Dana-Farber / Brigham and Women's Cancer Center

Novel Therapies and Innovative Neurosurgical Procedures for Patients with Malignant Brain Tumors

Procedures for Patients with Malignant Brain Tumors

Specialists at Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) are offering a range of early-phase studies evaluating novel therapies and innovative, image-guided neurosurgical approaches for malignant brain tumors, including glioblastoma and high-grade gliomas, and brain metastases.

Oncolytic Virotherapy

E. Antonio Chiocca, MD, PhD, Neurosurgeon-in-Chief at Brigham and Women’s Hospital (BWH) and Surgical Director of the Center for Neuro-Oncology at DF/BWCC, directs a research laboratory funded by the National Institutes of Health (NIH) and the National Cancer Institute (NCI), focused on the study of glial tumor biology and translational therapeutics, including oncolytic virotherapy.

He has developed an oncolytic herpes virus targeting nestin-expressing glioma stem-like cells (Cancer Res. 2005 Dec 15;65(24):11255-8) and is the Principal Investigator of an upcoming Phase I clinical trial of this approach, which involves injecting a genetically-altered herpes simplex virus directly into glioma tumors. This treatment does not harm non-replicating, healthy brain cells, and Dr. Chiocca has previously led numerous studies of virus-based therapies in the treatment of malignant gliomas.

“Oncolytic virotherapy represents a novel approach to treating patients with refractory tumors, and we’ve seen promising results in pre-clinical studies,” said Dr. Chiocca.

Novel Targeted Therapies

Patrick Y. Wen, MD, Director of the Center for Neuro-Oncology at DF/BWCC, and David A. Reardon, MD, Clinical Director of the Center for Neuro-Oncology at DF/BWCC, are leading a range of innovative treatment approaches for patients with primary and metastatic malignant brain tumors, including:

  • Phase I/II Trials of BKM120 for Glioblastoma – Led by Principal Investigator Patrick Y. Wen, MD, these trials are studying BKM120, a pan-PI3K inhibitor with excellent penetration through the blood-brainbarrier in recurrent glioblastoma patients alone and in combination with an inhibitor of the Sonic Hedgehog pathway LDE225, as well as in newly diagnosed glioblastoma patients together with temozolomide and radiotherapy;
  • Phase I/II Study of AMG386 with and without Bevacizumab in Patients with Recurrent Glioblastoma – This study, led by Principal Investigator David A. Reardon, MD, is evaluating AMG386, a first-in-class inhibitor of angiopoietins 1 and 2. Angiopoietins are critical contributors to tumor angiogenesis;
  • Phase I Study of Plerixafor (AMD3100) and Bevacizumab for Recurrent High-Grade Glioma – This study, led by Principal Investigator Eudocia Q. Lee, MD, MPH, is evaluating Plerixafor, a potent inhibitor of stromal derived factor-1α (SDF-1α) as a key mediator of tumor growth and angiogenesis.

“We are continuing to build on earlier success with targeted therapies, combining new agents to enhance treatment response,” said Dr. Wen.

malignant human glioblastoma cells
This series of four microphotographs shows a clump of malignant human glioblastoma cells (genetically modified to have red fluorescence for visualization) that have been treated with a tumor-specific oncolytic virus. When this virus attacks the tumor cells, it will turn it green. At the start (far left panel), tumor cells at the surface are attacked. As time goes on, more cells in the interior of the clump are attacked and destroyed (become green), as shown in the succession of right-sided panels. (Pictures were taken in collaboration with Dr. N. Dmitrieva and B. Kaur, Ohio State University.)

A Focus on Stem Cells and Immunotherapies

Specialists in the Center for Neuro-Oncology will soon offer a Phase 1b clinical trial combining LDE-225 and BKM120 to simultaneously target the stem cell and non-stem cell compartment of tumors. This study, led by Principal Investigator Patrick Y. Wen, MD, will be the first to evaluate this novel combination regimen for malignant glioma patients. “Tumor stem cells are exceptionally resistant to radiation and chemotherapy and are believed to be responsible for many cases of cancer recurrence,” said Dr. Reardon. “By targeting tumor stem cells along with tumor cells, we are hoping to improve longer-term outcomes among patients.”

Specialists in the Center for Neuro-Oncology also are applying immunotherapies for the treatment of glioblastoma and are conducting preclinical testing of new immune-based treatments. CDX-110, a cancer vaccine targeting the EGFRvIII mutant growth factor receptor, is being evaluated in a Phase II study for newly-diagnosed glioblastoma patients. In addition, studies are in development to evaluate ipilimumab, approved in 2011 for advanced melanoma, and other reagents capable of modulating immune responses against tumors for patients with glioblastoma.

Advancing Image-guided Neurosurgical Approaches

Specialists at DF/BWCC also are collaborating to employ new image-guided techniques in the Advanced Multimodality Image Guided Operating (AMIGO) suite at BWH in order to advance treatment for patients with malignant brain tumors and brain metastases. AMIGO’s innovative design enables multidisciplinary teams of surgeons, interventional radiologists, radiation oncologists, imaging physicists, computer scientists, biomedical engineers, nurses, and technologists to use multi-modality imaging to efficiently and precisely guide treatment – before, during, and after the procedure – without the patient or medical team leaving the operating room.

Innovative image-guided neurosurgical applications in AMIGO include:

  • MRI-guided Interstitial Laser Ablation of Brain Lesions – This approach was pioneered at BWH, and a new study evaluating the efficacy of this technique in patients with recurrent brain metastases is being led by radiologist Ferenc A. Jolesz, MD, Co-Principal Investigator of the National Center for Image-Guided Therapy at BWH, and Alexandra J. Golby, MD, Director of Image-guided Neurosurgery, Clinical Co-director of the AMIGO suite, and a neurosurgeon in the Center for Neuro-Oncology. Interstitial laser ablation is particularly advantageous for reaching lesions deep in the brain that are otherwise difficult to access by other treatment methods.

    During the procedure, a cooling catheter is inserted into the brain via a stereotactic approach. Placement is confirmed with MR imaging and a laser fiber is passed through the catheter. MR imaging is continuously repeated, and test heating is performed at a low level. Temperature mapping is provided with MR imaging, and ablation is monitored with MR imaging and software outlining damage to the treatment area.

    Flexibility in positioning of the laser fiber enables surgeons to begin the approach at the middle or the edge of the target area and to reposition the catheter as necessary throughout the procedure. The procedure also is being offered for patients with radiation necrosis.

  • MRI-assisted Craniotomy and Biopsy – In AMIGO, the neurosurgeon is able to use all advanced surgical and imaging tools, including electrophysiological mapping, ultrasound, and microscopic dissection. After initial resection, high-resolution 3T MR imaging is used to examine the margins for signs of residual tumor, and intraoperative DTI is used to demonstrate the intraoperative configuration and position of the critical white matter tracts.This information can then be used to guide the most complete resection which preserves the patient's neurologic function.

Dr. Chiocca concludes, “There are potentially hundreds of mutant cells present in dozens of aberrant pathways. We must continue to look for novel ways to find these cells and understand how to destroy them, with a virus, a vaccine, a combination of drugs or improved surgical techniques, to keep these tumor cells dormant and help patients stay healthy.”

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