neuro-oncology

2

UC San Diego among First in Nation to Treat Brain Cancer with Novel Viral Vector
Directly injected viral vector, Toca 511, is designed to spread through brain cancer cells and kill them while leaving healthy cells unharmed

UC San Diego Moores Cancer Center researchers and surgeons are among the first in the nation to treat patients with recurrent brain cancer by directly injecting an investigational viral vector into their tumor. The treatment is being developed by a local San Diego Company, Tocagen Inc.

“This clinical trial targets glioblastoma – one of the deadliest forms of brain tumor,” said principal investigator Santosh Kesari, MD, PhD, director of neuro-oncology in the Moores Cancer Center and in the Department of Neurosciences at the University of California, San Diego.  “Clinical trials of investigational therapies such as this may lead to new treatment options for patients battling this deadly disease.”
 
The current standard of care for a newly diagnosed, high-grade glioma includes surgically removing as much of the tumor as possible, followed by radiation therapy and chemotherapy.  Despite these measures, the tumor usually recurs making this trial a high priority.

The trial is investigating the use of Toca 511 (vocimagene amiretrorepvec), for injection in combination with Toca FC (flucytosine), extended-release tablets.  Toca 511 is a retroviral replicating vector (RRV) that is designed to deliver a cytosine deaminase (CD) gene selectively to cancer cells. After allowing time for the administered Toca 511 to spread through the cancerous tumor those cancer cells expressing the CD gene can convert flucytosine into the anti-cancer drug 5-fluorouracil (5-FU).  In this study, patients receive cycles of oral Toca FC monthly for up to six months.

Top Photo: The Toca 511 virus replicates by budding.
Bottom: The surgical procedure involves directly injecting the viral vector into the brain tumor.

More here

Investigators Discover Mechanism Responsible for Tumor Invasion in Brain Cancer

A neuro-oncology research team at Dartmouth’s Norris Cotton Cancer Center, led by the Director Mark A. Israel, MD with first author Gilbert J. Rahme, PhD, recently identified the transcription factor Id4 as a suppressor of tumor cell invasion in glioblastoma. Their paper, “Id4 suppresses MMP2-mediated invasion of glioblastoma-derived cells by direct inactivation of Twist1 function,” was recently published in Oncogene. A key finding was the mechanism by which Id4 silences matrix metalloproteinase 2 (MMP2), determined to be inhibition of the protein Twist1 that is required for MMP2 expression.

(Image caption: Invasion assays using Glioblastoma (GBM) cells on the left lacking Id4, in comparison to the same cells being genetically engineered to express Id4 on the right. Every invaded cell in this assay is colored green and the assay showed that the cells on the left, lacking Id4, invaded much more than the cells on the right in which there was forced expression of Id4)

“This finding suggests a novel therapeutic target to decrease invasion of tumor cells in patients and may also provide a novel biomarker that could help predict survival of patients with glioblastoma,” explained Israel.

Glioblastoma is the most lethal form of primary brain tumor and leads to death in patients by invading the brain tissue in a process that allows single cells to move through normal brain tissue, which makes complete surgical removal of the tumor impossible. Israel and his team sought to understand the mechanisms that drive tumor invasion of normal tissue in glioblastoma.

Using data from The Cancer Genome Atlas (TCGA), the Dartmouth team demonstrated that Id4 expression correlates with survival of glioblastoma patients and inversely correlates with MMP2 expression. The data suggests that the upregulation of MMP2 resulting from decreased Id4 expression in glioblastoma multiforme (GBM) may contribute to the morbidity and mortality of GBM patients.

This study used Dartmouth’s Shared Resources including Microscopy and Molecular Biology. “Using the core facilities greatly facilitated the conduct of the work saving time and reducing cost,” Rahme said. All 14 of Dartmouth’s Shared Resources are available to outside investigators by arrangement.

“Conventional drugs targeting the enzymes encoded by MMP genes have not been successful in the clinic due to adverse side effects,” said Rahme. “We believe that proteins in the pathway that controls the expression of MMP2 are likely to be better therapeutic targets. Targeting Twist1 might silence MMP2 and decrease tumor invasion, which will help patients with GBM. Furthermore, the expression of Id4 may serve as a tumor biomarker that can predict the degree of tumor infiltration.”

