VICC News & Publications Fri, 17 Apr 2015 16:09:23 +0000 en-US hourly 1 Cates lands grant to study desmoid tumor genetic factors Fri, 17 Apr 2015 15:11:47 +0000 The Desmoid Tumor Research Foundation (DTRF) has awarded Justin Cates, M.D., Ph.D., associate professor of Pathology, Microbiology and Immunology, with one of its five research grants for his work studying growth/recurrence determinants related to genetic factors in desmoid-type fibromatosis (DTF) patients.

Justin Cates, M.D., Ph.D.

Justin Cates, M.D., Ph.D.

Desmoid tumors are rare tumors that can form in the connective tissues of virtually any part of the body. Individuals between ages 15-60 are most commonly affected, but the disease can occur in anyone.

When aggressive, desmoid tumors can cause life threatening problems, or even death, as they compress and/or damage vital organs such as intestines, kidneys, lungs, blood vessels and nerves.

Approximately 900 people in the United States are diagnosed with desmoid tumors annually, but experts believe that number may be greater because of difficulty in diagnosing the disease. Treatment options include medication, radiation therapy or surgery.

“There is currently no cure for desmoid-type fibromatosis, and it has been traditionally difficult to identify a universally appropriate treatment,” Cates said.

“Identifying genetic factors that predict the disease’s likely behavior could have a huge impact on clinical outcomes for DTF patients and greatly improve relief of their symptoms.”

Clinical, histopathologic and molecular predictors of DTF outcome have remained elusive but specific mutations of the CTNNB1 gene have been shown to have prognostic significance.

Cates’ research seeks a correlation between specific mutations of the CTNNB1 gene (and other potential genetic drivers) and DTF behaviors.

DTRF is the only foundation in the country dedicated to funding desmoid tumor research and better treatment options for desmoid tumor patients. The foundation also provides patient support, awareness and education.

“Our work leads us to patients who endure painful, heartbreaking consequences from this disease,” said DTRF Executive Director Marlene Portnoy said. “Being able to participate in research that could maximize the effectiveness of treatment options reaffirms our primary goal of supporting patients.”

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Statin use improves renal cell cancer survival Fri, 17 Apr 2015 15:02:31 +0000 A new study led by Vanderbilt University investigators found that patients being treated with statins at the time of surgery for kidney cancer, also known as renal cell carcinoma, had improved overall survival and disease-specific survival. Drugs known as statins are widely used to lower cholesterol and previous studies have indicated that they could be associated with changes in cancer outcomes.

The study by lead author Peter Clark, M.D., professor of Urologic Surgery, and first author Samuel Kaffenberger, M.D., former VU medical resident, was published in the January issue of Urologic Oncology.

Peter Clark, M.D.

Peter Clark, M.D.

Statins work by inhibiting an enzyme in a specific cellular pathway and disrupting this pathway is thought to interfere with cancer growth and metastasis. However, previous research evaluating the association between statin use and cancer has produced contradictory results. Nearly 65,000 new cases of renal cell carcinoma are diagnosed each year in the United States, with approximately 13,500 deaths in 2012. Surgery to remove a portion or all of the cancerous kidney is a common treatment for a disease that does not always respond well to other anti-cancer therapies.

For this study, investigators conducted a retrospective analysis of 916 patients who underwent surgery at VUMC to remove all or part of a kidney harboring cancerous cells. The median follow-up of the patient group was 42.5 months.

The study revealed a 38 percent reduction in the risk of death and a 52 percent reduction in the risk of disease-specific death for patients taking the cholesterol-lowering drugs. The authors found three-year overall survival for patients taking statins at the time of surgery was 83.1 percent and 77.3 percent for nonusers. Three-year disease-specific survival was 90.9 percent for statin users and 83.5 percent for nonusers. The results were consistent in an analysis of patients whose disease had not spread beyond the kidney.

“Our data suggest that statin use at the time of surgery is independently associated with improved overall survival and disease-specific survival,” Clark said. “This study is among the first research confirming a survival advantage for patients who are taking these drugs.”

