Pran Datta, Ph.D., and colleagues previously showed that this loss of responsiveness to TGF-β occurs mainly through loss of expression of the TGF-β type II receptor (TβRII). However little is known about the mechanisms underlying this loss of expression – or how it might be restored.

In a recent study published in Neoplasia, Datta and colleagues identify several proteins/pathways involved in regulating TβRII expression in lung cancer cell lines, and that histone deacetylation – an “epigenetic” change that modulates gene expression – is involved in the loss of TβRII expression in lung cancer cells. Additionally, drugs called histone deacetylase inhibitors (HDIs) were shown to restore expression of TβRII, suggesting that these compounds – either alone or in combination with other agents – may hold potential in treating or slowing the progression of lung cancer.

The research was supported by grants from the National Cancer Institute and the Department of Veterans Affairs.

Watch video of Dr. Michael Neuss speaking about cancer.

Neuss spoke Feb. 1 as part of the Osher Lifelong Learning class, “Medical Advances.” The course is presented by faculty of the Vanderbilt University Medical Center and focuses on what the future of medicine holds. Physicians are now able to use a patient’s DNA to select the right drug for treatment. Oncologists can ‘read’ the DNA of a patient’s tumor and tailor treatment for their particular version of cancer. New medical devices have provided new heart valves, ‘pace-makers’ for the brain, and the tools needed to rebuild a spine. This series of lectures introduces medical and surgical treatments that are changing lives today and a preview of the discoveries that are still “works in progress” at Vanderbilt.

The class is part of the Osher Lifelong Learning Institute at Vanderbilt. The non-credit classes are intended for older adults who want to pursue lifelong learning with the stimulus of lectures and discussions in an informal and relaxed environment.

Daniel Barocas, M.D., MPH, assistant professor of Urologic Surgery

The size of a man’s prostate gland may help predict the severity of cancer, with a smaller prostate being more likely to harbor serious disease.

This finding by a group of Vanderbilt-Ingram Cancer Center researchers was published in the December issue of the Journal of Urology. Fourth-year medical resident Judson Davies, M.D., was first author on the paper.

The VICC cancer investigators reviewed 1,251 cases of prostate cancer among men who had their prostates surgically removed between January 2000 and June 2008. The patients were considered to have low-risk disease because their prostates were producing low levels of prostate specific antigen (PSA) and they had a Gleason score of six or less. The Gleason score is a measure of the grade or severity of cancer found during initial biopsies.

The researchers looked at cases of only low-risk patients who might be candidates for less aggressive treatment, including observation – sometimes called “active surveillance.” These options are considered safe for some patients because prostate cancer often grows so slowly that it may never pose a threat to the patient’s life.

The VICC investigators found that in 31 percent of the cases, when pathologists examined tissue removed after surgery, the severity of the cancer was upgraded from the pre-surgery analysis and men with smaller prostates were more likely to have their cancer upgraded after surgery.

“Our field suffers from this great confusion because in half of men you can find prostate cancer in microscopic amounts that may not be clinically significant and yet it’s the second leading cause of cancer death among men,” explained Daniel Barocas, M.D., MPH, assistant professor of Urologic Surgery and senior author on the study. “The more you look for it, the more you find it but that doesn’t help us figure out who needs treatment and who doesn’t.”

Cancer investigators are trying to ascertain additional clues that will help physicians counsel patients about whether it is safe to choose less aggressive treatment instead of removing the prostate gland or treating it with radiation. In earlier research, Barocas and his colleagues found hints that prostate size might provide additional prognostic information.

“There’s nothing about size that would necessarily predict a bad outcome. What it’s really about is the ratio of PSA to size, or PSA density, meaning that a small prostate that is making a lot of PSA is likely to be due to a bad tumor, whereas a large prostate making a lot of PSA is likely to be due to benign enlargement of the prostate (BPH),” said Barocas.

Barocas said the new findings provide one more piece of evidence for physicians to consider when talking with their patients. Based on these new findings, in a low-risk patient he would be more likely to recommend aggressive treatment if the prostate is very small because there may be a greater chance of high-grade disease.

But prostate size still isn’t a definitive clue and more precise tests are needed.

“The imaging for prostate cancer is relatively weak because the disease tends to be diffuse, rather than growing in what we think of as a tumor – a spherical nodule. Prostate cancer tends to grow along the glands in a sort of flat pattern, so it’s a little harder to detect. A better test, which we don’t yet have, would reliably image or identify where in the prostate the tumor lies,” said Barocas.

What will be necessary is larger scale investment in prospective research to identify better biomarkers and imaging techniques to determine which cancers are truly threatening to patients.

Media Inquiries:
Dagny Stuart McMillin
Information and Media Relations Officer
News & Communications
Phone: 615-322-4747
Email: dagny.stuart@vanderbilt.edu
http://www.vicc.org

The Melanoma Research Foundation and Vanderbilt-Ingram Cancer Center are proud to invite you to our Melanoma Patient Symposium!

