VICC News & Publications http://viccweb.gtm.mc.vanderbilt.edu/news Thu, 29 Jan 2015 21:06:28 +0000 en-US hourly 1 http://wordpress.org/?v=4.1 Grant bolsters pancreatic cancer drug discovery http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/grant-bolsters-pancreatic-cancer-drug-discovery/ http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/grant-bolsters-pancreatic-cancer-drug-discovery/#comments Thu, 29 Jan 2015 20:57:21 +0000 http://viccweb.gtm.mc.vanderbilt.edu/news/?p=7262 The Lustgarten Foundation has awarded a $1.5 million Research Investigator Grant to Stephen Fesik, Ph.D., professor of Biochemistry, Pharmacology and Chemistry, for research designed to discover new drugs for the treatment of pancreatic cancer.

This is Fesik’s second three-year award from the Lustgarten Foundation in support of his research targeting K-Ras, a protein mutated in 90 percent of pancreatic cancer cases, as well as other forms of cancer.Fesik is among 13 scientists nominated by their peers for significant achievements in the field of pancreatic cancer research who will receive a total of $19.5 million in research funding from the foundation.

Stephen Fesik, Ph.D.

Stephen Fesik, Ph.D.

“I am very happy to receive this award. This will greatly help our efforts in targeting this horrible disease,” said Fesik, Orrin H. Ingram II Professor of Cancer Research and co-leader of the Signal Transduction and Chemical Biology Research Program.

The pancreas is an organ located deep in the abdomen between the stomach and the spine. It produces juices containing enzymes that help digest food and also serves as a gland that produces insulin. Since pancreatic cancer may cause no obvious symptoms in its earliest stages, the disease is often diagnosed when the cancer is already advanced. Only 6 percent of patients are still alive five years after diagnosis, making pancreatic cancer one of the most deadly forms of cancer.

The K-Ras protein controls many processes that are important for tumor cell growth, but it is a challenging protein to target and has been considered undruggable.

Fesik and his colleagues recently discovered small molecules that affect the function of K-Ras by binding to a regulatory protein (SOS) responsible for activating K-Ras. In preliminary testing, the molecules kill cancer cells by inhibiting Ras signaling.

“We do not yet understand why these small molecules function in this manner and the compounds are not currently potent enough for use as pharmaceutical agents. Nevertheless, they represent a promising starting point for discovering more potent compounds that inhibit K-Ras function and could be used to treat pancreatic and other Ras-driven types of cancer,” Fesik said.

He and his colleagues plan to study the mechanism of action of the compounds and optimize them to inhibit K-Ras signaling and kill pancreatic tumor cells. In the future, they also plan to examine the ability of their compounds to shrink pancreatic cancer tumors in animal studies.

Fesik is a fellow of the American Association for the Advancement of Science (AAAS). In 2010, he received the National Institutes of Health (NIH) Director’s Pioneer Award for his efforts to revolutionize the process of drug discovery. He has also received the Lifetime Achievement Award in Nuclear Magnetic Resonance from the Eastern Analytical Society as well as the SBS Technology Innovation Award.

The Lustgarten Foundation is a nonprofit organization dedicated to promoting research that will lead to a cure for pancreatic cancer. Inspired by Marc Lustgarten, vice chair of Cablevision and chair of Madison Square Garden in New York City, the foundation was launched in 1999.

Lustgarten, who served on the initial board of directors for the foundation, died from pancreatic cancer at 52.

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New options enhance prostate cancer treatment http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/new-options-enhance-prostate-cancer-treatment/ http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/new-options-enhance-prostate-cancer-treatment/#comments Thu, 29 Jan 2015 20:37:25 +0000 http://viccweb.gtm.mc.vanderbilt.edu/news/?p=7257 Vanderbilt-Ingram Cancer Center (VICC) patient William Ostman smiled while gazing into a camera lens and declared, “I am a prostate cancer survivor.”

Ostman, 63, who now lives in Hermitage, Tennessee, was sharing his story recently in a video for the nonprofit organization ZERO – The End of Prostate Cancer.

Alicia Morgans, M.D., and patient

Alicia Morgans, M.D., left, talks with patient William Ostman and his wife, Liz, about new prostate cancer therapies available at the Vanderbilt-Ingram Cancer Center. (photo by Nathaniel Bryant)

The fact that he is still here to promote prostate cancer awareness more than eight years after his diagnosis is a direct result of new therapies for patients with advanced disease.

