VICC News & Publications Thu, 26 Mar 2015 21:03:22 +0000 en-US hourly 1 ‘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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Barocas named to Commission on Cancer Thu, 12 Mar 2015 20:26:51 +0000 Daniel Barocas, M.D., MPH, assistant professor of Urologic Surgery at Vanderbilt University Medical Center, was recently named a representative on the Commission on Cancer.

The program helps to raise the quality of care at hospitals across the country through developing standards for cancer care and uses those standards to accredit hospitals. Barocas will represent the American Urological Association on the national commission, which is a program of the American College of Surgeons.

Daniel Barocas, M.D., MPH

Daniel Barocas, M.D., MPH

“I view this as an outstanding opportunity to be involved further in developing standards for quality of cancer care in order to reduce unnecessary variation and elevate the quality of care on a national level,” Barocas said.

During his three-year term, Barocas will serve on the commission’s quality integration committee, which oversees quality measurement.

The role will also have Barocas representing the urological association on the commission.

“The Commission on Cancer is a key national organization in the effort to improve the quality of cancer care in the United States,” said David Penson, M.D., chair of Urologic Surgery. “Given Dan’s work on the quality of care here in the Vanderbilt Department of Urologic Surgery, he is a perfect person to represent all of urology on the commission. This is a great honor for him, and it is well-deserved.”

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Mutations may predict melanoma response to immunotherapies Thu, 12 Mar 2015 20:17:58 +0000 Melanoma patients whose tumors test positive for mutations in the NRAS gene were more likely to benefit from new immunotherapy drugs, according to a new study led by Vanderbilt-Ingram Cancer Center (VICC) investigators.

Douglas Johnson, M.D., assistant professor of Medicine, and Christine Lovly, M.D., Ph.D., assistant professor of Medicine and Cancer Biology, are co-first authors of the study, conducted in conjunction with colleagues from Memorial Sloan Kettering Cancer Center (MSKCC), New York, and Massachusetts General Hospital (MGH), Boston. The study was published in Cancer Immunology Research.

Douglas Johnson, M.D.

Douglas Johnson, M.D.

Researchers have discovered several driver mutations in oncogenes like NRAS, BRAF and CKIT and these “drivers” appear to be essential in supporting the cancer. NRAS mutations are found in 15- 20 percent of all melanomas, the most deadly form of skin cancer. However, no targeted therapies have yet been approved for NRAS-driven cancer. It has also been unclear how these gene mutations interact with immunotherapy.

Sixty melanomas harbored NRAS mutations, 53 had BRAF mutations and 116 had no NRAS or BRAF mutations (wild type).Vanderbilt investigators first noticed that melanoma patients with NRAS mutations who had been treated with immunotherapies appeared to do better on these therapies. Together with colleagues, they reviewed records of 229 patients at VICC, MSKCC and MGH treated with the immunotherapies ipilimumab, IL-2, or new therapies that inhibit immune checkpoint proteins like programmed cell death protein 1 (PD-1/PD-L-1).

Christine Lovly, M.D., Ph.D.

Christine Lovly, M.D., Ph.D.

“We found that patients with NRAS-mutant melanoma seemed to respond better to immunotherapy compared with patients whose tumors had other genetic subtypes, and this was especially true for patients treated with anti-PD-1/PD-L1 therapies,” Johnson said.

Twenty-eight percent of patients with NRAS-mutant melanoma had complete or partial responses to first-line immunotherapy compared with 16 percent of patients who had the wild type gene. The clinical benefit rate (CBR) with anti-PD-1/PD-L1 drugs was 73 percent for patients with mutant NRAS versus 35 percent for wild type. The CBR for NRAS-mutant patients treated with ipilimumab was 42 percent versus 19 percent in wild type. Clinical benefit rate was defined as complete or partial response or stable disease lasting 24 weeks or more.

“We studied a small group of patients but the results were quite suggestive,” Johnson said. “This study highlights the need to find predictive markers that can help us understand which patients will respond to therapy.”

