Recently by MD Anderson Staff Writer

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

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.

By Leslie Loddeke, Publications Coordinator, Melanoma Medical Oncology Department

M.D. Anderson Melanoma Medical Oncology Chair Patrick Hwu, M.D., and Professor  Wen-Jen Hwu, M.D., Ph.D., were coauthors of one of the papers named in Nature Medicine's "Notable advances 2012" list of the year's top basic biomedical discoveries.

The article notes "certain areas of biomedicine saw fast-paced discovery this year" in presenting its list of "the papers that helped these fields advance quickly" in 2012.

Under the heading "Immunotherapy: Co-receptor clampdown," the article cited two papers that made the inhibitory co-receptor PD-1 (programmed cell death protein 1, found on T cells) "one of the darlings of the cancer immunotherapy field this year."

A team led by scientists from the Johns Hopkins School of Medicine reported the findings of a study of a PD-1-specific antibody in patients with different types of cancer in a New England Journal of Medicine article, as well as those from a companion study in a second article, "Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer."  

M.D. Anderson's two co-authors on the second study reflect the department's participation inthe clinical trial. Wen-Jen Hwu was principal investigator at the M.D. Anderson site. In that study, researchers reported that "of 207 patients with advanced cancer who received an anti-PDL1 antibody, 6-17% of evaluable patients experienced an objective response (either complete or  partial)," Nature Medicine noted.

Despite the fact that it remains unknown why only certain tumors and patients responded to the antibodies, "these trials further validate immune modulation of T cell activity as a therapeutic approach to cancer treatment," Nature Medicine concluded.

By Will Fitzgerald, MD Anderson Staff Writer

Fifty years from now when an author is compiling a review of modern cancer therapy for a historical publication, he'll undoubtedly recognize the accomplishments of Gabriel Hortobagyi, M.D., a visionary cancer physician and researcher whose discoveries saved countless women from breast cancer.

He first became familiar with the disease walking the hallways of an Ohio hospital during his internal medicine residency. Hortobagyi was intrigued by the opportunity to help patients conquer a disease that posed more questions than answers.  More than 40 years later, this pursuit still passionately consumes his career as a physician in MD Anderson's Department of Breast Medical Oncology and through collaborations around the world.

Today, at the 35th annual San Antonio Breast Cancer Symposium, Hortobagyi was presented with the William L. McGuire Memorial Lecture Award for his outstanding achievements.

"It's very humbling and gratifying to be selected by one's peers because everyone on the selection committee is a very accomplishment individual," Hortobagyi said.  "It's very meaningful for me, and, of course, it's recognition of our group's accomplishments."

 

By Laura Sussman

A select number of high-risk pancreatic cancer patients initially deemed inoperable are, in fact, eligible for surgery and have a chance for a cure, thanks to a treatment protocol pioneered at MD Anderson.

The protocol combines a more accurate reading of CT scans, the use of chemo-radiation upfront and an advanced surgical resection of the pancreas and removal and reconstruction of appropriate blood vessels.   Jason Fleming, M.D., associate professor in the Department of Surgical Oncology and the study's lead author, says that collaboration between surgeons, radiologists, medical oncologists is also paramount.

Adenocarcinoma of the pancreas is the most common and lethal type of the disease, with a five-year survival rate of just 5%. According to the American Cancer Society, an estimated 43,920 new cases of pancreatic cancer will be diagnosed in the United States in 2012, with approximately 37,390 deaths expected. Surgical removal of the pancreas, known as the Whipple procedure, is a patient's best chance for survival, yet, currently, just 20% of patients are eligible for the high risk procedure.

Published in the Journal of American College of Surgeons, the MD Anderson study enrolled 88 high-risk pancreatic cancer patients from 1990-2010. All were initially told at outside institutions that they were surgical candidates; however, upon opening, their tumors were deemed more extensive and, thus, inoperable. They then were referred to MD Anderson for care.

Of these 88 patients, 66 were able to complete the MD Anderson protocol regimen, culminating with the removal of their tumor.  In surgical patients, the median survival was 29.6 months, compared to 10.6 months and 5.1 months in those with locally advanced disease at their time of referral or those who developed metastatic disease before resection, respectively.
 
"This exciting news was that of the 88 patients, 60 percent could have their tumor successfully removed, even though they had had surgery before and it was deemed unresectable, or not removable," said Fleming. "Even more exciting to us is that the survival of those patients who can have surgery here is the same as our group of patients on whom we do surgery first."