Ostman’s cancer was detected through a routine blood test that showed an elevated prostate-specific antigen (PSA) level.The prostate is a gland located just below the bladder in men. In 2014, the National Cancer Institute estimated 233,000 new cases of prostate cancer with 29,480 deaths.

He had surgery to remove the prostate, followed by external beam radiation a few months later.

“The next five years I still worked, I had no symptoms,” Ostman said.

But over time the cancer spread to his back and bones, eventually putting him in a wheelchair.

“Ten years ago, there were almost no therapies for men with metastatic disease,” said Alicia Morgans, M.D., assistant professor of Medicine.

Chemotherapy had just been approved for men with advanced disease but it gave patients only about three extra months of life.

According to Morgans, in the past five years five new therapies have been approved by the Food and Drug Administration (FDA) and each therapy attacks the disease in a different way.

“Mr. Ostman is a perfect example of someone who had advanced disease for many years and who, fortuitously, has had new treatments approved at each point where he has needed to change therapies,” explained Morgans.

Many of the new therapies are oral medications or are given by IV infusion every few weeks. Since most prostate cancer is fueled by the male hormone testosterone, some of the drugs target testosterone either by stopping production or disrupting the action of the hormone.

“Over time almost all of those cancers will become resistant to these therapies, and that’s when we add new treatments,” said Morgans.

Prostate cancer really likes to go to the bones and the lymph nodes, said Eric Shinohara, M.D., MSCI, associate medical director of Radiation Oncology.

“It can weaken a bone, meaning there is an increased risk of fracture and it can cause a lot of pain. If the cancer is in a vital bone like the spine, it can grow into the spinal cord and cause paralysis.”

With external beam radiation a focused beam is aimed at those problem areas “…like spot welding,” according to Shinohara.

A newly approved form of radiotherapy injected into the patient also targets cancer in the bone.

“Radium on the periodic table is in the same column as calcium, so your body thinks of it as calcium and puts it in bone. In patients with diffuse bony disease we use radium. It goes to the bones and limits dose to other normal tissues. It is a very powerful tool because we can control where the dose goes and treat multiple areas of disease effectively,” said Shinohara.

Today, Ostman is back on his feet, though he still uses a cane. With the help of his wife, Liz, he is able to navigate steps and spends time in his workshop.

So far the new therapies do not cure advanced prostate cancer, but Ostman is grateful the treatments are making his disease manageable.

“Luckily I haven’t had any bad side effects with any of them. I am slowly, very slowly getting better. If anything hurts, all I have to do is check with Dr. Morgans and …we’ll move on to something else.”

Some men still have very aggressive disease that pushes through all available treatments and is fatal, but for other patients the new therapies help manage the disease more like a chronic illness.

“They don’t need to suffer terribly just because they have advanced disease. There is hope that they can maintain quality of life and certainly live longer,” said Morgans.

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Yoga therapy for cancer patients studied http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/vusn%e2%80%88studies-yoga-therapy-for-cancer-patients/ http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/vusn%e2%80%88studies-yoga-therapy-for-cancer-patients/#comments Thu, 29 Jan 2015 20:28:47 +0000 http://viccweb.gtm.mc.vanderbilt.edu/news/?p=7248 Yoga Therapy

Cancer patient Michael Walsh works with yoga therapist Sujatha Yarlagadda as part of a School of Nursing study of using yoga to address lymphedema. (photo by Susan Urmy)

Cancer is bad enough.

But cancer patients who receive surgery, radiation and chemotherapy may suffer from side effects that run from irritating to crippling — problems that are postural, musculoskeletal and respiratory, along with lowered self-esteem. Many suffer from lymphedema, swelling caused by retained fluid in a compromised lymphatic system.

One answer may be the ancient practice of yoga. Researcher Sheila Ridner, Ph.D., MSN, R.N., Martha Rivers Ingram Professor of Nursing, is conducting a pilot study, in which head and neck cancer patients are receiving yoga therapy. It’s designed to increase the mobility of affected parts in order to address lymphedema symptoms, postural problems, and breathing issues, in addition to improving mood.

