding.

Enjoys two-way learning of teaching

"Not only do I love teaching and helping those who want to learn, but I also enjoy the two-way learning that takes place between the generations and the insights that occur as both aim to push the progress of cancer research," Lozano said. Twenty-five graduate students have received M.S. and Ph.D. degrees under her direction and she has trained 34 postdoctoral students and fellows in her lab.

She credits the mentorship of Arnold Levine, Ph.D., her postgraduate advisor at Princeton University and the discoverer of p53, and Peter Mueller of the Max Planck Institute for their guidance early in and throughout her career. "Their invaluable perspective has driven me to reach for goals I might never have dreamed of," Lozano said. She also is thankful for the support of her husband and daughter noting, "They keep me from doing too much at once."

Her research program has been supported by continuous funding from the National Cancer Institute. Other honors include the Sixth Annual AACR-Minorities in Cancer Research Jane Cooke Wright Lectureship and a position on the Scientific Advisory Committee for Stand Up To Cancer (SU2C). She was elected a fellow of the American Association for the Advancement of Science in 2011

Lozano is a distinguished alumnus of both University of Medicine & Dentistry of New Jersey - Graduate School of Biomedical Sciences and The University of Texas Pan American. Lozano received her Ph.D. from Rutgers University and completed post-graduate work at Princeton University.

Study uncovers actin's action in the nucleus, a break in protein's puzzling case

2013-03-25T18:58:49Z

By Sarah Adai

Actin is a protein that has been long known to work by linking itself into chains to form filaments. Providing rigidity to the cell, actin filaments are involved in a host of processes including muscle contraction, cell mobility and cell division. The protein does this job outside of the nucleus, in the cytoplasm.

When actin was first discovered in the cell's nucleus several decades ago, it was dismissed as a contaminant. But since then a growing list of studies have supported a nuclear role for the protein, and scientists have been stumped as to what exactly it's doing there.

At long last, one of actin's key nuclear functions was uncovered. The study was published this week in the Journal Nature Structural & Molecular Biology.

Senior author of the study Xuetong "Snow" Shen, Ph.D., associate professor in The University of Texas MD Anderson Cancer Center Department of Molecular Carcinogenesis, developed a unique model system to nail down actin's function in the nucleus: the actin-containing INO80 chromatin remodeling complex in yeast cells.

"Our model system opened up a new opportunity to look in depth at the function of nuclear actin as it relates to gene regulation, genome stability, and ultimately cancer," Snow said.

The authors found that a mutant form of actin impairs the ability of INO80 to function correctly, implicating nuclear actin in the process of chromatin remodeling - a mechanism that helps regulate the expression of genes.

Cancer studies have increasingly focused on chromatin -- the intertwined proteins and DNA that are packaged into chromosomes -- because of its ability to regulate genes important for either activating or inhibiting tumorigenesis.

Surprisingly, Shen's lab found that actin inside the INO80 complex is arranged in such a way that it can't link up with itself to form filaments. Instead, the protein functions singly, as a monomer.

"Our study challenges the dogma that actin functions through polymerization, revealing a novel and likely a fundamental mechanism for monomeric nuclear actin," Shen said.

Paper: http://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.2529.html

News Release:
http://www.mdanderson.org/newsroom/news-releases/2013/nuclear-life-of-actin.html

New drugs are too slow getting to children with cancer

2013-03-21T22:09:41Z

By Michael Rytting and Sara Farris

Recently, the U.S. Food and Drug Administration (FDA) approved the use of Gleevec in combination with chemotherapy to treat newly diagnosed children with Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL).

While this is good news, it comes more than 10 years after it was approved in adults and about 8 years after I treated my first pediatric patient with chemotherapy plus Gleevec followed by a stem cell transplant. This young patient came here from the Philippines with Ph+ ALL, and I was able to treat her 'off-label' since Gleevec had already been approved in adults and was well-tolerated. Today she is cured of cancer.

Historically, high-risk Ph+ ALL patients received chemotherapy and a stem cell transplant. However, in 2009, a study in the Journal of Clinical Oncology showed that the addition of Gleevec to chemotherapy increased the 3-year survival without relapse from 35% to 80.5%. In retrospect, perhaps my patient might not have needed the transplant (and its associated risks) to be cured of her cancer.

