Scientists from Duke University have found a strain of salmonella that causes food poisoning but useful in fighting glioblastoma, the most aggressive form of brain cancer.
The blood-brain barrier that separtates brain tissue from its blood vessels makes it difficult to send drugs to kill diseases in brain and often brain surgery fails to entirely remove such cells. Only 10 percent of patients survive five years once diagnosed from this deadly disease.
The Duke team turned to the bacterium Salmonella typhimurium which can be used with a few genetic tweaks, to become a cancer-seeking missile that produces self-destruct orders deep within tumors. Tests in rats showed 20 percent survival rate over 100 days, which means 10 human years, with the tumors going into complete remission.
The results were published in the journal Molecular Therapy – Oncolytics.
“Since glioblastoma is so aggressive and difficult to treat, any change in the median survival rate is a big deal,” said Jonathan Lyon, a PhD student working with Indian origin scientist Ravi Bellamkonda, Vinik Dean of Duke’s Pratt School of Engineering, whose laboratory is currently transitioning to Duke from Georgia Tech, where much of the work was completed. “And since few survive a glioblastoma diagnosis indefinitely, a 20 percent effective cure rate is phenomenal and very encouraging.”
Previous studies have shown that the presence of bacteria can cause the immune system to recognize and begin attacking tumors but follow-up clinical trials with genetically detoxified strains of S. typhimurium have since proven ineffective by themselves.
To use these common intestinal bacteria as tumor-seeking missiles, Lyon and Bellamkonda, working with lead co-author Nalini Mehta, selected a detoxified strain of S. typhimurium that was also deficient in a crucial enzyme called purine, forcing the bacteria to seek supplies elsewhere.
Then, the Duke engineers made a series of genetic tweaks so that the bacteria would produce two compounds called Azurin and p53 that instruct cells to commit suicide — but only in the presence of low levels of oxygen. And since cancerous cells are multiplying so energetically, the environment around and within tumors has unusually low oxygen.
In the 80 percent that did not survive, however, the treatment didn’t change the length of time the rats survived. After testing for common signs of resistance to the anti-tumor compounds and finding none, the researchers concluded the ineffectiveness was likely due to inconsistencies in the bacteria’s penetration, or to the aggressive tumor growth outpacing the bacteria. But every rat showed initial signs of improvement after treatment.
“It might just be a case of needing to monitor the treatment’s progression and provide more doses at crucial points in the cancer’s development,” said Lyon.
The researchers now plan to program their bacteria to produce different drugs that cause stronger reactions in the tumors besides studying potential side effects.