“Breathing, particularly diaphragmatic breathing, helps move the fluid and standing upright clearly takes away restrictive bends in the body that might keep fluid from moving,” Ridner said.

For the last year, study participants have been coming to the Vanderbilt University School of Nursing for 90-minute, one-on-one sessions with Sujatha Yarlagadda, yoga therapist and assistant in Nursing. Each session includes awareness practice, postures that focus on improving mobility in the neck, jaw and shoulders, breathing exercises, relaxation and meditation.

Ridner compares the participants’ physical measurements taken after the four weeks of treatment to before. Then, the patients come two times a week for another four weeks, a similar regimen to what they would receive if they received traditional physical therapy, Ridner said.They come three times a week for a month, while Yarlagadda helps determine which of 16 yoga poses are effective “to loosen the entire body and facilitate free flow of energy,” she said. The sessions are filmed, and participants can leave with a DVD of the session that they can use to practice yoga at home.

Yoga Therapy 2

From left, Sheila Ridner, Ph.D., MSN, R.N., patient Michael Walsh and Sujatha Yarlagadda. (photo by Susan Urmy)

So far, more than 20 people have participated, out of a pool of 40 that Ridner hopes to recruit. Though the study is not scheduled to end until July 31, Ridner is encouraged by the changes she’s seeing in patients.

“They walk better,” she said. “They’re standing up straighter. They say hi when they see people and they have a smile on their face that they literally didn’t have when they first came in the door.”

Michael Walsh, a neck cancer survivor who is finished with his part in the study but continues to practice yoga, said he’s much improved. He’s resumed playing ice hockey on weekends, something he had to give up after the cancer treatments rendered him unable.

“It feels a lot better, and I know that because I’m not getting my headaches that I used to get,” he said.

Ridner is closely measuring the effectiveness of each yoga position, and combinations of positions. Her hope is that this is one step toward a more comprehensive study that will lead to targeted yoga therapies that patients can do at home.

She emphasized that the postures are carefully chosen and are safe, and haven’t resulted in injury. This isn’t group yoga or hot yoga, which is practiced in a room heated to about 105 degrees.

Ridner has been passionate about head and neck patients since she treated them as a bedside nurse in the late 1970s. She said that often, lymphedema sufferers are either not diagnosed or asked to live with their conditions until they get much worse.

“These may be things that we can fix,” she said. “It’s not like you just have to accept that people have to be impaired after having head and neck cancer. We don’t have to accept that for them. We do not have to accept that’s just what happens.”

The study is being funded by the National Cancer Institute and the National Center for Complementary and Alternative Medicine and the Martha Rivers Ingram Chair in Nursing and the School of Nursing.

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Data mining reveals cancer-driving genes http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/data-mining-reveals-cancer-driving-genes/ http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/data-mining-reveals-cancer-driving-genes/#comments Thu, 22 Jan 2015 21:12:42 +0000 http://viccweb.gtm.mc.vanderbilt.edu/news/?p=7242 Prospecting for genes that might be implicated in cancer, a Vanderbilt University Medical Center research team has struck pay dirt.

Zhongming Zhao, Ph.D., Peilin Jia, Ph.D., and colleagues use novel computational methods to sift through online repositories of molecular data gathered by cancer researchers worldwide.

These results, and further analyses planned by the team, can help focus laboratory and clinical research, speeding more complete understanding of the molecular basis of cancer.

In the journal Genome Biology, in a massive analysis of cancer mutation records, the team demonstrates data mining methods capable of singling out known cancer-driving genes from amidst thousands of other genes isolated from cancer tissue. More to the point, the authors use these tools to decisively brand hundreds of genes as suspected agents of cancer (“candidate cancer genes”), and they reveal several associations, hidden until now, between known cancer-driving genes and additional types of cancer.

Peilin Jia and  Zhongming Zhao

Peilin Jia, Ph.D., Zhongming Zhao, Ph.D., and colleagues are using novel computational methods to single out cancer-driving genes. (photo by Daniel Dubois)

According to Zhao, when cancer tissue and normal tissue from the same patient are compared, the cancer tissue is apt to contain hundreds or thousands more mutations in the coding regions of the genome alone — that is, in the genes. And while some of these mutations might be helping to drive the cancer, many others will simply be along for the ride.