Fleming discusses the significance of the findings here:

By Will Fitzgerald

During the next two decades, breast cancer diagnoses in older women are expected to increase by 57%. It's a reality that highlights the importance of understanding this demographic and the unique management decisions associated with their treatment.

New research led by Benjamin Smith, M.D., in the Department of Radiation Oncology, found that a clinical tool, or nomogram, demonstrates accuracy in predicting which women are likely to benefit from radiation therapy.  The tool compiles readily available clinical and pathological data including age, race, tumor size and estrogen receptor status.

The study, published in the Journal of Clinical Oncology, examined 16,092 women ages 66--79 who were treated with breast-conserving surgery.  The primary outcome was mastectomy-free survival (MFS) at five and 10 years. Overall, the five- and 10-year rates of MFS were 98.1% percent and 95.4% percent respectively.

"We thought it was relevant and interesting to look at the risk of mastectomy after initial treatment for breast cancer, see if radiation therapy made a difference and then develop a tool to individualize recommendations based on a person's risk profile," Smith said.

Individualizing Treatment

Beyond providing baseline estimates of MFS, the tool provides physicians with individual estimates for whom radiation therapy might, or might not be effective.

For example, a 75-year-old woman with a 1.5 cm ER-positive tumor and node-negative disease who underwent radiation therapy, yields an estimated 10-year MFS of 97%. However, if this same patient did not receive radiation therapy, the 10-year MFS rate would be 95%, suggesting radiation offers limited benefit.

Additional studies are needed to more accurately determine the risk of recurrence for certain subgroups of older populations.

"Although no nomogram is perfect, it's step forward to actually have a validated model based on the outcomes of 16,000 patients," Smith said.

Additional resources:

JCO study and podcast

MD Anderson news release

By Jennifer Litton, M.D.

The Annual American Society of Clinical Oncology (ASCO) meeting will be discussing several new drugs in development. We have been investigating targeted therapies for many years, several with significant promise. These therapies work on a specific pathway that either speeds up cell division or lengthens the tumor cell survival.

Although we have had significant improvements in outcomes for our patients with these drugs, there are just too many of these pathways going on in the same tumor cell at the same time. 

It is important to note that even in this era of personalized medicine, we are not likely to find that one singular drug that will eradicate the disease. Instead, we will be looking at trying to simultaneously shut down the tumor from all directions. Chemotherapy, targeted therapies and what I hope will be one of the major game changers in this disease is the harnessing of the immune system.

We are hearing about new therapies such as Trastuzumab DM-1. This is an exciting therapy engineered to combine the immune system as the delivery of a lethal drug directly into the tumor cells, with minimal toxicity and improved results for patients. Also other stories include using a compound pd-1 which will help the T cells find the tumor and kill the tumor. 

As these tumor cells become more and more genetically abnormal, using the immune system may be even more important.

By Enica Jordan

MD Anderson has launched a new course on The Professional Oncology Education site.  Colorectal Cancer Survivorship is funded by a grant from the Cancer Prevention and Research Institute of Texas. The course assists physicians and other health care professionals in evaluating and managing care for colorectal cancer patients and survivors. It includes 10 lectures by MD Anderson's multidisciplinary team members.

The Professional Oncology Education site also features courses on breast cancer, inflammatory breast cancer, cancer survivorship, and an introduction to clinical oncology.  Lectures are offered in multiple languages, including Spanish, Portuguese, Chinese, Arabic and French. Additional courses and case studies are in development. You can share feedback, suggestions and ideas for lectures at the site, or follow POE on Twitter,@MDAnderson_POE.

Learn more about MD Anderson's online professional education initiative in a Cancerwise post.

By Laura Sussman

More than one third of patients with invasive cancer are undertreated for their pain, with minorities twice as likely to not receive appropriate medication, according to new MD Anderson-led research.  

The study published in Journal of Clinical Oncology, is the largest prospective evaluation of cancer pain and related symptoms ever conducted in an outpatient setting.

Almost 20 years ago, Charles Cleeland, Ph.D., professor and chair of the Department of Symptom Research at MD Anderson, published the first comprehensive study to look at the adequacy of pain management in cancer care.

"We've known for years that the undertreatment of pain is a significant public health problem in the cancer treatment process, and that minorities are at greatest risk for not receiving appropriate pain care," said Cleeland, the JCO's study's senior author. "This new research tells us that our progress has been limited, with only a 10 percent overall reduction in inadequacy of pain management from our findings almost two decades ago."

 

Read more about the study on chron.com, and watch lead author Michael Fisch, M.D., associate professor and chair of the Department of General Oncology, discuss the significance of the findings with ABC News.

 

Additional information

Paper in JCO

MD Anderson news release