Patients who were taking statin drugs at the time of surgery tended to be older men and the median age was 60.8 years.

Other investigators participating in the study include Opal Lin-Tsai, Daniel Barocas, M.D., MPH, Sam Chang, M.D., S. Duke Herrell, M.D., Joseph Smith Jr., M.D., Vanderbilt; Kelly Stratton, M.D., Memorial Sloan Kettering Cancer Center, New York; Todd Morgan, M.D., University of Michigan Health System, Ann Arbor; and Michael Cookson, M.D., University of Oklahoma College of Medicine, Oklahoma City.

The research was supported by funding from the National Institutes of Health (K08 CA113452, TL1 TR000447), and the Vanderbilt Medical Scholars Program.

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Cancer signaling pathway blocker Fri, 10 Apr 2015 16:20:55 +0000 Researchers at Vanderbilt University have discovered a new way to inhibit Hedgehog (Hh) signaling, an important regulatory pathway for vertebrate development – and cancer. Abnormal regulation of this pathway leads to several human malignancies, including small cell lung cancer and pancreatic cancer, and therefore it is a potential drug target for cancer.

Small molecules have been developed that target the G protein-coupled receptor Smoothened (Smo), one of the components in the Hh pathway, but their clinical efficacy is limited.

Using a chemical genetic zebrafish screen, Charles Hong, M.D., Ph.D., and colleagues identified a small molecule drug, eggmanone, which targets phosphodiesterase (PDE) 4, a protein downstream of Smo. PDE4 previously has been implicated as a driver of central nervous system tumors such as glioblastoma as well as lung and breast tumors, but this is the first time it has been identified as a potential drug target to block the Hh pathway.

Their report was published online March 26 in the journal Cell Reports.

The research was supported in part by National Institutes of Health grant R01HL104040.

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Micelle “packets” deliver cancer drugs Fri, 10 Apr 2015 16:06:42 +0000 Small interfering RNA (siRNA) molecules can suppress tumor growth and target cells otherwise untreatable by conventional therapeutics, but targeted, intracellular delivery is a significant limitation to siRNA translation.

To deliver the siRNA molecules into tumor cells, researchers have packaged them in micelles that express folic acid, which is internalized by cancer cells that overexpress folate receptors. A problem with this approach is that normal healthy tissue can also have a high expression of folate receptors, resulting in off-target effects.

To increase specificity, Craig Duvall, Ph.D., Todd Giorgio, Ph.D., and colleagues utilized an additional hallmark of breast cancer – elevated matrix metalloproteinase (MMP) – to create mixed micelles that have an outer layer of matrix metalloproteinase-7 (MMP7) cleavable peptide. Thus, only in an MMP-rich environment will the MMP7 be cleaved to expose the folic acid and deliver the therapeutic siRNA.

In a study published recently in Biomacromolecules, the researchers show that their new design has better target specificity and protein expression knockdown in breast cancer cells.

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Free head and neck cancer screening April 17 Fri, 10 Apr 2015 16:00:31 +0000 Head and neck screening

Sarah Rohde, M.D., examines Eleanor Manna during a recent screening for head and neck cancer. (photo by Joe Howell)

Of every 100 people in the United States, at least three men or women will be diagnosed with head and neck cancer in their lifetimes. These cancers can occur in the nasal cavity, sinuses, throat, lips, mouth, thyroid, salivary glands or the voice box (larynx).

Early detection of these serious diseases significantly reduces the risk of death.

Vanderbilt’s Department of Otolaryngology-Head and Neck Surgery and Vanderbilt-Ingram Cancer Center are providing free head and neck cancer screenings Friday, April 17, 9 a.m. – 3 p.m. The screenings are open to the public and no appointments are needed.

There are two locations for this year’s event:

• Vanderbilt Bill Wilkerson Center, Odess Head & Neck Surgery Clinic, 7209 Medical Center East, South Tower

• VA Tennessee Valley Healthcare System, Surgical Clinic No. 1 – ENT Clinic, First Floor, 1310 24th Ave. South.