“It’s not practical to test that many mutations in the lab or in clinical practice. So the idea is to somehow home in on mutations that are more apt to be clinically relevant. In that respect at least, we think these new methods are much better than previous methods,” Zhao said.

In many of our cells, the vagaries of DNA replication give rise to — among other things — DNA base insertions and deletions, together termed indels, and single base substitutions, called point mutations. Natural selection, here operating at the cellular level, is of course not indifferent to these accidents. In cancer these mutations often converge to form so-called hotspots in regions presumed to be somehow vital to the unchecked growth and success of the cancer.

The Vanderbilt team has gone in search of such hotspots. In the Cancer Gene Census, the most authoritative available count, the team saw that approximately one-third of the listed cancer-driving genes contained mutations of the sort eligible for hotspot analysis. Using two complementary methods, they found that 51 percent of these 183 genes bore significant hotspots.

Drawing on more than 840,000 mutation records from online repositories, the team proceeded to score some 18,284 eligible genes using a method called MSEA-clust (for mutation set enrichment analysis cluster). They found 947 genes with significant hotspots, including 82 known cancer genes.

This is an example of hypothesis-free, pan-cancer analysis, used previously to measure differential gene expression across different types of cancer.

“An important aspect that distinguishes our method is that we identify not only candidate cancer genes, but also the precise regions of interest within these genes,” Zhao said.

And that new level of detail presumably can aid understanding of how particular gene products might go awry in cancer.

MSEA-clust distinguishes among individual mutations with regard to their downstream consequences. The method keeps track, for example, of deleterious and non-deleterious mutations, a step that’s missing from the sole previous attempt to systematically associate hotspots with cancer. And according to Jia, for this reason the earlier hotspot analysis is much more likely to have produced considerably more false positives. “Just not as elegant,” she said.

With a second method called MSEA-domain, the Vanderbilt team looked for any disproportionately high occurrence of indels and point mutations in DNA corresponding to protein domains.

Protein domains are modular structures that pop up again and again in different configurations in different proteins.

“The idea is that domain regions are more apt to be functionally critical, and mutations that locate there may be more apt to confer abnormal cell growth,” Jia said.

They ran MSEA-domain on some 14,224 eligible genes and found 203 with significant hotspots, including 43 known cancer genes.

Other members of the team included Quan Wang, Ph.D., Qingxia Chen, Ph.D., M.S., William Pao, M.D., Ph.D., and doctoral candidate Katherine Hutchinson.

The study was supported by the National Institutes of Health (grants LM011177, CA68485, CA095103, CA098131), the American Cancer Society and the Joanna M. Nicolay Melanoma Foundation.

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Cancer groups call for regulation of e-cigarettes http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/cancer-groups-call-for-regulation-of-e-cigarettes/ http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/cancer-groups-call-for-regulation-of-e-cigarettes/#comments Thu, 15 Jan 2015 21:42:30 +0000 http://viccweb.gtm.mc.vanderbilt.edu/news/?p=7232 e-cigarette

The American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) are calling for regulation of e-cigarettes and other electronic nicotine delivery systems. (iStock)

Two leading cancer organizations are calling for regulation of e-cigarettes and other electronic nicotine delivery systems (ENDS).

The American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) issued the joint statement calling for greater oversight of the products and more research about their effects on the long-term health of users.

“As a physician-scientist who treats patients with cancer, I am concerned about the delayed time course that’s needed to assess the adverse impacts of ENDS use,” said Carlos L. Arteaga, M.D., professor of Medicine and Cancer Biology and director of the Center for Cancer Targeted Therapies and the Breast Cancer Program at Vanderbilt-Ingram Cancer Center.

Carlos Arteaga, M.D.

Carlos Arteaga, M.D.

Arteaga is serving as president of the AACR this year.

“Therefore, although we call for additional research to determine with certainty the potential negative public health consequences of these products, particularly in youth, we cannot afford to wait to take prudent steps to stop those under 18 from using e-cigarettes.

“This is especially important since e-cigarette use is growing fast among this age group, as reported in the most recent National Youth Tobacco Survey,” Arteaga said.

According to the cancer groups, tobacco use is responsible for 30 percent of all cancer deaths and is associated with increased risk for at least 18 types of cancer.

E-cigarettes and other ENDS, which are capable of delivering a nicotine solution in aerosolized form, have been promoted as potential tobacco cessation products and safer alternatives to cigarettes.

