Rules of thumb for drug discovery

*The* Chris Lipinski is talking at Winship Nov 5

Explainer: the locus coeruleus

Critical early site of neurodegeneration

Scaling up to a speck of dust

DNA bricks almost large enough to see with the naked eye

cancer

Cancer’s shield: PD-1

Gina Kolata has a section front story in Tuesday’s New York Times exploring the potential of a relatively new class of anticancer drugs. The drugs break through “shields” built by cancers to ward off the threat posed by the patient’s immune system. Many are based on blocking PD-1, an immune regulatory molecule whose importance in chronic infections was first defined by Emory’s Rafi Ahmed.

Of course, not every cancer research development described as transformative in the New York Times lives up to the hype. But the clinical trial results, reported in the New England Journal of Medicine, are solid enough that the researchers Kolata talks with think they are seeing “a moment in medical history when everything changed.” [Winship Cancer Institute's John Kauh was a co-author on one of the 2012 NEJM papers.]

Let’s take a moment to examine some of the roots of this story. Rafi Ahmed didn’t set out to study cancer. For the last two decades, he and his colleagues have been studying T cells, parts of the immune system that are critical for responding to infections. Read more

Posted on by Quinn Eastman in Cancer, Immunology 2 Comments

The challenges of graduate school

Biochemist Paul Doetsch’s recent appearance in a Science magazine feature on laboratory leadership led to a conversation with him about the challenges of graduate school.

He emphasized that scientific research is a team sport, and brilliance on the part of the lab head may not yield fruit without a productive relationship with the people in the lab. Doetsch suggested talking with Lydia Morris, a graduate student in the Genetics and Molecular Biology graduate program. Morris has been working in Doetsch’s lab for several years and is about to complete her degree. She has been examining the in vivo distribution of DNA repair proteins.

In this video, Morris and Doetsch talk about the differences between turn-the-crank and blue-sky projects, and the importance of backup projects, communications, high expectations and perseverance.

Posted on by Quinn Eastman in Cancer Leave a comment

The body’s anticancer defenses come in a variety of sizes

Sometimes you have to look at the whole picture, big and small.

Sarah Cork, PhD

That was the lesson that emerged from Winship Cancer Institute researcher Erwin Van Meir’s laboratory, highlighted in a recent paper in Oncogene. Van Meir’s team has been studying vasculostatin, a secreted protein that inhibits blood vessel growth by tumors (hence the name). Vasculostatin was discovered by Balveen Kaur, now at Ohio State, while she was in Van Meir’s lab.

Van Meir and his colleagues originally began studying vasculostatin because it is a product of a gene that brain tumors somehow silence or get rid of, and studying the obstacles our bodies throws in cancer’s way may be a good way to learn how to fight it via modern medicine. Eventually, it could form the basis for a treatment to prevent a tumor from attracting new blood vessels.

Vasculostatin is somewhat unique because it is a secreted fragment of a membrane-bound protein, called BAI1. BAI1 has an apparently separate function as an “engulfment receptor,” allowing the recognition and internalization of dying cells.

Most of the secreted vasculostatin is around 40 kilodaltons in size, not 120 as previously thought.

Graduate student Sarah Cork discovered that most of the vasculostatin protein being produced by cells is actually much smaller than what had been originally discovered. She and Van Meir were surprised to find that the smaller, cleaved form of the protein still has potent anti-angiogenic activity.

The researchers were using a technique where a mixture of proteins is separated within a gel by electric current, transferred to a polymer sheet, and probed with antibodies. The large proteins appear at the top and the small proteins at the bottom.

“Previously, we had been running the gels for a long time to detect large protein fragments, so missed out on what was happening with small fragments which run off the gel,” Van Meir says. “We were only looking at the top of the
gel, when the smaller form of vasculostatin was actually much more
abundant as you can see on the picture of a gel run for a shorter time.”

More broadly, Van Meir says that the finding adds to understanding about BAI1′s dual function in the brain and how vasculostatin (big or small) might be used in anticancer therapy.

Posted on by Quinn Eastman in Cancer Leave a comment

Dye me anticancer yellow

Over the last few years, pathologist Keqiang Ye and his colleagues have displayed an uncanny talent for finding potentially useful medicinal compounds. Recently another example of this talent appeared in Journal of Biological Chemistry.