For the most part, this latest approval doesn't really change the therapy for children with this disease. In fact, we have already moved forward with enrolling patients on similar therapies in clinical trials that involve newer variations of Gleevec. The new drugs may be more effective or have fewer toxicities.

]]> So what does this approval really mean for childhood cancer and drug development?

Positives

• For one, it confirms the positive impact Gleevec has on the treatment of Ph+ ALL in children.

• Also, from the studies conducted, it defines the best dosage for treating children.

• In addition, it may be beneficial to the pharmaceutical manufacturer, Novartis, by giving it an extension on its patent as a result of current legislation to incentivize companies to study therapies in children.

• It supports the benefit of having the Children's Oncology Group conduct a multi-institution trial bringing larger patients volumes and resulting in better, more comprehensive data.

• The results from the Gleevec pediatric clinical trials could potentially spare some kids from transplant.

Next steps to improve access to drugs

We need to partner with pharmaceutical companies and write trials that allow pediatric clinical trials to open after adult trials hit certain milestones and numbers. This could help speed up the time it takes from start to finish.

We have been able to initiate this model at MD Anderson, but it needs to occur on a more widespread basis. This could be aided by getting legislation enacted that would require pharmaceutical companies to build in a pediatric arm into their trials.

Financially, there isn't much incentive to try new drugs in children or rare cancers due to the smaller patient volume. Likewise, if anything goes wrong with a pediatric patient enrolled on trial, it could have far-reaching adverse effects on the progress and approval of the drug being researched. However, our pediatric patients have just as much right to these new agents as adults, and not decades afterwards.

Historically, there was a time when pediatric trials were pioneering treatments in adults - leukemia being a perfect example. We must look back and figure out how to regain this valuable role as pediatric oncologists in leading the development of new treatments for lymphoblastic leukemia patients.

It is interesting to see the FDA's approval of Gleevec. I hope there are many more approvals to come. In the meantime, we must continue to advocate for children with cancer and speed up their access to new agents

Michael Rytting, M.D., is an associate professor in MD Anderson's Division of Pediatrics. Sara Farris is a senior communications specialist in External Communications..

Cancer vaccine ingredient subverts immune attack, diverts it from tumors

2013-03-04T20:32:53Z

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.

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Mineral oil focuses attack at vaccination site

The culprit, the team found, is a mineral oil commonly used as an adjuvant in therapeutic cancer vaccines. The substance, incomplete Freund's adjuvant (IFA), does not break down quickly in the body.

"IFA sticks around the vaccination site for up to three months, along with the antigen designed to trigger immunity against the tumor," Overwijk says. "T cells keep attacking and secreting chemokines to call for reinforcements. But it's an un-killable target; T cells can't kill mineral oil."

T cells pile up at the injection site and die. "The vaccination site increasingly resembles a viral infection, with lots of damaged normal tissue and antigens," Overwijk says.

Substituting a saline solution for IFA reversed T cell traffic patterns, with more accumulating at the tumor and a small amount congregating at the injection site.

Saline-based vaccine puts 30 times more T cells on tumor

Cell fluorescence analysis of melanoma tumors in mice showed a 30-fold increase in T cells at the tumor site for those receiving saline-based vaccine compared with those who got an IFA-based vaccine.

A separate experiment using flow cytometry confirmed the accumulation of T cells in the tumor and minimal presence at the injection site in those injected with saline-based vaccine.

Overwijk and colleagues noted 98 federally approved U.S. clinical trials of IFA-based vaccines against a variety of cancers almost all failed. Another 37 trials are open, enrolling patients. The U.S. Food and Drug Administration has approved one therapeutic vaccine, for treatment of prostate cancer.

A clinical trial of with the saline-based vaccines is expected to open later this year led by Craig Singluff Jr., M.D., professor of surgery at the University of Virginia Medical School and Patrick Hwu, M.D., chair of MD Anderson's Department of Melanoma Medical Oncology.