For decades, head and neck cancers were associated with heavy tobacco and alcohol use and were often diagnosed in older patients. In recent years, there has been a decline in these tobacco and alcohol-related cancers. However, physicians are now seeing a jump in head and neck cancers among younger patients, especially white men.

These new cases are associated with human papilloma virus (HPV), a common sexually transmitted virus that is usually shed by the body with no lingering effects. In patients who remain infected with HPV, the virus can lead to head and neck cancers in men and women and cancer of the cervix among women.

Symptoms of head and neck cancer include difficulty swallowing, hoarseness, a change in the voice, lumps, bumps or sore spots on the head or neck and lesions on the tongue. Problems that persist for more than two weeks may be a sign of something serious and should be investigated by a health care professional.

“Early detection is the key to better outcomes or even a cure for head and neck cancer patients,” said Sarah Rohde, M.D., assistant professor of Otolaryngology. “Patients often think they are suffering from allergies or a lingering cold, but problems that don’t clear up quickly could be early signs of a serious disease.”

The free screening exams take only a few minutes and are painless. During the exam, physicians inspect the mouth, throat and tongue and check the neck for abnormalities in the thyroid, lymph nodes or salivary glands.

For more information about the screenings, contact Michelle Pham at 615-585-5388 or email

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NCI report shows U.S. cancer deaths on decline Thu, 02 Apr 2015 19:18:29 +0000 The death rates for most forms of cancer continue to decline at a modest pace among men, women and children in the United States, according to the Annual Report to the Nation on the Status of Cancer 1975 – 2011.

The report from the National Cancer Institute, a division of the National Institutes of Health, was published online March 30 in the Journal of the National Cancer Institute. Investigators found that there has been a relatively consistent decline in overall cancer death rates since the early 1990s.

Specifically, cancer death rates decreased:Cancer mortality decline infographic

  • Among men, by about 1.8 percent per year from 2002 through 2011
  • Among women, by about 1.4 percent per year from 2002 through 2011
  • Among children up to age 19, death rates have continued to mostly decrease since 1975

There was also a lower incidence of many forms of cancer. According to the study, the drop in the number of new lung cancer cases coincides with the steady decline in tobacco use in in recent years.

However, while incidence and death rates for most forms of cancer are declining, there has been an increase in some forms of cancer, including thyroid and kidney cancer among men and women, and oral cancer among white men. This increase in oral/oropharyngeal cancers may be associated with the human papilloma virus (HPV), despite a decline in oral cancers that are more closely linked with tobacco use.

For the first time, researchers also were able to quantify breast cancer incidence and mortality based on subtypes of the disease. For example, 73 percent of all breast cancer cases are considered hormone receptor positive (HR+) and are negative for the HER2 receptor (HER-). In HER2 cancer, the tumor makes high levels of a protein called HER2/neu which makes the cancer more aggressive. The HR+/HER2- molecular subtype of cancer is more easily treated in early stages of the disease.

Only 13 percent of breast cancer cases were found to be “triple negative,” which means that the tumor is not driven by the hormones estrogen and progesterone or by the HER2 mutation. However, triple negative breast cancer is the most difficult to treat and is more common among black women at all age and poverty levels.

Michael Neuss, M.D., chief medical officer at Vanderbilt-Ingram Cancer Center, said the report offers good news with the promise of even better outcomes in the future.

“The overall incidence of cancer is down for adults, nicely paralleling the falling rate of smoking. Vaccination for human papilloma virus promises to decrease the incidence of several cancers. Treatments for advanced cancers are improving survival for those who fall through prevention and screening efforts.

“The improvement in treatment effect is most clearly seen in childhood cancers where survival is up despite the worrisome and as yet unexplained trend of increased childhood cancer incidence. The clinical and research efforts at Vanderbilt will contribute to the efforts of many to sustain and build upon this encouraging news,” Neuss said.

