Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more

Cancer

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.

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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

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Making “death receptor” anticancer drugs live up to their name

Cancer cells have an array of built-in self-destruct buttons called death receptors. A drug that targets death receptors sounds like a promising concept, and death receptor-targeting drugs have been under development by several biotech companies. Unfortunately, so far results in clinical trials have been disappointing, because cancer cells appear to develop resistance pathways.

Death receptor-targeting drugs under development include: drozitumab, mapatumumab, lexatumumab, AMG655, dulanermin.

Winship Cancer Institute researcher Shi-Yong Sun, PhD and colleagues have a paper in Journal of Biological Chemistry that may help pick the tumors that are most likely to be vulnerable to death receptor-targeting drugs. This could help clinical researchers identify potential successes ahead of time and maximize chances of a good response for patients.

Postdoctoral fellow Youtake Oh is the first author. Winship deputy director Fadlo Khuri, MD and Taofeek Owonikoko, MD, PhD, co-chair of Winship’s clinical and translational research committee, are co-authors. Khuri’s 2010 presentation on death receptor drugs and lung cancer is available here (PDF).

Sun’s team shows that mutations in the cancer-driving genes Ras and B-Raf both induce cancer cells to make more of one of the death receptors (death receptor 5). In addition, they show that cancer cells with mutations in Ras or B-Raf tend to be more vulnerable to drugs that target death receptor 5.

Shi-Yong Sun, PhD

These mutations are known to be more common in some types of cancer. For example, roughly half of melanomas have mutations in B-Raf. Vemurafenib, a drug that inhibits mutated B-Raf, was approved in August 2011 for the treatment of melanoma. K-ras mutations are similarly abundant in lung cancer.

The selection and targeting of tumors via their specific mutations is a growing trend. Sun says lung, colon and pancreatic cancer are all cancer types where Ras and Raf mutations are common enough to become useful biomarkers. In lung cancer, Sun’s team’s results could be especially welcome news because, as a 2009 review concluded:

Recent studies indicate that patients with mutant KRAS tumors fail to benefit from adjuvant chemotherapy, and their disease does not respond to EGFR inhibitors. There is a dire need for therapies specifically for patients with KRAS mutant NSCLC.

 

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mTOR inhibitors gaining favor for breast cancer treatment

This week, breast cancer researchers have been reporting encouraging clinical trial results with the drug everolimus at the San Antonio Breast Cancer Symposium. Everolimus is a mTOR inhibitor, first approved by the FDA for treatment of kidney cancer and then for post-transplant control of the immune system.

Ruth O’Regan, MD, director of the Translational Breast Cancer Research Program at Winship Cancer Institute, has led clinical studies of everolimus in breast cancer and has championed the strategy of combining mTOR inhibitors with current treatments for breast cancer.

She recently explained the rationale to the NCI Cancer Bulletin:

She views the combination therapy as a potential alternative to chemotherapy for treating ER-positive advanced breast cancer when hormonal therapies have stopped working.

When resistance to hormonal therapies occurs, Dr. O’Regan explained, additional signaling pathways become activated. Unlike chemotherapy, which targets rapidly dividing cells, mTOR inhibitors are an example of the kind of treatment that may block growth-promoting signaling pathways.

Currently, Winship researchers are examining a combination involving everolimus and the EGFR inhibitor lapatinib for “triple-negative” breast cancer, a particularly aggressive and difficult-to-treat variety.

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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.

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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.

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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.

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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.

 

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What cancer researchers can learn from fruit fly genetics

What can scientists studying cancer biology learn from fruit flies?

Quite a lot, it turns out.  At a time when large projects such as the Cancer Genome Atlas seek to define the changes in DNA that drive cancer formation, it is helpful to have the insight gained from other arenas, such as fruit flies, to make sense of the mountains of data.

Drosophila melanogaster has been an important model organism for genetics because the flies are easy to care for, reproduce rapidly, and have an easily manipulated genome. This NCI newsletter article describes how some investigators have used Drosophila to find genes involved in metastasis.