However, e-cigarettes are currently unregulated and it is unclear if the chemicals used in the products are safe.

There is also no current scientific consensus on the effectiveness of ENDS as a smoking cessation tool.

ASCO and AACR are calling for FDA regulation of e-cigarettes, vaporizers and other ENDS, safety labels on packaging warning about nicotine addiction and prohibition of any advertising or marketing to youths. They also recommend child-proof caps for all liquid nicotine containers.

As a smoke-free campus, Vanderbilt University amended the smoking policy in 2014 and added e-cigarettes and vaporizers to the list of items that are banned inside facilities and which may be used only in outdoor designated areas.

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Enzyme affects tumor metastasis http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/enzyme-affects-tumor-metastasis/ http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/enzyme-affects-tumor-metastasis/#comments Thu, 08 Jan 2015 18:11:24 +0000 http://viccweb.gtm.mc.vanderbilt.edu/news/?p=7228 Breast cancer remains the most common type of cancer in females, with survival rates decreasing sharply for those with distant metastases. MMP2, a type of enzyme that degrades the extracellular matrix, has previously been implicated in the development of distant tumor metastases, but without a clearly defined role.

In the Journal of Pathology, Barbara Fingleton, Ph.D., and colleagues establish a role for MMP2 in the development of lung metastases from primary breast cancer. Using mice without the Mmp2 gene, the team found that metastatic tumors in the lung proliferate less in the absence of fibroblast MMP2.

The researchers showed that one function of MMP2 in lung metastasis is the regulation of fibroblast activation and collagen expression. They suggest that MMP2 generates active TGFbeta-1, and showed that supplying active TGFbeta-1 restores collagen expression in Mmp2-deficient fibroblasts.

The results indicate that selective MMP2 inhibitors may serve as potential pharmacologic agents for breast cancer treatment.

This research was supported by grants from the National Institutes of Health (CA084360, CA163072, GM062459, CA119925).

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Combo therapy may help fight melanoma http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/combo-therapy-may-help-fight-melanoma/ http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/combo-therapy-may-help-fight-melanoma/#comments Thu, 08 Jan 2015 18:10:55 +0000 http://viccweb.gtm.mc.vanderbilt.edu/news/?p=7215 Ann Richmond and Anna Vilgelm

Ann Richmond, Ph.D., left, Anna Vilgelm, M.D., Ph.D., and colleagues are studying combined therapies to treat many different sub-types of melanoma. (photo by John Russell)

Melanoma is the most lethal form of skin cancer, with high mortality rates. While new drugs have been approved to treat the disease, patients nearly always develop resistance to the therapies and the cancer advances.

This is especially relevant for patients with a mutation in the BRAF gene who generally have a robust, but temporary, response to BRAF inhibitor therapies. Researchers have been trying to identify therapies that can be combined to improve patient response.

A new study, led by first author Anna Vilgelm, M.D., Ph.D., a Vanderbilt postdoctoral fellow, and corresponding author Ann Richmond, Ph.D., Ingram Professor of Cancer Research, and Senior Research Career Scientist, Tennessee Valley Healthcare System Department of Veterans Affairs, indicates that two therapies already in clinical development as single agents may work in combination to treat many subtypes of melanoma. The study was published online recently in Cancer Research.

The investigators’ ultimate target was to block cell proliferation and induce cell death by targeting two proteins — MDM2, a protein which facilitates degradation of the tumor suppressor p53, and Aurora kinase A (AURKA), a protein that regulates cell division and growth. TP53, the gene that encodes p53, is seldom mutated in melanoma, which makes the activation of the p53 cellular pathway through MDM2 targeting feasible. AURKA is often highly expressed in melanoma tumor cells.

Early tests of an AURKA inhibitor found that the drug was stopping tumor cells from multiplying, making them big and sluggish (senescent), but the cells still weren’t dying. So Vilgelm decided to combine this therapy with a second drug (MDM2 antagonist) which kills tumor cells by restoring p53 function.

“The tumor cells made senescent by treatment with the AURKA inhibitor were not dying and might later start growing again, so we wanted to treat them with this agent that induces p53 and death of the senescent cells.

“The senescent cells also release cytokines that bring in immune cells to help remove and kill the senescent tumor cells,” said Vilgelm.