• When: Saturday, March 10
• Time: 9:30 a.m.- 2:30 p.m.
• Where: Vanderbilt-Ingram Cancer Center, Room 898J in Nashville, TN

This free education day is dedicated to melanoma patients and the people who support them.

Please join us as these top melanoma doctors provide attendees with the latest information in melanoma prevention, diagnosis and treatment. Morning refreshments and lunch will be provided. Be sure to register below!

Please fill out and submit your information.

Scott Williams, Ph.D., graduate student Marquitta White and colleagues are studying the APC gene’s role in colorectal cancer risk. (photo by John Russell)

Individuals who are outside the “normal” range of expression for the APC gene have an increased risk of colorectal cancer, according to a study published in the January issue of Gastroenterology.

Mutations in the APC (adenomatous polyposis coli) gene – and variations in the expression of the gene’s two copies (allele-specific expression) — are associated with inherited forms of colorectal cancer.

Scott Williams, Ph.D., and graduate student Marquitta White, both in the Center for Human Genetics Research at Vanderbilt University, teamed with investigators in Italy to examine whether variations in APC allele-specific expression also contribute to common, sporadic forms of colorectal cancer.

The investigators examined APC expression in patients with colorectal cancer and in controls. They found no difference in the average APC allele-specific expression between cases and controls. But looking more carefully at the data, they noticed that the overall distribution of values was broader and more variable in the cases.

“One of the things I like to say is: before you analyze the data, look at the data, and after you analyze the data, look at the data,” said Williams, professor of Molecular Physiology and Biophysics.

In general, scientists test for a difference between two groups by asking, “Is the mean (average) different? That’s what everybody does,” Williams explained.

“But in this case, the mean’s not different, but people who are at increased risk of disease are more likely to be farther away from that mean value.”

There appears to be a normal, acceptable range for allele-specific expression of APC, Williams said, and “the farther you get away from that range, the worse off you are.”

Individuals who were farthest away had an increased risk for colorectal cancer that approached the risk of individuals with inherited colorectal cancer.

The findings suggest that “there’s a continuum of APC allele-specific expression, with familial cases of colorectal cancer at the extremes and sporadic cases somewhere between extreme and normal,” Williams said.

In cases where expression differed most from the typical value, the investigators determined the sequence of the APC gene. In one patient, they found a mutation known to be associated with inherited colorectal cancer, and a re-examination of the pathology confirmed that the patient had numerous polyps.

The findings suggest that allele-specific expression of APC may serve as a marker for colorectal cancer risk.

Williams noted that differences in the distribution of gene expression – rather than in an average value – between cases and controls could play a role in other disease processes.

“No one’s ever looked at this in a rigorous way,” he said. “I think our approach has the potential to change how we view disease risk, not only in colon cancer but perhaps other diseases.”

Next up for the investigators is a search for genetic associations that cause the change in allele-specific expression of APC.

“If we know what’s causing this difference in expression, we may be able to therapeutically intervene,” Williams said.

The research was supported by the Italian Ministry of Instruction, University, and Research and the National Institute of General Medical Sciences-funded Training Program on Genetic Variation and Human Phenotypes at Vanderbilt.

Jeffrey Sosman, M.D.

Investigators at Vanderbilt-Ingram Cancer Center and several other centers may be one step closer to finding out why some melanoma patients relapse after treatment with a promising new drug.

Approximately half of all patients with the most deadly form of skin cancer have a mutation in the BRAF gene in their tumors that drives the growth of their cancer.

The discovery of this altered molecular pathway in cells led to the development of the new drug vemurafenib, which blocks the pathway.

Melanoma patients with the BRAF mutation who are treated with vemurafenib live significantly longer than patients on conventional treatments and derive a striking clinical benefit.

“This new drug doesn’t just extend life, it gives our patients a new lease on life,” said Jeffrey Sosman, M.D., professor of Medicine and director of the Vanderbilt Melanoma Program.

“The sad thing is all of these patients eventually relapse, so this has just been a roller coaster for patients and their families.”

Now, researchers have found clues to the mystery of what is causing resistance to the BRAF-inhibitor drug and have suggested new targets for treatment.

Sosman, Mark Kelley, M.D., associate professor of Surgery, and Kimberly Dahlman, Ph.D., research instructor in Cancer Biology, are among the co-authors on the paper published last month in Nature.

The investigators exposed BRAF-mutant cell lines to increasing doses of vemurafenib until some of the cell lines developed resistance to the drug.
Then they analyzed the DNA from the resistant cell lines, as well as DNA from tumors of patients who had developed resistance to the anti-BRAF drug.

“We found that certain resistant cells create a different form of BRAF that is shorter,” explained Sosman. “The fact that it’s smaller means that it has lost a portion of the protein which allows it to couple with itself, and by coupling it can activate the pathway.

“In fact, the drug may enhance the activation so what you’ve done is give the cell another way to activate the pathway even in the presence of the drug.”

Why the protein is spliced differently is still unknown.

