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Winship Cancer Institute

Cells in “little brain” have distinctive metabolic needs

Cells’ metabolic needs are not uniform across the brain, researchers have learned. “Knocking out” an enzyme that regulates mitochondria, cells’ miniature power plants, specifically blocks the development of the mouse cerebellum more than the rest of the brain.

The results were published in Science Advances.

“This finding will be tremendously helpful in understanding the molecular mechanisms underlying developmental disorders, degenerative diseases, and even cancer in the cerebellum,” says lead author Cheng-Kui Qu, MD, PhD, professor of pediatrics at Emory University School of Medicine, Winship Cancer Institute and Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta.

The cerebellum or “little brain” was long thought to be involved mainly in balance and complex motor functions. More recent research suggests it is important for decision making and emotions. In humans, the cerebellum grows more than the rest of the brain in the first year of life and its development is not complete until around 8 years of age. The most common malignant brain tumor in children, medulloblastoma, arises in the cerebellum.

Qu and his colleagues have been studying an enzyme, PTPMT1, which controls the influx of pyruvate – a source of energy derived from carbohydrates – into mitochondria. They describe pyruvate as “the master fuel” for postnatal cerebellar development.

Cells can get energy by breaking down sugar efficiently, through mitochondria, or more wastefully in a process called glycolysis. Deleting PTPMT1 provides insight into which cells are more sensitive to problems with mitochondrial metabolism. A variety of mitochondrial diseases affect different parts of the body, but the brain is especially greedy for sugar; it never really shuts off metabolically. When someone is at rest, the brain uses a quarter of the body’s blood sugar, despite taking up just 2 percent of body weight in an adult. More here.

Also, see this 2017 item from Stanford on the cerebellum (Nature paper).

Posted on by Quinn Eastman in Neuro Leave a comment

Overcoming cisplatin resistance

Despite being studied for decades, the chemotherapy drug cisplatin is revealing new aspects of how it works. Researchers at Winship Cancer Institute of Emory University have identified an enzyme responsible for making tumors and cancer cell lines resistant to cisplatin, along with an experimental drug that targets that enzyme.

The results were published on July 19 in Cancer Cell.

Winship researcher Sumin Kang, PhD

Cisplatin is a DNA-damaging agent used in standard treatment for lung, head and neck, ovarian, and testicular cancers. It has a simple structure, grabbing DNA with its metallic (platinum) arms to form crosslinks. It used to be known as “cis-flatten” because of its nausea-inducing side effects. The experimental drug, lestaurtinib, has already been tested in clinical studies in combination with other chemotherapy drugs, which means it could easily go into trials against tumors displaying cisplatin resistance.

Sumin Kang, PhD, and colleagues at Winship decided to look for enzymes whose activity was necessary for cancer cells to withstand cisplatin treatment. They chose kinases, enzymes that often control some aspect of cell growth and are have plenty of existing drugs targeting them. The researchers found that in combination with a sub-lethal amount of cisplatin, “knocking down” the activity of the kinase MAST1 kills a cell. But how does that combination work?

Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Navigating monstrous anticancer obstacles

A new PNAS paper from geneticist Tamara Caspary’s lab identifies a possible drug target in medulloblastoma, the most common pediatric brain tumor. Come aboard to understand the obstacles this research seeks to navigate. Emory library link here.

Standard treatment for children with medulloblastoma consists of surgery in combination with radiation and chemotherapy. Alternatives are needed, because survivors can experience side effects such as neurocognitive impairment. One possibility has emerged in the last decade: inhibitors of the Hedgehog pathway, whose aberrant activation drives growth in medulloblastoma.

Medulloblastoma patients are caught “between Scylla and Charybdis”: facing a deadly disease, the side effects of radiation and/or existing Hedgehog inhibitors. From Wikimedia.

As this 2017 Oncotarget paper from St. Jude’s describes, Hedgehog inhibitors are no fun either. In adults, these agents cause muscle spasms, hair loss, distorted sense of taste, fatigue, and weight loss. In a pediatric clinical trial, the St. Jude group observed growth plate fusions, resulting in short stature. The drug described in the paper was approved in 2012 for basal cell carcinoma, a form of cancer whose growth is also driven by the Hedgehog pathway. Basal cell carcinoma is actually the most common form of human cancer, although it is often caught at an early stage that doesn’t require harsh treatment.