For additional information

Full MD Anderson news release

Nature Medicine paper

New approach helps more smokers connect to tobacco treatment

2013-02-26T21:28:45Z

Smoking remains the leading cause of preventable illness and death in the United States, so the health benefits of quitting are substantial. The majority of smokers are motivated to quit and more than half of all smokers attempt to quit each year. Sadly, only a small minority succeeds.

Researchers at MD Anderson are working to change this by changing the culture of how they reach self-admitted smokers with a new approach aimed at connecting through family practice clinics.

A collaboration involving MD Anderson researchers, the Texas Quitline and Kelsey-Seybold Clinics targeted smokers and their enrollment in tobacco treatment programs by directly connecting smokers with cessation quit lines.

Ask-Advise-Connect

Ask-Advise-Connect, a new approach designed to efficiently link smokers with cessation treatment, showed a significant increase in tobacco treatment enrollment by smokers who were directly contacted by quit line staff, according to results published online today in JAMA Internal Medicine.

JAMA published a video interview Feb. 27 with study principal investigator Jennifer Irvin Vidrine, Ph.D., associate professor in the Department of Health Disparities Research at MD Anderson.

]]> The nine-month study randomized five clinics to the Ask-Advise-Connect approach where vocational nurses and medical assistants collected tobacco-use information from self-identified smokers and recorded it in their electronic health record (EHR). Information was then delivered to MD Anderson researchers and the Texas Quitline. Quit line staff followed up with smokers directly via phone.

The 13-fold increase in smokers signing up for tobacco treatment through the Ask-Advise-Connect approach was compared to the control group of five Kelsey Seybold clinics that administered the Ask-Advise-Refer method - an approach that relies on smokers to contact the quit line on their own.

"These findings indicate that smokers in health care settings are interested in smoking cessation treatment," Vidrine says. "The EHR-based approach not only addresses barriers to connecting smokers with treatment programs, but dramatically enhances the likelihood that smokers will enroll in cessation treatment."

More than 32,000 unique patients' information was recorded in the EHR and 3,663 patients reported being current smokers. Study results: 7.8 percent of smokers identified at Ask-Advise-Connect clinics enrolled in treatment with the quit line compared to 0.6% of smokers identified at Ask-Advise-Refer clinics. Vidrine says this is the highest rate of tobacco cessation treatment enrollment reported to date.

Vidrine is working on another randomized trial comparing the two different approaches in a large health care system that provides care to low socioeconomic status and predominately minority patients.

Additional information

Read the MD Anderson News Release
Read the Publication

New initiatives drive personalized cancer care via genetic analysis of tumors

2013-02-20T21:49:38Z

By William Fitzgerald

Gordon Mills, M.D., Ph.D., recalls a proposal he wrote 18 years ago detailing the concept of personalized cancer therapy and its potential impact. Today, that idea is no longer a proposal, but a reality, and it's about to get a boost.

Under a new and innovative institutional protocol called Clearing House, which started in March 2012, scientists are delving deeper into the biology of patients' tumors, with hopes of identifying specific genetic markers and prescribing therapies to attack those markers directly.

Funda Meric-Bernstam, M.D., professor in MD Anderson's Department of Surgical Oncology, and Mills, professor and chair of the institution's Department of Systems Biology, are leading the effort that will test up to 200 genes known to influence cancer in patients with aggressive or recurring disease.

"In the first year, we'll have sequenced the genes of far more than 1,000 MD Anderson patients and are targeting to have more than 3,000 by the second year," Meric-Bernstam says. "This will accelerate our discovery approaches, and we can develop new clinical trials, in which we already have patients pre-identified to enroll."

While the research began with solid tumors, the Clearing House protocol has expanded to all diseases that have ongoing genomically selected trials, Meric-Bernstam says.

Mills is co-director of MD Anderson's Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy and Meric-Bernstam is medical director of the institute.

]]> A transformation in cancer care

This undertaking is made possible through a revolution taking place in oncology. The costs to conduct these complicated tests have plummeted, and emerging technologies are making them easier and faster. To this end, researchers have developed another program, Unusual Responders, geared toward understanding more specific patient populations.