Keqiang Ye, PhD

Postdoctoral fellow Qi Qi is first author on the paper. Collaborators include Jeffrey Olson, Liya Wang, Hui Mao, Haian Fu, Suresh Ramalingam and Shi-Yong Sun at Emory and Paul Mischel at UCLA.

Qi and Ye were looking for compounds that could inhibit the growth of an especially aggressive form of brain cancer, glioblastoma with deletion in the tumor suppressor gene PTEN. Tumors with this deletion do not respond to currently available targeted therapies.

The researchers found that acridine yellow G, a fluorescent dye used to stain microscope slides, can inhibit the growth of this tumor:

Oral administration of this compound evidently decreases the tumor volumes in both subcutaneous and intracranial models and elongates the life span of brain tumor inoculated nude mice. It also displays potent antitumor effect against human lung cancers. Moreover, it significantly decreases cell proliferation and enhances apoptosis in tumors…

Optimization of this compound by improving its potency through medicinal chemistry modification might warrant a novel anticancer drug for malignant human cancers.

Ye’s team observed that acridine yellow G appears not to be toxic in rodents. However, the acridine family of compounds tends to intercalate (insert itself) into DNA and can promote DNA damage, so more toxicology studies are needed. Other acridine family compounds such as quinacrine have been used to treat bacterial infections and as antiinflammatory agents, they note.

A paramecium stained with acridine orange, which shows anticancer activity for tumors containing PTEN mutations

Posted on by Quinn Eastman in Cancer Leave a comment

A twist on epigenetic therapy vs cancer

Epigenetic therapies against cancer have attracted considerable attention in recent years. But many of the drugs currently being studied as epigenetic anticancer therapies may have indiscriminate effects. A recent paper in Cancer Research from brain cancer researcher Erwin Van Meir’s laboratory highlights a different type of target within cancer cells that may be more selective. Postdoctoral fellow Dan Zhu is the first author of the paper.

Erwin Van Meir, PhD

The basic idea for epigenetic therapy is to focus on how cancer cells’ DNA is wrapped instead of the mutations in the DNA. Cancer cells often have aberrant patterns of methylation or chromatin modifications. Methylation is a punctuation-like modification of DNA that usually shuts genes off, and chromatin is the term describing DNA when it is clothed by proteins such as histones, a form of packaging that determines whether a gene is on or off.

In contrast to mutations that are hard-wired in the DNA, changes in cancer cells’ methylation or chromatin may be reversible with certain drug treatments. But a puzzle remains: if a drug wipes away methylation indiscriminately, that might turn on an oncogene just as much as it might restore a tumor suppressor gene.

The ability of an inhibitor of methylation to treat cancer may depend on cell type and context, explains chromatin/methylation expert and co-author Paula Vertino. She points out that one well-known methylation inhibitor, azacytidine (Vidaza), is a standard treatment for myelodysplastic syndrome, but the strategy of blanket-inhibition of methylation can’t be expected to work for all cancers. A similar challenge exists for agents that target histone acetylation in a global fashion.

Epigenetic therapies seek to modify how DNA is packaged in the cell.

Van Meir’s laboratory has been studying a tumor suppressor protein called BAI1 (brain angiogenesis inhibitor 1), which prevents tumor and blood vessel growth. BAI1 is produced by brain cells naturally, but is often silenced epigenetically in glioblastoma cells. His team found that azacytidine de-represses the BAI1 gene.

Methylation won’t turn a gene off without the help of a set of proteins that bind preferentially to methylated DNA. These proteins are what recognize the methylation state of a given gene and recruit repressive chromatin. Zhu and colleagues in Van Meir’s group found that one particular methyl-binding protein, MBD2, is overproduced in glioblastoma and is enriched on the BAI1 gene.

“Taken together, our results suggest that MBD2 overexpression during gliomagenesis may drive tumor growth by suppressing the anti-angiogenic activity of a key tumor suppressor. These findings have therapeutic implications since inhibiting MBD2 could offer a strategy to reactivate BAI1 and suppress glioma pathobiology,” the authors write.