Other investigators for the study include Gregory Ayers, M.S., Zhiguo Zhao, M.S., Wade Iams, M.D., Charles Terry, M.D., Elizabeth Berry, M.D., Jeffrey Sosman, M.D., Vanderbilt; Marisa Flavin, M.D., Katherine Panageas, Dr.PH., Marta Colgan, B.S., and Richard Carvajal, M.D., MSKCC; Sarah DeNoble, B.S., A. John Iafrate, M.D., Ph.D., Ryan Sullivan, M.D., MGH.

The research was supported by funding from the National Institutes of Health (K12 CA 0906525, UL1TR000445), VICC, Damon Runyon Cancer Research Foundation, American Cancer Society, Joyce Family Foundation, T.J. Martell Foundation, Bradford Family Foundation, and the Anbinder Fund.

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‘Cancer: The Emperor of All Maladies’ Wed, 11 Mar 2015 16:19:08 +0000

VICC Cancer Research promotional spot highlighting Carlos Arteaga, M.D.

The Vanderbilt-Ingram Cancer Center, in collaboration with Nashville Public Television, American Cancer Society, and Gilda’s Club, will host a free preview of Cancer: The Emperor of All Maladies, a new three-part documentary by Barak Goodman, presented by Ken Burns, panel discussion and moderated Q&A on Wednesday, March 25 at the Vanderbilt University Student Life Center.

The event is free and open to the public; RSVP via

The panelists are:

  • Carlos L. Arteaga, M.D.: Director, Center of Cancer Targeted Therapies; Associate Director for Clinical Research, Vanderbilt-Ingram Cancer Center; and President, American Association for Cancer Research.
  • Felice Apolinsky, LCSW: Program Director, Gilda’s Club Nashville; and cancer survivor.
  • Christopher Brown: American Cancer Society volunteer and cancer survivor.

Who: NPT, American Cancer Society, Gilda’s Club and VICC

What: Preview screening & panel discussion of Cancer: The Emperor of  All Maladies, a new three-part documentary by Barak Goodman, presented  by Ken Burns

When: 6-7:30 p.m. Wednesday, March 25, 2015

Where: Vanderbilt University Student Life Center, 310 25th Ave. S., Nashville, Tenn. 37240. Complimentary valet parking; free parking in the 25th Avenue parking garage.

Cancer: The Emperor of All Maladies  is a three-part, six-hour major television event from preeminent documentary filmmaker Ken Burns based on the 2010 Pulitzer Prize-winning book by Dr. Siddhartha Mukherjee. The documentary airs March 30-April 1on NPT. NPT will also air three short spots that localize the documentary’s content and feature representatives from each of our three partner organizations.


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Zanic’s journey to lab followed winding path Mon, 09 Mar 2015 20:45:16 +0000 Marija Zanic, Ph.D.

VUMC’s Marija Zanic, Ph.D., is studying the microtubule, a fundamental structure that makes up the cytoskeleton of the cell. (photo by Anne Rayner)

It’s roughly 5,000 miles from Croatia to Tennessee as the crow flies.

For Marija Zanic, Ph.D., who joined Vanderbilt University’s Department of Cell and Developmental Biology as an assistant professor last August, the journey from her home country took a more circuitous route — from cell biology to theoretical physics and back again.

Zanic’s dissertation explored string cosmology, which describes the fundamental structure of the universe. Today she is an expert on the microtubule, a fundamental structure that makes up the cytoskeleton of the cell.

“Microtubules are polymers inside of cells that build a lot of different structures, including the mitotic spindle, essential for cell division,” she explained. “They are essential for cellular motility.”

They also are implicated in disorders ranging from Alzheimer’s disease to cancer.

“Cancer cells often divide faster than regular cells,” Zanic said. “If we know how to control (microtubules), how to change their behavior and build these structures, then we can affect how cancer cells behave. If you can freeze (microtubule) action, you can stop cancer cells from dividing.”

Zanic has always been interested in science. Both of her parents had math degrees.  “I loved math, and physics was a natural,” she said. “But I have been fascinated by cell biology since high school.”