"For generations, some patients have shown exciting and almost unbelievable responses to therapy," Mills says. "It became absolutely clear that patients were trying to teach us something important, if we only paid attention and had the tools to learn from their responses."

For example, when an MD Anderson patient displays an exceptional response, Mills and his team will work to identify the possible genetic rationale. Then, they'll employ that knowledge to determine if the same drug will elicit a response in patients with similar circumstances.

Collectively, the two programs represent an integrated approach that begins on a level only visible through high-powered microscopes, but with an eventual impact that no loved one, friend or companion can deny.

Two exceptional responders

Erin Bond and Rachel Midgett have had unusually good responses to new treatments.

A study drug has controlled stage 4 melanoma for Bond (pictured at right).

Clinical trials and a rare surgical approach have kept Midgett's metastatic breast cancer at bay.

Additional information

Read about this topic and much more in MD Anderson's 2011-2012 Annual Report.

Drug is first to control recurrent low-grade ovarian cancer

2013-02-08T16:40:57Z

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.

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Out of treatment options in 2007, her MD Anderson oncologist, Rob Coleman, M.D., told her about a phase II clinical trial of the MEK1/2 inhibitor selumetinib. The drug aims to block two common mutations in low-grade ovarian cancer, KRAS and BRAF.

"They gave me literature, suggested I call my family, talk about it and think about it. I said 'there's nothing to think about, I'm doing it.' That was five years ago, and I'm still here. I'm not complaining," says Elliott, who is known to all as Dotsy, a childhood nickname bestowed by her sister.

Elliott has lived in Shiner, Texas, all of her life. She works in hospitality at Spoetzl Brewery, maker of Shiner Beers. "I've worked at the brewery for 17 years. It's been fun." The souvenir shop where she works is popular with visitors because they can get a free beer (or lemonade) there.

"I work full time and I still do everything I've always done," she says. Elliott remains on the clinical trial, making monthly visits down U.S. Highway 90 to MD Anderson.

Side effects

"What's so unusual about her is that she's run the gamut of therapy before coming onto this novel molecularly targeted approach and has responded really remarkably for a refractory situation like hers," Coleman says.

There were side effects, Elliott notes. As a veteran of multiple chemotherapy regimens, she recognizes those come with the territory. The worst was blistering and a rash on her face and neck.

"It was really, really bad at first. My face was one big sore. It lasted several months," she says. "I got some strange looks, but I didn't care, I'm still here." A few blisters endure, but she covers them with makeup.

Clinical trials can be nerve-wracking for some, because it's hard to know what to expect, she says. "It's like anything, Advil works for me, but doesn't for my brother. It's too bad this drug doesn't work for everybody. But it's sure worth the try."

Gershenson will lead a larger phase 2-3 international clinical trial with investigators from the National Cancer Institute's Gynecological Oncology Group (GOG) and the United Kingdom. The study will enroll 250 patients and is likely to begin later this summer.

In an accompanying commentary in Lancet Oncology, two German oncologists who did not participate in the research, note that the study is a step toward individualized treatment for ovarian cancer that reflects important molecular differences between low-grade and high-grade disease.

Additional information

MD Anderson news release

Killer wound-healing; stress and ovarian cancer; blood vessels' bad signals

2013-02-04T18:16:11Z

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

Chromatin gets a makeover; review in Cell explains

2013-01-31T23:19:52Z

By Sharon Dent, Ph.D., David Johnson, Ph.D., and Sarah Adai

Chromatin, the intertwined histone proteins and DNA that are packaged into chromosomes, has long been recognized as a gatekeeper to the underlying DNA template.

While chromatin is typically on the receiving end of the cell's intricate signaling pathways - culminating in the regulation of gene expression - evidence is emerging to give chromatin a previously unrecognized role: as a dynamic participant that transmits received signals back to other proteins to effect changes in cellular responses.

This week in the journal Cell, faculty from MD Anderson's Department of Molecular Carcinogenesis and Center for Cancer Epigenetics review a number of recent studies highlighting chromatin's role as both receiver and transmitter of signals in various cell functions.

Review authors Sharon Dent, Ph.D. and David Johnson, Ph.D., highlight this growing area of research, which is relevant both for understanding basic cell regulation and for determining how signaling goes awry in diseases such as cancer.