By itself, MBD2 appears to be dispensable, since mice seem to be able to develop and survive without it. Not having it even seems to push back against tumor formation in the intestine, for example. Targeting MBD2 may represent an alternative way to steer away from cancer cells’ altered state.

Van Meir cautions: “We need to have a better understanding of all the genes that are turned on or off by silencing MBD2 in a given cancer before we can envision to use this approach for therapy.”

Vertino and Steven Hunter, both at Emory, are co-authors on the paper. The work was supported by grants from the NIH and the Southeastern Brain Tumor Foundation and the Emory University Research Council.

Posted on by Quinn Eastman in Cancer 1 Comment

Esophageal lesions meet their match

Field Willingham, MD, MPH

Once esophageal tumors establish themselves, a patient’s prognosis is grim and morbidity vast. But when lesions are caught early and removed, especially in the premalignant stage, the odds of survival markedly improve.

When a case calls for it, Emory gastroenterologist Field F. Willingham, MD, MPH, uses a hybrid approach to ousting superficial esophageal lesions. Superficial esophageal lesions are commonly caused by acid reflux disease, or GERD. GERD occurs when stomach acid flows into the esophagus and can lead to a condition known as Barrett’s esophagus, where the cells in the lower esophagus become damaged. This in turn can lead to dysplasia, or pre-cancerous cells.

But for superficial cancers, it is now possible to remove a portion of the lining layer of the GI tract, containing the tumor, with an endoscope.  This can help carefully selected patients avoid a major surgery. The technique, known as an EMR, allows the removal of superficial esophageal tumors and pre-cancer with an endoscope, a slender tube-like instrument.

Detecting and removing esophageal tumors early is essential for a favorable outcome. Once tumors firmly establish themselves in esophageal tissue, the prognosis is grim and morbidity vast. In the past, a diagnosis of an esophageal tumor meant the removal of the esophagus and often the stomach. But now EMR can be used in tandem with radio frequency ablation.

In surgical situations in which radio frequency ablation is not feasible, Willingham and his colleagues are beginning to use an alternate technique, known as cryotherpay, in tandem with EMR. Cryotherapy involves freezing superficial cells to rid the esophagus of suspect cells.

“So, if the end of the esophagus is twisted, or if we can’t touch it with this balloon device, then we can use cryotherapy,” says Willingham. “We’re trying to kill the lining layer with the tumor cells without killing the deeper layer.”

Willingham and his colleagues are seeing evidence that using these very three very different, technologies in tandem or alone will provide patients with a better way to rid them of esophageal lesions while preserving their quality of life.

Posted on by Robin Tricoles in Uncategorized Leave a comment

Genetic alteration opens door to targeted treatment of rare tumor

A cross section of an epithelioid hemangioendothelioma

Emory pathologist Sharon Weiss, MD, was the first to describe an extraordinarily rare tumor known as an epithelioid hemangioendothelioma (EHE). Thirty years later, researchers have identified a genetic alteration linked to this odd vascular tumor.

It’s hoped this newfound information will lead to a better understanding of the mechanisms underlying the development of this tumor and hence development of a targeted treatment. None yet is available. However, these findings already have been used to develop a new diagnostic test for this blood vessel disease.

The research, published in a recent issue of Science Translational Medicine, was done in collaboration with Cleveland Clinic’s Taussig Cancer Institute and led by Brian Rubin, MD, PhD, of Cleveland Clinic’s Pathology and Laboratory Medicine Institute and Lerner Research Institute.

The genetic alteration formerly in question involves a translocation between chromosomes 1 and 3, where chromosomes 1 and 3 exchange DNA fragments that are transposed onto opposite chromosomes. The result: the swapped DNA encodes a unique, fused gene that contains components from each chromosome. Because genes are translated into proteins, the result of this unique gene is a correspondingly unique protein, one thought to cause cancer.

Epithelioid hemangioendotheliomas comprise less than one percent of all cancers. Roughly 100 new cases are diagnosed in the United State each year. EHE are eccentric in their epidemiology, structure and aggressiveness. Slow to metastasize, they tend to occur in both young men and women when soft tissue is involved but occur mostly in women when the liver and lungs are affected.

