Glioblastomas are tumors that develop from astrocytes and grow in the cerebral hemispheres of the brain. These tumors contain multiple cell types and are highly malignant. Glioblastomas rarely grow outside of the brain and most commonly lead to symptoms such as headache, nausea, vomiting and drowsiness. In some cases, memory, speech and vision can be impaired. Glioblastomas pose a significant challenge to treat as they grow rapidly, have an ample blood supply, and drug delivery is impaired due to the blood-brain barrier. Additionally, glioblastomas contain mixed cell types within the tumor that may respond differently to therapy and develop finger-like projections that grow in the brain, making surgical removal of the tumor difficult. Relieving pressure on the brain from growing glioblastomas by surgical resection is the first step, followed by radiation therapy or chemotherapy to slow the growth of tumors that cannot be removed. With standard treatment, prognosis is relatively poor, with the median survival of adult glioblastoma patients being somewhere between 14 months and three years with less than 10% of patients surviving longer than five years after diagnosis.
Given the difficulty in treating glioblastomas and the poor prognosis, researchers within Biomedical Engineering groups at Duke University, Georgia Institute of Technology and Emory School of Medicine have taken a new and innovative approach to treating this aggressive form of brain cancer. Dr. Ravi V. Bellamkonda and collaborators have demonstrated that use of a mutated form of the bacterium Salmonella typhimurium (S. thyphimurium) may be an effective method to pass the blood-brain barrier and destroy glioblastomas. Their findings were recently published in Molecular Therapy – Oncolytics.
Tumor seeking and destroying bacteria
S. typhimurium is a facultative anaerobic bacterium that colonizes the gastrointestinal tract and can easily be mutated into an avirulent form. This strain of bacteria has previously been shown to grow in hypoxic regions within a tumor and was tested in clinical trials to treat metastatic melanoma, but tumoricidal effects were not observed. Bellamkonda and collaborators sought to optimize the avirulent bacterial strain to effectively identify and destroy tumors. The bacteria was mutated to lose the ability to synthesize purines. Purines are required for bacterial growth and survival, and the mutated form of the bacteria must search for alternative sources of purines. Tumors are abundant in purine, and in essence, this mutated strain of S. typhimurium is now a tumor-seeking bacteria. In addition to creating tumor-seeking bacteria, the researchers wanted to demonstrate that the bacteria could be used as a carrier to treat tumors. The bacteria were further designed to express tumor suppressor protein p53 and azurin, proteins that can induce apoptosis, in the hypoxic environment of a tumor to prevent damage to healthy tissues.
In vivo studies where the mutated bacterial strain was injected into the brains of rats showed that 19% of treated rats were cleared of aggressive glioblastomas and survived significantly longer than untreated rats. In the 81% of treated rats that did not survive, tumoricidal activity was still evident. Inconsistencies in the penetration of the bacteria or aggressive tumor growth in the non-surviving population of rats could explain differences in survival. Still in its early stages of research and development, these findings demonstrate that S. typhimurium is a promising bacterial carrier to be used in the treatment of glioblastomas. This bacteria is able to pass through the blood-brain barrier, localize to tumors and deliver treatment to tumors with little to no consequence to surrounding tissues. Further studies will show if this bacteria can be optimized to be more effective in the treatment of glioblastomas.