Identification Of Novel Tumor Biomarkers Holds Promise For Improved Outcome In Patients With Brain Tumors

Main Category: Neurology / Neuroscience
Also Included In: Cancer / Oncology;  Biology / Biochemistry;  Clinical Trials / Drug Trials
Article Date: 29 Apr 2008 - 0:00 PDT

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Brain tumors are the most common solid cancer of childhood and are presently the leading cause of death in children, excluding trauma. In 2005, an estimated 43,800 new cases of primary nonmalignant and malignant brain and central nervous system (CNS) tumors were diagnosed in the United States. Of these, an estimated 3,410 cases were diagnosed in children. The overall mortality rate attributed to primary brain and CNS tumors was estimated at 12,760 in 2005. In adults, the number of primary and metastatic brain tumors is steadily increasing, while mortality rates for most other tumor types have remained essentially unchanged. These statistics underscore the urgent need for the development of innovative modalities to improve outcome for patients with brain tumors.

One of the most difficult issues in treating brain tumors is the lack of effective methods to detect novel or recurrent disease. Despite recent advances in the imaging and treatment of brain tumors, the ability to prospectively diagnose new tumors or to detect tumor recurrence remains poor. Currently, there are no generally accepted screening protocols for the discovery of asymptomatic brain tumors, particularly primary brain tumors. Early detection of tumors in other organ systems, both novel and recurrent, has frequently resulted in markedly improved patient outcome. It would be invaluable to replicate the successes achieved in other organ systems through the development of noninvasive biomarkers capable of identifying brain tumors.

Researchers at Children's Hospital Boston and Brigham and Women's Hospital in Boston, recently analyzed the role of urinary matrix metalloproteinases (MMPs) as diagnostic biomarkers for brain tumors. The results of this study, Urinary Biomarkers Predict Brain Tumor Presence and Response to Therapy, will be presented by Edward R. Smith, MD, 2:45 to 2:59 p.m., Monday, April 28, 2008, during the 76th Annual Meeting of the American Association of Neurological Surgeons in Chicago. Co-authors are Marsha A. Moses, PhD, Ali Saad, MD, R. Michael Scott, MD, and David Zurakowski, PhD.

MMPs, a multigene family of degradative enzymes, have been implicated in the establishment and maintenance of the vasculature required for tumor progression and metastasis, as well as in the initial angiogenic phase of tumor growth in experimental models and human tumors. In the CNS, MMPs have been associated with brain tumor development. Studies of primary brain tumors reveal that MMP-2, MMP-9 and several other MMPs are overexpressed in both experimental models and tissue samples from human patients.

"Recent studies from our laboratory, now confirmed by others, support the premise that tumor stage and progression correlate with urinary levels of MMPs," said Dr. Smith. Urinary levels of MMP-2 (gelatinase A) and MMP-9 (gelatinase B), and their complexes are elevated in patients with a variety of cancers, both organ confined and metastatic, both within and outside the urogenital tract. "These studies are the first to suggest that the measurement MMPs and related biomarkers in the urine of affected patients might represent a novel, noninvasive method of detecting disease status, progression and therapeutic efficacy," stated Dr. Smith.

Specimens from pediatric and adult patients were collected in accordance with protocols submitted to, and approved by the Institutional Review Boards (IRB). The number of patients analyzed is based on all patients presenting with nonmetastatic brain tumors over a one-year period who were willing to participate in the study. All tumor patients had intrinsic brain tumors with pathologic confirmation of diagnosis.

-- Specimens from a total of 28 tumor patients and 23 control subjects were subjected to analysis.

-- Tumor diagnoses included both primary glial tumors (glioblastoma, anaplastic astrocytoma, fibrillary astrocytoma and pilocytic astrocytoma, n=12) and other primary central nervous system tumors (meningioma, choroid plexus carcinoma, ependymoma, medulloblastoma, atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, ganglioglioma, hemangioblastoma and craniopharyngioma, n=16).

"Early results from our ongoing protocol evaluating the role of urinary MMPs as noninvasive biomarkers for brain tumors are encouraging, particularly in light of this uniquely challenging cohort of cancer patients," remarked Dr. Smith.

These findings suggest that elevated urinary MMPs and vascular endothelial growth factor (VEGF) may be indicative of the presence or recurrence of brain tumors, and that monitoring urinary levels of these proteins may have potential utility for improving the ability of clinicians to predict the presence of these tumors. Moreover, the finding that the combination of MMP-2 and VEGF provided superior accuracy in predicting tumor presence as compared to any biomarker alone substantiates the premise that biomarker accuracy can be improved through multiplexing.

"Ultimately, we envision that routine sampling of urinary MMPs and other biomarkers may enhance current methods of brain tumor detection and follow-up by facilitating earlier detection of both novel and recurrent disease through noninvasive surveillance for abnormal urinary biomarker profiles. And most exciting, is that this has real potential to equate to improved patient outcome," concluded Dr. Smith.

Founded in 1931 as the Harvey Cushing Society, the American Association of Neurological Surgeons (AANS) is a scientific and educational association with more than 7,200 members worldwide. The AANS is dedicated to advancing the specialty of neurological surgery in order to provide the highest quality of neurosurgical care to the public. All active members of the AANS are certified by the American Board of Neurological Surgery, the Royal College of Physicians and Surgeons (Neurosurgery) of Canada or the Mexican Council of Neurological Surgery, AC. Neurological surgery is the medical specialty concerned with the prevention, diagnosis, treatment and rehabilitation of disorders that affect the entire nervous system, including the spinal column, spinal cord, brain and peripheral nerves.

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