The investigators tested the combination therapy in several melanoma mouse models, including one that grafts human melanoma tumor samples directly into the mouse.

Richmond said combining the MDM2 antagonist drug with the AURKA inhibitor worked as a form of indirect immunotherapy and blocked the growth of the tumors.

“The combined effect of inducing senescence and then blocking MDM2 led to massive production of chemokines that recruited immune cells that helped participate in the inhibition of tumor growth,” Richmond said.

“The majority of the tumors that we tested were able to respond to the therapy, regardless of BRAF gene mutation, suggesting that a large cohort of patients could be treated with these drugs, including patients whose tumors had developed resistance to BRAF inhibitor therapy,” said Vilgelm.

The authors say the results provide a sound rationale for further studies of the combination therapy.

Other investigators involved in the study include Jeff Pawlikowski, Ph.D., Yan Liu, Ph.D., OrianaHawkins, Ph.D., Tyler Davis, Ph.D., Kevin Weller M.S., Linda Horton, M.S., Colt McClain, M.D., Gregory Ayers, M.S., Jeffrey Sosman, M.D., Mark Kelley, M.D., and Jeffrey Johnston, Ph.D., Vanderbilt; Jessica Smith, B.S., Meharry Medical College; David Turner, Ph.D., David Essaka, Ph.D., and Clinton Stewart, Ph.D., St. Jude Children’s Research Hospital, Memphis, Tennessee; and Jeffrey Ecsedy, Ph.D., Takeda Pharmaceuticals, Osaka, Japan. The Tennessee Valley Healthcare System, Department of Veterans Affairs, also participated in the study.

The study was supported by funding from the Department of Veterans Affairs (5101BX000196-04), the National Institutes of Health (CA116021, CA116021-S1, CA90625, 5T32CA119925-03, 1F32CA171895-01, GM084333 and CA68485), and a Senior Research Career Scientist Award to Richmond.

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Potential Prostate Cancer Blood Test http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/potential-prostate-cancer-blood-test/ http://viccweb.gtm.mc.vanderbilt.edu/news/2015/01/potential-prostate-cancer-blood-test/#comments Tue, 06 Jan 2015 22:47:22 +0000 http://viccweb.gtm.mc.vanderbilt.edu/news/?p=7207 prostate cancer cells

Prostate cancer cells. (Wellcome Images)

Vanderbilt University researcher William Mitchell, M.D., Ph.D., and colleagues in Germany and Canada have demonstrated a method for detecting “cell-free” tumor DNA in the bloodstream.

Mitchell believes the technique will be transformative in providing improved cancer diagnostics that can both predict treatment outcomes and monitor patient responses to therapy.

In a large retrospective study of blood samples, the researchers showed that the method, called a “liquid biopsy,” could accurately distinguish prostate cancer from normal controls without prior knowledge of the genetic “signature” of the tumors, and with over three times the sensitivity of current prostate-specific antigen (PSA) screening.

The study appears in the January issue of Clinical Chemistry (volume 61, page 239), which is dedicated to “Molecular Diagnostics: A Revolution in Progress.”

Willliam Mitchell, MD, PhD

Willliam Mitchell, M.D., Ph.D.

“Based on the reported data and work in progress, I believe the ‘liquid biopsy’ will revolutionize cancer diagnostics, not only before a patient begins therapy but also following patient responses to therapy,” said Mitchell, the paper’s corresponding author and professor of Pathology, Microbiology and Immunology.

The study collected serum from more than 200 patients with prostate cancer and more than 200 controls. The samples included PSA levels and prostate tissue biopsy grading, called the Gleason score.

The researchers reported that the technique distinguished prostate cancer from normal controls with 84-percent accuracy, and cancer from benign hyperplasia and prostatitis with an accuracy of 91 percent.

Because the method quantifies the inherent chromosomal instability of cancer and can be followed as a function of time without having to do an invasive tissue biopsy, it is called a “liquid biopsy.”

It’s been known for many years that dying cells, including tumor cells, shed DNA into the bloodstream.

But only recently has technology, notably “next-generation sequencing,” made it possible to reliably distinguish and quantify cancer-specific DNA from normal controls by the identification and chromosomal location of billions of specific DNA fragments present in blood as cell-free DNA.