“This is a unique mechanism and it was present in about 30 percent of the samples we studied,” said Sosman.

Other recent melanoma research has found additional alternate pathways around the mutated BRAF gene, which means that the cancer can be reactivated by several different mechanisms.

Sosman said there may be multiple mechanisms in different sites within the same patient that can find a way around anti-BRAF drugs.

“So how do you treat in this situation? You can’t give the patient dozens of drugs so there has to be a way to prevent this from developing,” Sosman explained.

VICC investigators are collaborating with other cancer researchers on new studies aimed at finding treatments that give patients with metastatic melanoma a more durable response.

Mary Carroll, Ph.D.

Mary Carroll, Ph.D., a postdoctoral research fellow in Biochemistry, was recently named one of 18 Damon Runyon Fellows by the Damon Runyon Cancer Research Foundation.

The three-year, $156,000 award provides independent funding for outstanding postdoctoral scientists to pursue innovative projects. Carroll is the first postdoctoral fellow from Vanderbilt to receive this award.

“I am honored to join an elite group of young scientists as a Damon Runyon Fellow,” said Carroll. “The fantastic facilities at Vanderbilt and the excellent guidance of my postdoctoral mentor will aid in my goal of designing novel therapeutics for the treatment of cancer.”

Carroll, working with her sponsor, Stephen Fesik, Ph.D., aims to design small molecule inhibitors of the protein Vav1, an attractive target for treating pancreatic cancer. Although normally found only in cells of the bone marrow, Vav1 is also expressed in some pancreatic cancers, where its presence is correlated with poor prognosis.

Inhibiting the function of Vav1 would potentially prevent the activation of pro-cancer signaling, thereby halting tumor formation and further growth.

“I am very happy that Mary obtained this coveted award,” said Fesik, professor of Biochemistry, Pharmacology and Chemistry and the Orrin H. Ingram II Chair in Cancer Research. “Mary is an outstanding structural biologist with a great work ethic. I am confident that she will have a successful career in science.”

The Damon Runyon Cancer Research Foundation is a non-profit organization focused on supporting innovative early career researchers. Each of its award programs is extremely competitive, with less than 10 percent of applications funded.

Since its founding in 1946, the foundation has invested more than $240 million and funded more than 3,300 young scientists.

This year’s Pink Out! Vanderbilt Women’s basketball game tips off at 2 p.m. on Sunday, Jan. 29. (photo by Joe Howell)

Pink will be the color of the day during the Vanderbilt Commodore Women’s Basketball Team Pink Out! event to raise awareness for breast cancer research Sunday, Jan. 29, at 2 p.m.

The Commodores will wear pink uniforms in their matchup in Memorial Gymnasium against the LSU Tigers. Fans are also invited to wear pink, the color that has become associated with breast cancer survivorship and research.

There were approximately 229,000 new cases of breast cancer in the United States last year and nearly 40,000 deaths, according to the National Cancer Institute.

The annual Pink Out! game is part of the Women’s Basketball Coaches Association “Play4Kay” breast cancer awareness program, which is designed to encourage support for breast cancer research. The initiative is named in honor of former North Carolina head women’s basketball coach Kay Yow, who died from breast cancer in 2009.

Tickets for the Vanderbilt-LSU matchup are $11 and the first 1,000 fans to arrive will receive free pink T-shirts.

At halftime, breast cancer survivors will be recognized and invited onto the floor to welcome the Commodores back onto the court. There also will be a mini-basketball clinic and free autograph session with the Commodore players after the game.

“This annual Pink Out! event has become a wonderful on-campus tradition and we are proud of the Commodores Women’s Basketball Team for their support of breast cancer research,” said Carlos Arteaga, M.D., professor of Medicine and Cancer Biology, and director of Vanderbilt-Ingram Cancer Center’s Breast Cancer Research Program.

Tickets for the Pink Out! game can be ordered online at www.vucommodores.com or by telephone at 322-GOLD. Tickets also are available at the Memorial Gymnasium box office on the day of the game.

Ryan Delahanty, Ph.D., Xiao Ou Shu, M.D., Ph.D., and colleagues have evaluated the association between known obesity-related genetic variants and endometrial cancer risk in the Shanghai Endometrial Cancer Genetics Study. In the Nov. 15 American Journal of Epidemiology, the researchers report that obesity-associated variants in 22 of 26 genetic loci examined were present more often in women with endometrial cancer compared to control subjects. Nine of the obesity-linked variants – which represented seven genetic loci – were significantly associated with increased risk of the disease.

The results suggest that in addition to BMI, genetic markers of obesity may provide value in predicting endometrial cancer risk.

The research was supported by grants from the National Cancer Institute.

(photo by Steve Green)

Platinum-selling country music group Blackhawk recently visited Vanderbilt-Ingram Cancer Center to present a check for $10,000 for cancer research and sing for patients. Here, patient Julie Wallace talks with band members, from left, Randy Threet, Dave Robbins and Henry Paul.