Caspary’s lab studies the Hedgehog pathway in early embryonic development. In the PNAS paper, former graduate student Sarah Bay and postdoc Alyssa Long show that targeting a downstream part of the Hedgehog pathway may be a way to avoid problems presented by both radiation/chemo and existing Hedgehog inhibitors. Read more

Posted on by Quinn Eastman in Cancer, Neuro Leave a comment

A sickly sweet anticancer drug

Cancer cells are well known for liking the simple sugar glucose. Their elevated appetite for glucose is part of the Warburg effect, a metabolic distortion that has them sprinting all the time (glycolysis) despite the presence of oxygen.

A collaboration between researchers at Winship Cancer Institute, Georgia State and University of Mississippi has identified a potential drug that uses cancer cells’ metabolic preferences against them: it encourages the cells to consume so much glucose it makes them sick.

Their findings were published in Oncotarget. Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Exosomes as potential biomarkers of radiation exposure

Kishore Kumar Jella, PhD

Winship Cancer Institute postdoc Kishore Kumar Jella has been invited to speak at the NATO advanced research workshop BRITE (Biomarkers of Radiation In the Environment): Robust tools for Risk Assessment in Yerevan, Armenia, on 28-30 November, 2017. The workshop brings together leading international experts to evaluate currently and developing radiation biomarkers for environmental applications.

Jella works in the Departments of Biochemistry and Radiation Oncology under the direction of Professors William S. Dynan and Mohammad K. Khan. He will speak on “Exosomes as Radiation Biomarkers”. He will describe how radiation influences exosome production and how these exosomes influence the immune system. The work has applications both to radiation carcinogenesis and combination radio-immunotherapy.

Jella is supported in part by a grant from the National Aeronautics and Space Administration to Dynan.

Exosomes are nano-sized membrane-clothed capsules containing proteins and RNA that are thought to facilitate cell-cell communcation. They were previously implicated in the ability of cancer cells to influence healthy neighbor cells, and have also been proposed as anti-cancer therapeutic vehicles. Jella’s previous research on exosomes and radiation-induced bystander signaling was published in Radiation Research in 2014.

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Winship summer scholars glimpse the future

Guest post from Megan McCall at Winship Cancer Institute. It is not very often that a high school student has the opportunity to work in a lab or clinic shadowing a world-renowned doctor, but for the past six weeks, ten Georgia high schoolers have done just that at Winship Cancer Institute.

Summer scholars in Medical Simulation Lab. Photo by Megan McCall.

The Summer Scholars Research Program, now in its 16th year, exposes students to a multitude of experiences, such as research from Winship’s top experts, lectures by doctors from a variety of specialties, and field trips to Grady Memorial Hospital and the Centers for Disease Control and Prevention. The students have also seen different parts of Emory’s campus through visits to the School of Medicine’s Medical Simulation Lab and the Health Sciences Research Library.

The SSRP pairs each student with an oncologist with whom they complete their own research project and get an in-depth look at a specific cancer specialty. The program will culminate on Friday (8:30 am to 12:30 pm, C5012) with the students presenting their projects to an audience of their peers, mentors, and the Winship community.

“Our goal with this program is to engage scholars at a young age and promote their interest in cancer research. I view this program as a critical part of my work and as a critical piece of Winship’s mission,” says program director Jonathon Cohen, MD. “The SSRP is a unique opportunity for Winship researchers to interact with some of the brightest young people out there, many of whom we hope to consider as colleagues in the future.”

The students attend weekly lectures with a wide array of speakers including oncologists, cancer survivors, and statisticians. Guest lecturer and 10-year cancer survivor Carolyn Higgins says, “It is wonderful to see such a fresh example of today’s future doctors.”

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Urine tests for prostate cancer could reduce biopsies

In the prostate cancer field, there has been a push to move beyond PSA testing. With urine tests, it may be possible to avoid biopsies for men with suspected prostate cancer.

Martin Sanda, MD is chair of urology and leads Winship’s prostate cancer program

With PSA testing to guide decisions, only one in five men is found via biopsy to have a cancer that is sufficiently aggressive (Gleason score of 7 or higher) to warrant treatment right away.

A recently published paper in JAMA Oncology from urologist Martin Sanda and colleagues in the NCI’s Early Detection Research Network shows the potential of urine testing. Sanda’s team reports that two prostate cancer RNA biomarkers detectable in urine (PCA3 and T2:ERG) could be combined to enhance their discriminatory power and reduce unnecessary biopsies by almost half.