The prostate cancer study identified 20 “hotspots” of greatest chromosomal instability as additions or deletions in less than 0.5 percent of the total DNA present in human chromosomes.

While researchers around the world are working on their own “liquid biopsies,” Mitchell said the group’s technique takes a broader approach. It examines the entire genome rather than known specific gene point mutations.

Robust mutation panels vastly improve monitoring since cancer cells are constantly deleting chromosomal DNA and liquid biopsies with only one or two mutations will allow cancer cell escape variants to go undetected, he said.

Since the entire genome was surveyed, the researchers were able to identify a non-coding region of the genome as a “hotspot,” which may be generating previously unrecognized chromosomal control elements in prostate cancer.

The other 19 “hotspots” were rich in genes involved in replication and cell control processes that are highly relevant to cancer.

“Since cell-free DNA has a relatively short half-life in the circulation, sequencing of cell-free DNA soon after therapy may be used to detect minimal residual disease in solid tumors,” Mitchell said.

The researchers reported similar results in a study of breast cancer at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. Mitchell further predicted that liquid biopsies will quantify immediate tumor responses to therapy.

The paper’s senior author, Steven Narod, M.D., and colleagues who included Robert Nam, M.D., and William Zhang, M.D. at the University of Toronto provided the clinical samples and de-identified patient data for the study.

Chronix Biomedical in Germany was responsible for next generation sequencing. Co-authors from Chronix included first author and chief technology officer Ekkehard Schütz, M.D., Ph.D., senior scientist Julia Beck, Ph.D., and Chronix Biomedical co-founder and CEO/CSO Howard Urnovitz, Ph.D.

Mitchell is an independent member of the Chronix board of directors.

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Visit unites stem cell transplant patient, donor http://viccweb.gtm.mc.vanderbilt.edu/news/2014/12/visit-unites-stem-cell-transplant-patient-donor/ http://viccweb.gtm.mc.vanderbilt.edu/news/2014/12/visit-unites-stem-cell-transplant-patient-donor/#comments Mon, 15 Dec 2014 16:29:27 +0000 http://viccweb.gtm.mc.vanderbilt.edu/news/?p=7198 stem cell patient, donor meeting

Darlena Clark hugs Jon Strong, who donated the stem cells that were transplanted into Clark to treat her blood disorder. (photo by Anne Rayner)

When Darlena Clark of Hendersonville, Tennessee, saw Jon Strong for the first time at Nashville International Airport she, “just grabbed him and hugged him and just held on.”

Strong, a U.S. Navy hospital corpsman based at Camp Pendleton, California, was the stranger from across the country who had volunteered to be a bone marrow donor, and it was his stem cells that saved Clark’s life.

Clark, 67, waited a year before learning the name of her donor — the time required under the rules of the stem cell donation program. But as soon as the deadline expired, and Strong agreed to be identified, the pair started talking, and soon Clark and her husband, Dennis, decided to fly Strong, his wife, Stephanie, and their two children to Nashville to celebrate Thanksgiving week together.

“It’s hard to imagine how grateful you could feel to someone you’ve never met,” said Clark. “You have someone’s blood and they’ve saved your life. How much more could anyone give? So, it’s an amazing experience to be in that position and to be able to meet the person.”

Clark had been diagnosed with myelodysplastic syndrome (MDS), the same blood disorder that ABC News anchor Robin Roberts has been battling. In MDS some of the cells in the bone marrow become damaged and the disease can progress to a form of cancer called acute myeloid leukemia (AML).

Years before Clark became a patient in the Stem Cell Transplant Clinic at Vanderbilt-Ingram Cancer Center, Strong, now 37, had helped lead a bone marrow donation registration drive at his naval base.

Strong was flown to Georgetown University Medical Center in Washington, D.C., and for five days he stayed at a local hotel, making daily visits to the Georgetown clinic, where he received shots to stimulate his stem cells.In June 2013, he received a call that his stem cells appeared to be a match for a patient in need.
“When asked, there was no question, at least in my mind, whether I was going to donate or not,” Strong said. “It was just ‘how soon do you need it done?’ That’s how I like to think the hospital corpsman field is anyway. As medical people we would always strive to do our best.”