Emory cell biologist Ken Moberg says that he and postdoctoral fellow Melissa Gilbert crafted a Drosophila-based strategy to identify growth-regulating genes that previous researchers may have missed. Their approach allowed them to begin defining the function of a gene that is often mutated in lung cancer. The results are published online in Developmental Cell.

Part of the developing fly larva, stained with an antibody against Myopic. Groups of cells lacking Myopic, which lack green color, tend to divide more rapidly.

Moberg writes:

Many screens have been carried out in flies looking for single gene lesions that drive tissue overgrowth. But a fundamental lesson from years of cancer research is that many, and perhaps most, cancer-causing mutations also drive compensatory apoptosis, and blocking this apoptosis is absolutely required for cancer outgrowth.

We reasoned that this class of ‘conditional’ growth suppressor genes had been missed in prior screens, so we designed an approach to look for them. The basic pathways of apoptosis are fairly well conserved in flies, so it’s fairly straight forward to do this.

Explanatory note: apoptosis is basically a form of cellular suicide, which can arise when signals within the cell clash; one set of proteins says “grow, grow” and another says “brake, brake,” with deadly results.

Gilbert identified the fruit fly gene Myopic as one of these conditional growth regulators. She used a system where mutations in Myopic drive some of the cells in the fly’s developing eye to grow out more – but only when apoptosis is disabled.

Gilbert showed that Myopic is part of a group of genes in flies, making up the Hippo pathway, which regulates how large a developing organ will become. This pathway was largely defined in flies, then tested in humans, Moberg says. The functions of the genes in this pathway have been maintained so faithfully that in some cases, the human versions can substitute for the fly versions.

Myopic’s ortholog (ie different species, similar sequence and function) is the gene His-domain protein tyrosine phosphatase, or HD-PTP for short. This gene is located on part of the human genome that is deleted in more than 90 percent of both small cell and non-small cell lung cancers, and is also deleted in renal cancer cells.

How HD-PTP, when it is intact, controls the growth of cells in the human lung or kidney is not known. Gilbert and Moberg’s findings suggest that HD-PTP may function through a mechanism that is similar to Myopic’s functions in the fly.

Besides clarifying what Myopic does in the fly, their paper essentially creates a map for scientists studying HD-PTP’s involvement in lung cancer, for example, to probe and validate.

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A path to treatment of lymphedema

Lymphedema, or swelling because of the impaired flow of lymph fluid, can occur as a consequence of cancer or cancer treatment. Chemotherapy can damage lymph ducts, and often surgeons remove lymph nodes that may be affected by cancer metastasis. Lymphedema can result in painful swelling, impaired mobility and changes in appearance.

Young-sup Yoon, MD, PhD

Emory scientists, led by cardiologist and stem cell biologist Young-sup Yoon, have shown that they can isolate progenitor cells for the lining of lymph ducts. This finding could lead to doctors being able to regenerate and repair lymph ducts using a patient’s own cells. The results are described in a paper published recently in the journal Circulation.

The authors used the cell surface marker podoplanin as a handle for isolating the progenitor cells from bone marrow. Previous research has demonstrated that podoplanin is essential for the development of the lymphatic system.
In the paper, the authors use several animal models to show that the progenitor cells could contribute to the formation of new lymph ducts, both by becoming part of the lymph ducts and by stimulating the growth of nearby cells.

“This lymphatic vessel–forming capability can be used for the treatment of lymphedema or chronic unhealed wounds,” Yoon says.

Isolated lymphatic endothelial cells (red) incorporate into lymph ducts (green) in a model of wound healing in mice.

The authors also show that mice with tumors show an increase in the number of this type of circulating progenitor cells. This suggests that tumors send out signals that encourage lymph duct growth – a parallel to the well-known ability of tumors to drive growth of blood vessels nearby. Yoon says the presence of these cells could be a marker for tumor growth and metastasis. Because tumors often metastasize along lymph ducts and into lymph nodes, studying this type of cells could lead to new targets for blocking tumor metastasis.

A recent review in the journal Genes & Development summarizes additional functions of the lymphatic system in fat metabolism, obesity, inflammation, and the regulation of salt storage in hypertension.

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