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New driver behind lung cancer progression Thu, 02 Apr 2015 19:06:16 +0000 Pierre Massion, M.D., and Jun Qian, Ph.D

Pierre Massion, M.D., left, Jun Qian, Ph.D., and colleagues are studying the mechanisms used by a gene and its binding protein to drive the growth of cancerous tumors. (photo by John Russell)

Vanderbilt-Ingram Cancer Center investigators have identified the mechanisms used by a gene and its binding protein to drive tumor growth in several forms of cancer, including non-small cell lung cancer.

In a report published online recently in the Proceedings of the National Academy of Sciences (PNAS), first author Jun Qian, Ph.D., lead investigator Pierre Massion, M.D., and colleagues report that the RNA binding protein FXRI is a regulator of tumor progression, and when it is overexpressed it is predictive of poor survival in many types of cancer.

The gene for this protein is a family member of the Fragile X mental retardation 1 (FMR1) gene. There has been much research on the Fragile X gene but not much was known about FXR1.

“One of the central hypotheses tested in our study is that in cancer there is no one driver gene in an amplicon — a piece of a chromosome that harbors multiple copies of the same segment of DNA — but several oncogenes that work together to drive the cancer,” Massion said.

“FXR1 is a binding protein and it binds to either RNA or a protein complex that it regulates closely,” said Qian.

In cell lines, animal models and non-small cell lung cancer tissue samples, the investigators found that FXR1 engages with two partner oncogenes, PRKC1 and ECT2, to promote tumor progression. The finding provides additional evidence that tumor progression is the result of multiple oncogenes working in concert.

Massion’s research laboratory specializes in lung cancer, a disease with a poor five-year survival rate.

“In greater than half of the cases, we still we don’t have a known driver mutation detected,” said Qian.

Identifying a driver mutation and the way in which it operates is a crucial first step in understanding how a type of cancer grows and evades treatment. The study suggests that FXR1 may be a novel target for potential new cancer therapies.

“I think one of the exciting things about our study is we present not only evidence about this potential oncogene in lung cancer, but we are also finding a role for it in breast, head and neck and ovarian cancer,” Qian said. “There must be a mechanistic link between these cancers, so I think that is very relevant to cancer biology and an exciting field for future investigation.”

Meharry Medical College and Veterans Affairs Tennessee Valley Healthcare Systems also contributed to the study. Other investigators include Mohamed Hassanein, Ph.D., Megan Hoek-sema, Bradford Harris, Yong Zou, M.S., Heidi Chen, Ph.D., Pengcheng Lu, M.D., Rosana Eisenberg, M.D., Jing Wang, Ph.D., Allan Espinosa, M.D., Xiangming Ji, Ph.D., Fredrick Harris, Ph.D., and S.M. Jamshedur Rahman, Ph.D.

The study was supported by funding from the National Cancer Institute, a division of the National Institutes of Health (R01 CA102353, CA090949), and the Department of Defense (CDMRP LC090615P3).

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‘Docking stations’ on chromosomes new anti-cancer target Thu, 26 Mar 2015 21:02:17 +0000 Vanderbilt University researchers have discovered a cleft in a chromosome-binding protein that may hold the key to stopping most cancers in their tracks.

The protein, WDR5, is a “docking station” for a family of transcription factors called MYC that is overexpressed in the majority of malignancies and which contributes to an estimated 100,000 cancer-related deaths each year in the United States.

Once an MYC protein slips a “loop” of itself into the crevice in WDR5, it is able to turn on genes involved in growth and development. In the case of cancer, it turns on runaway growth.

“MYC regulates thousands of genes involved in growth and duplication,” said lead author William Tansey, Ph.D., Ingram Professor of Cancer Research and professor of Cell and Developmental Biology. “It’s sort of the Holy Grail of the targeted cancer therapy world.”

William Tansey, Ph.D.

William Tansey, Ph.D.

Researchers have tried unsuccessfully to develop small molecules that can bind directly to MYC and block its ignition of cancerous growth. But the discovery of the crevice, reported in this week’s Molecular Cell, opens up a whole new vista of cancer-fighting possibility.

