Spring 2011

Racing to Improve Brain Tumor Treatment

Even with state-of-the-art treatment, survival rates for malignant brain tumors don't typically exceed 12 to 15 months. One of the primary reasons is that the invasive nature of these tumors makes it extremely difficult to medicate residual cancer after surgery.

To address that challenge, a new trial led by Mitchel S. Berger, M.D., chair of the UCSF Department of Neurological Surgery, builds on studies that have indicated stem cells are naturally attracted to tumor activity. In principle, these cells can be modified to deliver an effective therapy against tumors while minimizing harm to surrounding, healthy tissue.

David James, Ph.D., coordinator of the $19 million California Institute for Regenerative Medicine project, said, "We hope by focusing on 'smart' stem cell therapies, we will finally increase survival rates for brain tumor patients," which is investigating treatment of glioblastoma, the most aggressive form of primary brain tumor. The goal is to file an investigational new drug application with the U.S. Food and Drug Administration within four years.

Zeroing In Quickly

The project began in early 2010 by looking at 12 possible approaches — three stem cell hosts, two drugs and two routes of administration. In the first nine months, possibilities have narrowed to four.

  • The stem cell hosts — Originally, investigators were looking at mesenchymal stem cells (derived from adult bone marrow), adult neural stem cells (derived from adult neurosurgical patients) and fetal neural stem cells (derived from fetal brain tissue). The adult stem cells have been eliminated because of limited proliferative activity.
  • The drugs — The two possibilities are tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and the enzyme cytosine deaminase (CD).
    • TRAIL activates by interacting with agents on glioblastoma cells and, once activated, induces cell death.
    • CD converts the nontoxic prodrug 5-fluorocytosine (5-FC) into cytotoxic 5-fluorouracil (5-FU), which effectively kills tumor cells in animal models.
  • Route of administration — After testing both intravascular injection and delivering therapies directly into the brain tumor after surgery, the team has chosen the latter method. “The numbers of cells that reach the tumor intravascularly are insufficient when compared with introducing the therapeutic stem cells at multiple points in the resection cavity," James said.

    Advanced Imaging Techniques Follow Encouraging Progress

    To noninvasively track the cell migrations, the team loads the stem cells with small iron particles and uses magnetic resonance imaging (MRI) to answer questions such as:

    • Will modification alter the stem cells' ability to find their target?
    • How long will it take for the stem cells to reach their target?
    • Will the modified cells penetrate the target cancer cell as expected?

    Co-investigator Sabrina Ronen, Ph.D., from the UCSF Department of Radiology and Biomedical Imaging, said, "One key advantage of the MRI technique is that we can adapt it to human patients. So far, we have shown that the cells do migrate to the areas where we want them to migrate."

    Other advanced imaging could play a role later. "We might use MRSI [magnetic resonance spectroscopic imaging] with hyperpolarized C-13, an innovative imaging method currently in clinical trials at UCSF, to track metabolic biomarkers that indicate whether the cell is responding to therapy," Ronen said.

    Safety First

    The team also will be watching carefully for any effect on surrounding normal tissue, any deleterious alteration of the stem cells, and the action of a "suicide gene" designed to cause each stem cell to self-destruct after it has delivered its payload.

    "Our first concern is safety, and the amount of proof we will have to produce on that front is substantive," James said.

    And to move the work into a clinical trial in 2015, proof of safety will have to go hand in hand with proof of efficacy. "Improved survival of animal subjects receiving this therapy will be a critical determinant for deciding whether this novel treatment is evaluated in brain tumor patient clinical trials," James said.

    Understanding the Origin of Brain Tumors

    Another research avenue for finding more effective brain tumor treatments explores how tumors begin and function. The lab of Claudia Petritsch, Ph.D., is identifying which brain cells are most affected by mutations that give rise to tumors, and mechanisms by which a normal brain cell becomes a tumor cell.

    Petritsch said, "Our lab is the first to establish that asymmetric cell division is critical for the normal function of oligodendrocyte progenitors, and among those to establish that a switch to symmetric cell division is an important, early aspect of turning normal progenitor cells into cancer cells." She is studying both low-grade and high-grade brain tumors through this lens.

    For low-grade tumors, her lab uses primary tumor cells from surgical tissue to create preclinical mouse models that will help more precisely define how tumors form and grow. From this, Petritsch expects to identify a target and create a therapy that restores asymmetric cell division, and so instructs premalignant cells to develop into normal cells and prevent tumor regrowth after initial therapy.

    For aggressive, high-grade tumors, she and her colleagues are looking at how immature cells within the tumor hierarchically divide to generate a tumor with increased resistance to radiation and chemotherapy. They have found indications that hierarchical divisions — and how these hierarchical divisions are regulated — affect the tumor cells' response to conventional therapy.

    "These findings show that oligodendroglioma responds well to therapies because the tumor derives from progenitor cells, which nonhierarchically divide. Glioblastoma cells, on the other hand, appear to divide hierarchically to generate treatment-resistant cells," Petritsch said. "This work, therefore, gives cancer doctors and researchers new cellular pathways to target in developing therapies. Specifically, we’re seeking ways to interfere with the tumor cell hierarchy so that the tumor cells are more responsive to therapies."

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