Understanding epilepsy in pediatric tumors

Pediatric brain tumors are characterized by frequent complications due to intractable epilepsy compared to adult brain tumors. However, the genetic cause of refractory epilepsy in pediatric brain tumors has not been elucidated yet, and it is difficult to treat patients because the tumors do not respond to existing antiepileptic drugs and debilitate children's development.

A Korean research team led by Professor Jeong Ho Lee, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST) has recently identified a neuronal BRAF somatic mutation that causes intrinsic epileptogenicity in pediatric brain tumors.

Preoperative and postoperative brain MRI (left panel), tumor H&E (right upper panel) and GFAP immunohistochemical (right lower panel) staining images from a patient with ganglioglioma (GG231) carrying the BRAFV600E mutation. The white arrow and the black arrowhead indicate the brain tumor and a dysplastic neuron, respectively.

Credit: KAIST

The research team studied patients' tissue diagnosed with ganglioglioma (GG), one of the main causes of tumor-associated intractable epilepsy, and found that the BRAF V600E somatic mutation is involved in the development of neural stem cells by using deep DNA sequencing. This mutation was carried out in an animal model to reproduce the pathology of GG and to observe seizures to establish an animal model for the treatment of epileptic seizures caused by pediatric brain tumors.

Using immunohistochemical and transcriptome analysis, they realized that the BRAF V600E mutation that arose in early progenitor cells during embryonic brain formation led to the acquisition of intrinsic epileptogenic properties in neuronal lineage cells, whereas tumorigenic properties were attributed to a high proliferation of glial lineage cells exhibiting the mutation. Notably, researchers found that seizures in mice were significantly alleviated by intraventricular infusion of the BRAF V600E inhibitor, Vemurafenib, a clinical anticancer drug.

The authors said, "Our study offers the first direct evidence that the BRAF somatic mutation arising from neural stem cells plays a key role in epileptogenesisin the brain tumor. This study also showed a new therapeutic target for tumor-associated epileptic disorders."

In collaboration with the KAIST startup company, SoVarGen, the research team is currently developing innovative therapeutics for epileptic seizures derived from pediatric brain tumors. This study was supported by the Suh Kyungbae Foundation (SUHF) and the Citizens United for Research in Epilepsy.

 

We encourage researchers all around the globe to submit abstract on their latest research at our upcoming conference Cell Tissue Science 2019 which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment   and many more.We welcome you to the our upcoming conference “ 12th World Congress on Cell & Tissue Science” . For more info visit :Cell Tissue Science 2019

Unexpected cell population key to blood cancer relapse

McMaster University researchers have provided evidence of new cancerous cells they have termed cancer regenerating cells, which are responsible for the return of acute myeloid leukemia after remission.

Current therapy is effective at inducing remission in adult patients with acute myeloid leukemia, but most patients later succumb after a relapse. That relapse has been thought to be caused by rare and dormant cancer stem cells that escape chemotherapy.

The study suggests that leukemia cells change in unique ways in response to the chemotherapy, allowing them to masquerade for a short time so they are able to start disease regeneration.

The research involved combined efforts from both scientists and physicians and spanned more than five years in development. The team took on the challenge of hunting down the rare leukemic cells that remain right after chemotherapy treatment. The surprise was that the most resilient cells left behind after the treatment did not fit the profile of cancer stem cells.

"Many cancer researchers, including our team, have thought it was dormant cancer stem cells that can resist chemotherapy treatment which go on to cause relapse," said Mick Bhatia, Director, McMaster Stem Cell and Cancer Research Institute.

Bhatia noted that, until now, the initial aftermath immediately after chemotherapy treatment has been largely unexplored, because leftover leukemia cells easily blend into the body and go undetected amid the chaos caused by the therapy itself."Chemotherapy is not entirely specific and destroys a lot of other tissues, making the patient's body a difficult place to do the detective work to find cells responsible for relapse," he said. He continues by saying "It's like trying to find a pen of unknown color or type in an office where a bomb went off. What we were trying to find is what causes the relapse somewhere where a bomb -- in this case chemotherapy -- had already caused so much collateral damage."

"This design allowed us to zero in on the few human leukemic cells that survived, because we could easily distinguish them from non-diseased mouse cells," said Lili Aslostovar, Postdoctoral Fellow, McMaster Stem Cell and Cancer Research Institute. "We were finally able to detail what takes place during this transient period before the storm of relapse occurs."

The key finding was to identify the point at which the disease retaliates by becoming highly regenerative, setting the stage for eventual relapse. This offered a new roadmap to identify the camouflaged cancer cells that hide out in the bone marrow of leukemia patients shortly after chemotherapy treatment. Importantly, similar patterns of leukemic regeneration could be seen across a spectrum of different patient subtypes, providing a common thread to guide the development of new therapies at the critical time point after chemotherapy.

"This is a major clinical opportunity because this type of leukemia is very diverse and responds differently across patients," said Allison Boyd, Postdoctoral Fellow, McMaster Stem Cell and Cancer Research Institute. She said, "It has been a challenge in a clinical setting to find a commonality for therapeutic targeting across the wide array of patients, and these regenerative cells provide that similarity."

The researchers hope that this new understanding of leukemic regeneration will provide physicians the opportunity to introduce additional drugs in combination with chemotherapy treatment. This will take advantage of chemotherapy's benefits while counteracting its shortcomings at the same time by targeting these altered cancer cells, said Bhatia.

"We were impressed that after chemotherapy, the disease seems to get very weak because the cancerous stem cells have been largely eliminated," said Boyd. "We think there are opportunities here because now we have a window where we can kick the cancer while it's down."

"Chemotherapy has increased the number of years cancer patients survive, but if you look at the overall death rates for people with leukemia, they are relatively unchanged," said Bhatia. "The problem is that the tumour comes back. It's the relapse, then, that kills the patients. Our goal is to prevent the relapse altogether."

We encourage researchers all around the globe to submit abstract on their latest research at our upcoming conference Cell Tissue Science 2019 which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more.We welcome you to the our upcoming conference “ 12th World Congress on Cell & Tissue Science” . For more info visit :Cell Tissue Science 2019