In her first year at the University of Zagreb in Croatia’s capital city, Zanic applied to both the physics and molecular cell biology programs. Physics won out, but she said her interest in cell biology never waned.

Later, while pursuing her doctorate at the University of Texas at Austin, Zanic audited a biophysics course and decided to switch from pure theory to experimental science. Still, physics informs her work.

“There are no direct applications between studying string theory and studying cells, but it stretched my capabilities and gave me a toolbox of (quantitative) approaches I can apply to the field of biology, which is very qualitative,” she said.

In college Zanic met her husband-to-be, Thomas, a Croatian-American who comes from a family of physicists and has a Ph.D. in environmental engineering.  He now works for a consulting company in Brentwood, Tennessee.  They have two children, Andrew, a fourth-grader at Julia Green Elementary, and Anna, a 3-year-old.

After earning her Ph.D., Zanic won a Cross-Disciplinary Postdoctoral Fellowship from the Human Frontier in Science Program to do research in biophysics at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany. The program supports young scientists who are transitioning from physical sciences to biology.

She went on to continue her research at Yale University.

Several years ago Zanic attended a Gordon Conference in New Hampshire where she met Ryoma Ohi, Ph.D., associate professor of Cell and Developmental Biology. She decided Vanderbilt was a good match for her.

Ian Macara, Ph.D., the Louise B. McGavock Professor and chair of the Department of Cell and Developmental Biology, agreed.

“She brings a fresh new perspective to quantitative cell biology that nicely complements our strengths within the department in the cytoskeleton and cell dynamics,” he said.

Upon her arrival, Zanic immediately began to collaborate with colleagues in the department and in the School of Engineering as well. A recent $300,000 career development award from the Human Frontier in Science Program is helping her set up her lab.

“The combination of cell biology — using the cells — and the approach I’m taking from the other side — looking at how single molecules behave and how we can build these systems in a quantitative, rigorous and controlled manner — has great potential for discovery,” Zanic said.

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Moses, Shyr named to IOM cancer therapies panel Mon, 09 Mar 2015 20:44:14 +0000 Two Vanderbilt-Ingram Cancer Center (VICC) leaders have been named to a panel of the Institute of Medicine (IOM) to help shape national policies on the use of biomarkers for targeted cancer therapies.

Harold L. (Hal) Moses, M.D.

Harold L. (Hal) Moses, M.D.

Harold L. (Hal) Moses, M.D., Ingram Professor of Cancer Research and director emeritus of VICC, will chair the IOM’s ad hoc committee, Policy Issues in the Clinical Development and Use of Biomarkers for Molecularly Targeted Therapies. Moses is a member of the IOM and founding chair of the group’s National Cancer Policy Forum.

Yu Shyr, Ph.D., director of the Vanderbilt Center for Quantitative Sciences and VANGARD (Vanderbilt Technologies for Advanced Genomics Analysis and Research Design), also will serve as a committee member. This information can be used to guide selection of therapies most likely to benefit a particular patient. New technologies have identified gene mutations in patient tumors as well as molecular biomarkers that signal key attributes of a patient’s disease.

Yu Shyr, Ph.D.

Yu Shyr, Ph.D.

The development of these new technologies and their use in clinical practice is a hallmark of precision medicine which seeks to match the right therapy to the right patient at the right time.

Biomarkers also have become important in the selection of targeted therapies in diseases other than cancer.

“This is a critical time to examine these issues as the FDA is moving toward exerting more oversight and regulation of biomarker tests, and input from the broader scientific community should be helpful in assuring appropriate FDA oversight,” Moses said.

Using previously published IOM reports as a starting point, the committee will examine opportunities for, and challenges to, the use of biomarker tests to select optimal therapy. The committee will formulate recommendations to accelerate progress in this field.

The committee will also address the standards of evidence used by the Centers for Medicare and Medicaid Services (CMS) and other payers to make decisions about coverage and interpretation of molecular tests and clinical decision-making.