The National Cancer Institute’s Cancer Currents blog has an extensive discussion of the JAMA Oncology paper. Read more

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Invasive lung cancer cells have distinct roles

When cancer cells split off from a tumor to seed deadly metastases, they are thought to travel as clusters or packs, a phenomenon known as collective invasion. The members of an invasive pack are not all alike, scientists at Winship Cancer Institute of Emory University have learned.

Lung cancer cells making up an invasive pack have specialized roles as leaders and followers, which depend on each other for mobility and survival, the scientists report in Nature Communications.

The differences between leaders and followers — and their interdependence — could be keys for future treatments aimed at impairing or preventing cancer metastasis, says senior author Adam Marcus, PhD, associate professor of hematology and medical oncology at Winship Cancer Institute and Emory University School of Medicine.

“We’re finding that leader and follower cells have a symbiotic relationship and depend on each for survival and invasion,” he says. “Because metastatic invasion is the deadliest aspect of cancer, our goal is to find agents that disrupt that symbiotic relationship.”

Marcus and former graduate student Jessica Konen, PhD began by observing how a mass of lung cancer cells behaves when embedded in a 3-D protein gel. The cells generally stick together, but occasionally, a few cells extend out of the mass like tentacles, with the leader cell at the tip.

“We saw that when the leader cell became detached or died unexpectedly, the followers could no longer move,” says Konen, now a postdoctoral fellow at MD Anderson. “In one particular movie, we saw a leader cell come out away from the rest of the cells, and then seem to realize that nobody was following him. He actually did a 180, and went back to grab cells to bring with him.” Read more

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Cancer immunotherapy responses in the clinic: T cell revival as predictor

In lung cancer patients who were taking immunotherapy drugs, testing for revived immune cells in their blood partially predicted whether their tumors would shrink. The results were published online by PNAS on April 26.

This finding comes from a small study of 29 patients, who were being treated at Winship Cancer Institute of Emory University with drugs blocking the PD-1 pathway, also known as checkpoint inhibitors.

The study supports a straightforward idea: if tumor-specific CD8 T cells appear to respond to the drug (nivolumab, pembrolizumab or atezolizumab), that’s a good sign. This avenue of investigation may also help researchers figure out why some patients do not benefit from checkpoint inhibitor drugs, and how to combine those drugs with other treatments to increase response rates.

While looking for activated immune cells in the blood is not yet predictive enough for routine clinical use, such tests could provide timely information. Monitoring the immune response could potentially help oncologists and patients decide, within just a few weeks of starting immunotherapy drugs, whether to continue with the treatment or combine it with something else, says co-senior author Suresh Ramalingam, MD, Winship’s deputy director.

“We hypothesize that re-activated CD8 T cells first proliferate in the lymph nodes, then transition through the blood and migrate to the inflamed tissue,” says Rafi Ahmed, PhD, director of the Vaccine Center and a Georgia Research Alliance Eminent Scholar. “We believe some of the activated T cells in patients’ blood may be on their way to the tumor.”

The rest of the Emory Vaccine Center/Winship Cancer Institute press release is here. A few additional points: Read more

Posted on by Quinn Eastman in Cancer, Immunology Leave a comment

Melanoma mutation likes fat for fuel

Cancer cells love glucose, the simple sugar the body uses for energy, so a high-fat, low-carb diet should starve them, right?

Where does this idea come from? Most cancer cells display enhanced glucose uptake, a phenomenon known as the Warburg effect, after 1931 Nobel Prize winner Otto Warburg.

Resurgent interest in exploiting the Warburg effect was described by Sam Apple in NYT Magazine and by Bret Stetka for NPR. High-fat, low-carb “ketogenic” diets are known to be effective against some types of epilepsy, and have also been explored by endurance athletes. Ketogenic diets have been tried as a clinical countermeasure against cancer in a limited way, mainly in brain cancer.

Before everybody gets too excited, let’s think about how particular cancer-driving mutations affect cell metabolism, suggests Winship Cancer Institute researcher Jing Chen. His team’s work in mice suggests that cancers with a common melanoma mutation (BRAF V600E) will grow faster in response to a ketogenic diet. In addition, the Winship researchers found that lipid-lowering agents such as statins curb these cancers’ growth, even in the context of a more normal diet.

The results were published on January 12 in Cell Metabolism.

Caveats: the findings cover just one mutation and need to be tested clinically.

Consumers and cancer patients already get a lot of advice about the right diet to fight cancer, but this research points toward an intriguing concept:  a “precision diet,” tailored to an individual patient’s cancer.  Read more

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