Looking forward, the therapeutic targets revealed in this study to be actors in tumor invasion need to be further characterized as drug targets and, if possible, therapeutically inhibited. Their pursuit of Id4 as a biomarker for patients with GBM continues in hopes of making useful predictions of tumor invasion and survival.

Study provides comprehensive look at brain cancer treatments

Led by the Translational Genomics Research Institute (TGen) and UC San Francisco (UCSF), a comprehensive genetic review of treatment strategies for glioblastoma brain tumors was published today in the Oxford University Press journal Neuro-Oncology.

The study, Towards Precision Medicine in Glioblastoma: The Promise and The Challenges, covers how these highly invasive and almost-always-deadly brain cancers may be treated, reviews the continuing challenges faced by researchers and clinicians, and presents the hope for better treatments by harnessing the power of the human genome.

The study also describes a pioneering clinical trial underway for 15 patients at UCSF, guided by TGen research, in which an individual patient’s genomic profile is used to offer treatment recommendations to an expert, multidisciplinary panel.

“This study thoroughly explores how we arrived at the current standard-of-care, and how – through cutting-edge genomic technologies – we might find better answers for these patients who need our help today,” said Dr. Jeffrey Trent, TGen President and Research Director and the study’s senior author.

Funded by The Ben & Catherine Ivy Foundation, the study is one of several simultaneous and coordinated efforts seeking to uncover the molecular source of this deadly brain cancer with the goal of prolonging survival of glioblastoma patients.

“Despite pivotal advances in the characterization of genomic mutation in glioblastoma, targeted drug agents have so far shown minimal effect in clinical trials, and patient survival remains poor,” said Dr. Michael D. Prados, the Charles B. Wilson, MD, Endowed Chair in Neurological Surgery at UCSF, and one of the study’s co-lead authors.

One of the major difficulties in treating brain tumors is finding drugs that can penetrate the blood-brain barrier, which buffers the brain from the rest of the body’s blood-circulatory system. Located along capillaries, the blood-brain barrier protects the brain from rapid changes in the body’s metabolic conditions and minimizes exposure to molecules that are toxic to neurons in the brain.

“This study outlines strategies for overcoming past failures, primarily by applying targeted combination therapies that match the tumors’ genetic changes with drug compounds that can reach the central nervous system,” said Dr. Sara Byron, Research Assistant Professor in TGen’s Center for Translational Innovation, and the study’s other co-lead author.

Another major challenge in treating glioblastoma is its intrusive penetration into adjoining tissues, which prevents the complete surgical removal of the tumors from the brain, even with follow-up radiation and chemotherapy: “It is this invasive, infiltrative disease component that is the ultimate cause of recurrence, resistance and death,” the study says.

“All patients will continue to show tumor growth and progression because of rapidly proliferating infiltrative disease remaining after surgery,” according to the study. “Effective treatment for glioblastoma remains an unmet need.”

The only FDA-approved drugs to treat glioblastoma are temozolomide, nitrosoureas, and bevacizumab.

In the clinical trial begun at UCSF, multiple biopsies are performed on each patient at the time of surgery in different regions of the brain tumor. That is followed by extensive genome-wide profiling, leading to a selection of drugs that would target the brain cancer and diffuse regions of the lesion that cannot be removed by surgery.

Drug selection is individualized, and multiple FDA-approved agents (up to four) allowed. “Rules” for drug selection are implemented, using the specialized drug pharmacopeia designed for this trial. The drugs are chosen carefully, considered with knowledge about the ability of the drug to reach the brain and the patient’s past treatment history and concomitant therapies, with the assistance of multi-specialty, multi-institutional molecular tumor board that drafts a report to the treating physician.

In addition, “Small, informative, tissue-based clinical trials that take into account the individual molecular features of patients and provide early ‘go’ or 'no go’ decisions are needed and should be prioritized over unselected, large, population-based strategies,” the study recommends.

A separate clinical trial that follows this path, also guided by TGen genomic research, is underway at Barrow Neurological Institute. This clinical trial also is funded by The Ben & Catherine Ivy Foundation. For more about this clinical trial, go to: http://www.tgen.org/home/news and click on March 10, 2015.

“These studies, and their associated clinical trials, have the potential to lift our knowledge of glioblastoma to an unprecedented new level,” said Catherine Ivy, President of The Ben & Catherine Ivy Foundation. “Developing drug compounds that breach the blood-brain barrier and are effective against tumors would fulfill one of the medical community’s most critical unmet needs, and boost the hopes of brain tumor patients everywhere.”