In collaboration with Tansey’s group, a team led by Stephen Fesik, Ph.D., solved the crystal structure of the MYC-WDR5 interaction. Now they’re now testing small molecules for their ability to block the crevice and prevent MYC from binding to the DNA.

Previously it was thought that MYC only needed to attach to another protein called MAX in order to create a DNA-binding “domain” capable of latching onto the DNA. MAX is still in the picture, but it is MYC’s interaction with WDR5 that may be the key to stopping it, Tansey said.

“This (cleft) is a surface you can develop a drug against,” he said. “If someone can make a small molecule that sits in here, then MYC won’t see WDR5 and it won’t get to its chromosomal locations.”

The potential is exciting.

“It’s very clear from preclinical models that inhibiting MYC in just about any cancer will offer some therapeutic opportunity,” Tansey said. If a small molecule is discovered, and is effective in pre-clinical and clinical trials, “you could imagine the impact of this could be quite significant.”

WDR5 has been known to bind chromatin, the DNA-bearing material that makes up chromosomes, for many years.

But its connections to MYC were unknown until Tansey and Lance Thomas, first author of the study, found that a central portion of the MYC protein conserved in nearly every species in the animal kingdom binds to it.

“That’s when we realized this must be important,” he said.

Fesik, the Orrin H. Ingram II Professor of Cancer Research, solved the crystalline structure of the MYC-WDR5 interaction, and disrupted the interaction by changing a single amino acid in the MYC protein.

At that point, three other labs at Vanderbilt joined the effort to determine the functional significance of the interaction:

Zhongming Zhao, Ph.D., and colleagues in Biomedical Informatics performed the genomics analyses;

Christine Eischen, Ph.D., and colleagues in Pathology, Microbiology and Immunology developed mouse models to test the tumorigenicity of altered MYC proteins; and

Kevin Ess, M.D., Ph.D., and colleagues in Pediatric Neurology conducted stem cell experiments to get at the basic biology of the interaction.

“I’ve never been on a paper with this many authors (18 all told),” Tansey said. “I think it really does testify to the fact that (Vanderbilt is) a very collaborative environment.”

The research was supported in part by National Institutes of Health grants AG039164, NS078289, LM011177, CA148950 and OD006933.

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VICC’s Johnson to study cancer survivorship with immune inhibitor drugs Thu, 19 Mar 2015 18:25:19 +0000 Douglas Johnson, M.D., assistant professor of Medicine, has been named a recipient of the National Comprehensive Cancer Network  (NCCN) Foundation Young Investigator Awards.

The two-year grant will provide $150,000 in funding for his research on survivorship among cancer patients who receive drugs called immune checkpoint inhibitors.

Douglas Johnson, M.D.

Douglas Johnson, M.D.

The formal announcement of the grant awardees was made March 13 at the NCCN Annual Conference.

Johnson is the principal investigator of several clinical research trials at Vanderbilt-Ingram Cancer Center (VICC) for patients with melanoma.

“I am honored to receive this funding support from the NCCN Foundation,” said Johnson, who specializes in treating melanoma patients at VICC.

“This award will help us take the next steps in our research to more effectively use these new therapies for cancer patients.”

Johnson’s mentors for this grant are Jeffrey Sosman, M.D., professor of Medicine and director of the VICC Melanoma and Tumor Immunotherapy Program, and Debra Friedman, M.D., E. Bronson Ingram Professor of Pediatric Oncology and director of Pediatric Hematology/Oncology.

Melanoma is the most lethal form of skin cancer and while early stage disease is treatable, for decades there were no effective therapies for advanced disease which does not respond well to chemotherapy.

Within the past few years, however, two new classes of treatments have been developed. These include new targeted therapies for melanoma tumors which harbor specific mutations.

For example, the BRAF gene is mutated in about half of all melanoma cases and new drugs have been developed which target BRAF.

VICC investigators were among the leaders of the clinical trials that tested these new targeted therapies.

In addition, immune checkpoint inhibitors are playing a major role in melanoma treatment.