However, it’s their peculiar structure that has so far made targeted treatment problematic, especially in the liver and lungs. “Instead of being one mass as you might expect with liver cancer, the patient with EHE often presents with little nodules throughout the liver,” says Weiss.

“The reason this occurs is that the growth starts in the liver’s portal vein, grows along its length, and then tracks out through the vessels. The growths blister out from the vessel creating these little nodules. Epithelioid hemangioendothelioma don’t possess the classic features of vascular tumors. In fact, EHE may have so many sites of involvement that the cancer can’t be cured, short of transplantation.”

Using EHE tissue samples gleaned from Weiss’s vast library, Rubin developed a genetic probe to detect the distinct chromosomal translocations in the tumor. The probe now serves as a powerful diagnostic tool of EHE and opens the door to understanding these tumors’ mechanisms.

“Once you understand the mechanism behind it, you can start trying to target those pathways in a therapeutic way,” says Weiss.

Posted on by Robin Tricoles in Cancer 1 Comment

Magnanimous magnolias keep on giving

Honokiol, the versatile compound found by Emory dermatologist Jack Arbiser in the cones of magnolia trees, makes a surprise appearance in a recent paper in Nature Medicine.

Jack Arbiser, MD, PhD, and colleagues originally isolated honokiol from magnolia cones. It can also be found in herbal teas.

The paper, from Sabrina Diano, Tamas Horvath and colleagues at Yale, probes the role of reactive oxygen species (ROS) in the hypothalamus, a part of the brain that regulates appetite. In the paper, Horvath’s laboratory uses honokiol as a super-antioxidant, mopping up ROS that suppress appetite. Arbiser initiated the collaboration with Horvath after finding, while working with Emory free radical expert Sergei Dikalov, how effective honokiol is at neutralizing ROS.

The paper is intriguing partly because it’s an example of a situation where ROS, often thought to be harmful because of their links to aging and several diseases, are actually beneficial. In this case, they provide a signal to stop eating. A recent paper from Andrew Neish’s lab at Emory provides another example, where probiotic bacteria stimulate production of ROS, which promote healing of the intestine.

Arbiser notes that since honokiol can increase appetite, the compound may be helpful in situations where doctors want patients to eat more.

“This might be particularly valuable in patients who are nutritionally deficient due to chemotherapy and provides a rationale for adding honokiol to chemotherapy regimens,” he writes.

Satiety producing neurons in the hypothalamus

A note of caution: in the Nature Medicine paper, honokiol is infused directly into the brain.

Honokiol has been shown to counteract inflammation and slow the growth of blood vessels (important in fighting cancer). Collaborating with Arbiser, Emory endocrinologist Neale Weitzmann has recently found that honokiol stimulates osteoblasts, the cells that build bone, suggesting that it could reduce bone loss in osteoporosis.

Posted on by Quinn Eastman in Cancer Leave a comment

Brain tumor patient gives back and moves forward

Jennifer Giliberto

Don’t sweat the small stuff.

That’s the motto 36-year-old Jennifer Giliberto now lives by after recently welcoming a third child into the world. Late night feedings, diaper changes, mounds of dirty laundry and caring for two older boys (ages six and eight) would certainly be a challenge for most moms. But this mom is different.

Four years ago, Giliberto was diagnosed with a brain tumor – a slow growing Grade II astrocytoma located in her posterior right temporal lobe. The shocking diagnosis left Giliberto and her family with many choices and decisions to make.

Giliberto’s inspiring story was profiled on CNN on Aug. 16, 2011 in a special “Human Factor” segment, which takes a look at people accomplishing something significant after overcoming the odds.

The Long Road Ahead

After her second child was born in 2005, Giliberto began noticing a pattern of problems with her fine motor skills. Neurological testing revealed little, but an MRI (magnetic resonance imaging) revealed a lesion and possible tumor in the brain. Follow-up MRIs over the next year showed no new growth, but in June 2007, a definite brain tumor was detected by MRI.

While taking the watch and wait approach to determine if the tumor would grow, she became involved with the Southeastern Brain Tumor Foundation (SBTF) as a volunteer. She focused her efforts on raising money to support critical brain and spinal tumor research. She also met Emory neurosurgeon Costas Hadjipanayis, MD, PhD.