Histone modifications: key players in chromatin signaling

Posttranslational modification of histones is one way that the cell regulates the packing and unpacking of chromatin, which in turn helps to determine whether a gene is activated or repressed.

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Multiple modifications (acetylation, methylation, ubquitination, phosphorylation) of multiple histones (5 major families) combined with a multitude of effects on chromatin give rise to a complex "histone code" that signals the transcriptional machinery to turn genes on or off. In recent years, crosstalk has been observed between different histones, giving rise to further complexity in the histone code.

Most of this research was established in yeast cells, but connections between histone ubquitination and histone methylation, for example, also occur in human cells. In fact, mutations in a human protein highly related to the yeast histone methyltransferase Set1, called MLL, are involved in leukemia.

This work raises the possibility that histones can signal to non-histone proteins in human cells, and that deregulation of these events caused by MLL mutations might contribute to leukemia development.

Chromatin as a signal receiver and transmitter

Research by Sharon Dent and colleagues revealed for the first time that histone modifications - instead of being an end-point for transcriptional regulation - can actually relay information to non-histone proteins, and that the role of chromatin in these events is not limited to DNA-templated events like gene activation. In a series of yeast experiments, Dent and colleagues showed that a signal through a histone protein regulates another protein called Dam1, which is involved in the separation of chromosomes during cell division.

Communication between H2B and Dam1 was the first such instance of crosstalk observed between histone and non-histone proteins. The signaling connection between a chromatin change and a non-DNA-templated process such as chromosome separation was also new.

The review article highlights additional non-transcriptional signaling events in which chromatin plays a role:

·         DNA repair and checkpoint signaling
·         Mitotic exit
·         Chromosome segregation

New disease targets

Chromatin's new identity as a non-transcriptional signaling agent opens up a plethora of research avenues. The relevance of the yeast work to normal and disease mechanisms in humans needs to be explored. Defining these networks should also provide new strategies and targets for combating diseases that result from disrupted signaling pathways, including cancer.

Additional information

Secret life of chromatin: news release and 2011 Cell paper

Rescuer has TRAF3's back, keeping cancer and autoimmunity at bay

2013-01-23T23:47:42Z

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."

]]> Dodging annihilation, turning the tables

Sun earlier found an alternative, or non-canonical, pathway that activates the protein complex known as NF-kB, a family of proteins that turns on genes that are important in immune response, inflammation, cell growth and survival, and development.

They found that NF-kB activity increases when TRAF3 is tagged with the homing targets, called ubiquitins, and is destroyed by the proteasome, a complex of proteins that hunts down ubiquitin-decorated proteins.

When TRAF3 evades attack, it turns that same destructive mechanism against a protein that's central to NF-kB activity, tagging it with ubiquitins. .

The key question was: What regulates TRAF3's destruction and, in the process, controls NF-kB?

Enter OTUD7B

Sun and colleagues had a candidate, the enzyme OTUD7B, also known by its more lyrical name, Cezanne. It was genetically quite similar to another enzyme active in the canonical pathway for NF-kB called A20. Both are deubiquitinases, enzymes that cleave ubiquitin polymers.

By applying inducers of the non-canonical NK-kB pathway to cells derived from OTUD7B-deficient mice, the researchers found:

Degradation of TRAF3 and resultant accumulation of its target protein
Ubiquitination of TRAF3
Cells with OTUD7B intact suppressed non-canonical NF-kB signaling.

Mice with OTUD7B suppressed had greatly increased lymphoid cell growth in the lining of the intestine and hyper-responsiveness to antigens by B cells. "If these two symptoms occur persistently, as they did in the knockout mice, they may contribute to autoimmunity or inflammation," Sun said.

However, knockout mice also had an improved immune response to the lethal intestinal bacterial pathogen C. rodentium. All of the mice with normal OTUD7B died of the bacterial infection, while 75 percent of the knockout mice survived.

Understanding these effects and developing OTUD7B as a target for inhibitors to boost immunity in the lining of the intestine will take more research, Sun says.

MD Anderson news release