“As a quantitative scientist on this committee, I want to make sure that there is solid data supporting the policies for biomarker tests and especially genomics-based tests,” said Shyr, Harold L. Moses Professor of Cancer Research.

The committee’s next meeting is scheduled to be held in April, with two additional meetings later in the year. The group will generate a report with specific conclusions and recommendations for the FDA, CMS, and other agencies, and the report will undergo a rigorous peer review prior to publication.

The IOM is the health arm of the National Academies, which also includes the National Academy of Sciences, National Academy of Engineering and National Research Council.

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Grant boosts head and neck lymphedema research Mon, 09 Mar 2015 20:41:51 +0000 Vanderbilt University School of Nursing (VUSN) has been awarded a four-year, $2.4 million grant from the National Institutes of Health/National Institute of Dental and Craniofacial Research to establish a valid, clinically useful measurement battery for head and neck lymphedema and fibrosis (LEF).

Principal investigator Jie Deng, Ph.D., R.N., developed the proposal because she commonly sees oral cavity and oropharyngeal cancer patients who have under-identified late treatment effects that impair function or decrease quality of life.

Jie Deng, PhD, RN

Jie Deng, PhD, RN

The study aims to equip clinicians with validated measures to identify lymphedema and fibrosis-associated symptoms, refer appropriate patients for LEF treatment and monitor the results of therapy. LEF measurement in oral cavity and oropharyngeal cancer patients is challenging. There is no validated patient-reported outcome measure available.

Deng, Sheila Ridner, Ph.D., professor of Nursing, and Barbara Murphy, M.D., medical oncologist at Vanderbilt-Ingram Cancer Center, have shown in previous work the limitations of existing measurements, such as the Patterson Scale, for this patient population. They conclude that while imaging tools hold promise, they have not been systemically evaluated in this patient population.

“Many people are interested in this field of study and this particular line of research has the capacity to empower both patients and clinicians alike with much-needed measurement tools. We are very pleased that it has received such a high level of funding,” said Ann Minnick, Ph.D., R.N., Julia Eleanor Chenault Professor of Nursing and senior associate dean for Research at VUSN.

The specific aims of the grant are to determine reliability and validity of patient-reported outcome measures and  clinician-reported outcome measures and imaging techniques for assessing and identifying LEF in oral cavity and oropharyngeal cancer patients across the trajectory of treatment, recovery and survival. Starting this month, the research team will begin recruiting 120 participants for this four-year longitudinal study. Data collection will occur at pre-treatment, end of treatment and every three months up to 12 months post-cancer treatment.

Colleagues on the study include Mary Dietrich, Ph.D., Arthur Fleischer, M.D., and Joseph Aulino, M.D.

Linda Norman, DSN, R.N., Valere Potter Menefee Professor of Nursing and dean of VUSN, said Deng is an exceptionally insightful nurse scientist.

“Jie is passionate about helping solve the many complications associated with lymphedema and fibrosis. She first came to VUSN when she was a nurse manager in China on a study visit with an interest in acute care. From there, her interests have grown and propelled her through her doctoral, and post-doctoral work at the School of Nursing and now this R01 grant,” Norman said.

The research is supported by National Institutes of Health grant 1R01DE024982-01.

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MDS patient and family forum March 14 Mon, 02 Mar 2015 23:29:14 +0000 The Myelodysplastic Syndrome Foundation, Inc., is sponsoring a patient and caregiver forum on March 14, 2015 at the Marriott Nashville at Vanderbilt.

Michael Savona, M.D.

Michael Savona, M.D.,

The forum will feature a presentation and Q&A session with Vanderbilt-Ingram Cancer Center’s Michael Savona, M.D., about new therapies and treatment options for MDS.

The conference runs from 9:30 a.m. to 2:00 p.m. and will also feature:

  • Patient Support Group Open Discussion
  • Quick Tips for Patients and Caregivers
  • The MDS Foundation’s Building Blocks of Hope

See the agenda for more details

The one-day conference is free, but registration is required.

Register for the event online or contact Deborah Murray at 1-800-637-0839 or for more information.

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