Hadjipanayis, an assistant professor in Emory’s Department of Neurosurgery, would soon become Giliberto’s physician. He confirmed her diagnosis and recommended surgical removal of the tumor.

Costas Hadjipanayis, MD, PhD and patient Jennifer Giliberto

On August 18, 2008, at Emory University Hospital Midtown, Hadjipanayis removed Giliberto’s brain tumor. “Jennifer underwent a craniotomy and had a gross total resection of the tumor, with no complications,” explains Hadjipanayis, who is chief of neurosurgery at the hospital. “She spent one night in the neurosurgical ICU and her recovery afterwards went well.”

Then he encouraged her to embrace life and live it to the fullest. Giliberto has taken her doctor’s orders to heart, and lives life with a new purpose than before.

Giving Back

To support and encourage other brain tumor patients, Giliberto serves as a patient and family advisor at Emory University Hospital Midtown. She visits with hospitalized patients and their families who are in similar situations as the young mother of three.

“This has been a very fulfilling experience and an outlet to give back,” says Giliberto. “Being a patient is lonely, even when you know you have support. Working to assist other patients and families and improve a system goes a long way to ease that lonely journey of the patient experience.”

Patient and family advisors also work to improve hospital processes and procedures from a patient perspective.

She also serves as vice president of the Southeastern Brain Tumor Foundation, continuing the mission to raise funds for research. The SBTF consistently funds innovative brain tumor research at Emory’s Winship Cancer Institute.

And she is a devoted wife and mother.

Moving Forward

Last year, when Giliberto and her husband decided they would like to expand their family of four, she consulted with Hadjipanayis. He, once again, encouraged her to live life and move forward. They did, and their youngest child was born in July 2011.

While Giliberto has remained stable since her surgery in 2008, she continues to have MRI’s every six to nine months to check for any tumor recurrence. Astrocytomas, even once removed, can recur and can also become cancerous.

But for now, it’s on with life as she knows it – stable, moving ahead and enjoying every day with a new sense of hope.

And as for the small stuff – Giliberto’s learned there’s just no reason to sweat it at all.

Posted on by Janet Christenbury in Uncategorized 2 Comments

Emory researchers receive grants to further work in pediatric brain tumor research

Dr. Castellino explains his research on medulloblastomas to participants attending the SBTF’s Grant Award Ceremony.

Two Emory researchers are being recognized by the Southeastern Brain Tumor Foundation (SBTF) for their work in pediatric brain tumor research.

Tracey-Ann Read, PhD, assistant professor in the Department of Neurosurgery, Emory University School of Medicine and director of the Pediatric Neuro-Oncology Laboratory at Emory was awarded a $75,000 grant for her work. She is studying the cell of origin that is responsible for the highly malignant pediatric brain tumor known as an Atypical Teratoid Rhabdoid Tumor (AT/RT). She is also developing a mouse model to study this very lethal brain cancer that occurs in early childhood.

Robert Craig Castellino, MD, assistant professor of pediatrics at Emory and pediatric hematologist/oncologist at Children’s Healthcare of Atlanta at Egleston received $50,000 to support his research efforts. He is studying how the childhood brain cancer, known as medulloblastoma, can metastasize from the brain to other sites in the body, specifically the spine. Medulloblastoma is the most common pediatric malignant brain tumor.

SBTF board members and researchers who were awarded grants pose following the April ceremony.

Read and Castellino received the awards at the SBTF’s Grant Awards Ceremony in April at Emory University Hospital Midtown. Two other researchers from Duke University were also presented with grant money for their contributions in brain tumor research in adults.

Emory neurosurgeon Costas Hadjipanayis, MD, PhD, is the president of the Southeastern Brain Tumor Foundation. He says research, from young investigators such as these, is crucial in the race to find a cure for brain tumors. As federal research funding becomes even more difficult to obtain with cuts in funding, private foundation grants, such as from the SBTF, can permit researchers to start important research projects that can provide preliminary data for bigger grant proposals.

The SBTF awards $200,000-300,000 each year to major medical centers throughout the Southeast in support of cutting-edge brain and spinal tumor research.

 

Posted on by Janet Christenbury in Cancer Leave a comment
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