“After the Navy, those shots were no big deal,” said Strong, with a grin. He took Tylenol and hung out in the hotel hot tub to manage the joint pain from the shots.

stem cell donor, patient

During a visit to the Vanderbilt-Ingram Cancer Center Stem Cell Transplant Clinic, Madan Jagasia, MBBS, center, talks with stem cell recipient Darlena Clark, second from left, her husband, Dennis, left, stem cell donor Jon Strong, second from right, and his wife, Stephanie. (photo by Anne Rayner)

After his stem cells were harvested, they were sent to VICC and on July 11, 2013, Clark received the infusion of stem cells. It was a significant date for patient and donor — transplant day for Clark and the 15th wedding anniversary for Jon and Stephanie Strong.

A year and a half later, Clark is doing well, and she wanted Strong and his family to tour the VICC Stem Cell Transplant Clinic and meet some of the medical professionals who made the transplant possible, including Madan Jagasia, MBBS, section chief of Hematology and Stem Cell Transplant and director of the Outpatient Stem Cell Transplant Unit.

“This is what we live for. This is the most rewarding experience for us because in what we do there are lots of wins and losses. So this is really rewarding for us to see a patient doing so well, to see a human save a human,” said Jagasia.

He pointed out that 70 percent of the stem cell transplants performed at Vanderbilt are done on an outpatient basis, and the program is growing every year.

More information on the donor registry is available at the National Marrow Donor Program, or visit www.BeTheMatch.org.

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Tindle to lead Tobacco Research and Treatment http://viccweb.gtm.mc.vanderbilt.edu/news/2014/11/tindle-to-lead-tobacco-research-and-treatment/ http://viccweb.gtm.mc.vanderbilt.edu/news/2014/11/tindle-to-lead-tobacco-research-and-treatment/#comments Fri, 21 Nov 2014 15:50:25 +0000 http://viccweb.gtm.mc.vanderbilt.edu/news/?p=7167 November is well-known as Lung Cancer Awareness Month. It is also the month that highlights awareness of less publicized forms of cancer including pancreatic cancer and stomach cancer.

All three of these diseases share a common risk factor — cigarette smoking.

“Smoking is the leading cause of preventable disease and death and it is claiming 480,000 people a year,” said Tindle, associate professor of Medicine. “The public may not realize that smokers die an average of 13 years earlier than non-smokers.”

Fifty years after the first U.S. Surgeon General’s historic report that linked tobacco products to lung cancer, Vanderbilt has recruited Hilary Tindle, M.D., MPH, as director of Tobacco Research and Treatment. Tindle is a well-known tobacco researcher who contributed to the 2014 50th anniversary Surgeon General’s report.

Hilary Tindle, M.D., MPH

Hilary Tindle, M.D., MPH

In addition to cancer, smoking also leads to cardiac diseases by hastening plaque buildup in blood vessels, or atherosclerosis.

Tobacco use is costing the U.S. $300 billion annually in health care costs and lost productivity. These societal costs are not geographically uniform. States like Tennessee and Kentucky still have some of the highest percentages of smokers, which may contribute to the region’s designation as the Stroke Belt and the Cancer Belt.

Tindle said eight in 10 smokers see a doctor annually and seven in 10 want to quit smoking. Over half of smokers actually try to quit every year. But most don’t use quit aids like nicotine replacement products, prescription medications or counseling programs and, as a result, 95 percent of unaided quit attempts fail.

“We need to track and treat smokers in order to have an impact,” explained Tindle. “We can leverage the Electronic Health Record to track and treat tobacco users. We can proactively treat people over time and if they are not motivated to quit smoking, we can help get them motivated.”

Over the next year, VUMC will create and implement the new patient-centered tobacco control program which will include education for providers and staff.

The program will include assistance to patients while they are hospitalized.

“We can manage their nicotine withdrawal symptoms while they are in the hospital, regardless of the reason that brought them there,” said Tindle. “We will visit the patient at the bedside, talk to them about their tobacco use and discuss the relationship of smoking to their illness.”

At the time of discharge, VUMC will arrange for medication and counseling and provide an e-Referral to the Tennessee Tobacco Quit Line, a free telephone support program available at (800) QUIT-NOW (800-784-8669.)

Tindle said there are already compelling signs that Americans are willing to make lifestyle changes regarding tobacco use.

“There are now more former smokers than smokers. We can do it. We can’t afford to be pessimistic about changing smoking habits.”

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