These agents have now been approved and are in use in melanoma and are beginning to also show activity in other cancers (including cancers of the lung, kidney and bladder,  Hodgkin lymphoma, and others).

In contrast to most cancer treatments, immune checkpoint inhibitors may cause responses that last for years.

Johnson said the body’s immune system normally detects and addresses threats from invaders. But in many forms of cancer, the immune system is suppressed by proteins that put a brake on the immune response. New checkpoint inhibitor drugs can remove this braking effect and allow the immune system’s T-cells to identify and attack the malignant cells.

“These immunotherapies are producing promising and long-lasting responses in patients with melanoma and other cancers,” explained Johnson.

“This grant will allow us to study long-term outcomes and treatment responses for patients who benefit from these new therapies.”

Johnson graduated Summa Cum Laude with a Bachelor of Science degree from Abilene Christian University, Texas, and his M.D. from the University of Alabama School of Medicine, Birmingham.

He completed an Internal Medicine Residency at Duke University, Durham, North Carolina, a fellowship in Hematology/Oncology at Vanderbilt University, and received a Master of Science in Clinical Investigation degree at Vanderbilt.

He joined the Vanderbilt faculty in 2014.

The NCCN is a nonprofit alliance of 26 of the world’s leading cancer centers, including VICC, and is devoted to research and education to improve the quality, effectiveness and efficiency of cancer care so that patients can live better lives.

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Team blends high-end imaging techniques Mon, 16 Mar 2015 16:25:24 +0000 high-end imaging

Image of a section of the brain shows the fusion of microscopy (pink area) and mass spectrometry (pixelated colors at bottom) to produce a detailed “map” of the distribution of proteins, lipids and other molecules within sharply delineated brain structures (upper left).

Vanderbilt University researchers have achieved the first “image fusion” of mass spectrometry and microscopy — a technical tour de force that could, among other things, dramatically improve the diagnosis and treatment of cancer.

Microscopy can yield high-resolution images of tissues, but “it really doesn’t give you molecular information,” said Richard Caprioli, Ph.D., senior author of the paper published last week in the journal Nature Methods.

Mass spectrometry provides a very precise accounting of the proteins, lipids and other molecules in a given tissue, but in a spatially coarse or pixelated manner. Combining the best features of both imaging modalities allows scientists to see the molecular make-up of tissues in high resolution.

“That to me is just phenomenal,” said Caprioli, the Stanford Moore Professor of Biochemistry and director of the Mass Spectrometry Research Center.

Caprioli said the technique could redefine the surgical “margin,” the line between cancer cells and normal cells where the scalpel goes to remove the tumor.

Currently that line is determined by histology — the appearance of cells examined under the microscope. But many cancers recur after surgery. That could be because what appear to be normal cells, when analyzed for their protein content using mass spectrometry, are actually cancer cells in the making.

“The application of image fusion approaches to the analysis of tissue sections by microscopy and mass spectrometry is a significant innovation that should change the way that these techniques are used together,” said Douglas Sheeley, Sc.D., senior scientific officer in the National Institute of General Medical Sciences (NIGMS).

“It is an important step in the process of making mass spectrometry data accessible and truly useful for clinicians,” he said. The NIGMS, part of the National Institutes of Health (NIH), partially funded the research (grant numbers GM058008 and GM103391).

The image fusion project was led by Raf Van de Plas, Ph.D., a research assistant professor of Biochemistry who also has a faculty position at Delft University of Technology in the Netherlands. Other co-authors were postdoctoral fellow Junhai Yang, Ph.D., and Jeffrey Spraggins, Ph.D., research assistant professor of Biochemistry.

Using a mathematical approach called regression analysis, the researchers mapped each pixel of mass spectrometry data onto the corresponding spot on the microscopy image to produce a new, “predicted” image.

It’s similar in concept to the line drawn between experimentally determined points in a standard curve, Caprioli said. There are no “real” points between those that were actually measured, yet the line is predicted by the previous experiments.

In the same way, “we’re predicting what the data should look like,” he said.

The research was supported in part by National Institutes of Health grants GM058008 and GM103391.


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