脳腫瘍を食中毒菌で治療

A fluorescent stained image of a tumor marking bacterial nanocarriers in pink, cancer cell nuclei in blue, and human mitochondria (another indicator of tumor cells) in green.

 

「最悪の脳腫瘍」を遺伝子操作の食中毒菌で叩く

実験では生存率が2倍に

米デューク大学の研究チームが遺伝子操作したネズミチフス菌を使い、根治困難な悪性脳腫瘍の膠芽腫(こうがしゅ)を治療する方法を開発したと発表しました。

ネズミチフス菌とは名前のとおり、サルモネラ属のなかでも主にネズミを宿主とするチフス菌の一種。

脳腫瘍の中でも膠芽腫は「最悪の悪性腫瘍」とも呼ばれます。

非常に進行が早いのが特徴で、数週間で病状が大きく悪化することもあります。

腫瘍といえばまず考えられるのが外科的に取り除く治療方法ですが、膠芽腫には浸潤性があり、正常な細胞との境目を見極めるのが困難。

手術で完全に取り除くことはほぼ不可能とされます。

研究チームの説明によれば治療後の5年生存率は10%未満しかなく、発見後の平均余命は15ヶ月とも言われます。

さらに、脳に送られる血液は血液脳関門とよばれる体内のフィルター機構によって異物や薬品を通さない仕組みになっており、これが脳腫瘍の抗がん剤や放射線治療を困難なものとしています。


治療法の研究にあたり、研究者らは膠芽腫を叩くためネズミチフス菌に遺伝子操作を施して無害化。さらにPurineと呼ばれる酵素が常に欠乏した状態にしました。Purineは膠芽腫に多く含まれるためこの操作によってネズミチフス菌は脳腫瘍へと誘導され、そこで増殖するようになります。

ネズミチフス菌にはさらに、細胞の自己破壊を促すAzurianタンパク質およびp53と呼ばれる化合物を産生するようにしました。これらは低酸素状況で多く作り出されるため、特に腫瘍内では効果的に作用します。これによって、大量にネズミチフス菌を抱えた腫瘍細胞が自滅していくように仕掛けたわけです。

研究チームのRavi Bellamkonda氏は「外科的に除去が困難な腫瘍に送り込み、目的の作用を果たす細菌の設計作業は、非常に刺激的でした」と延べ、「役割を終えれば細菌は機能を停止するので、免疫的にも悪影響を起こしません。

実験では、細菌は効果的に"食料源"を食い尽くし、その後自然に作用は失われました」と説明しています。

ラットを使った実験では、治療に使用した個体の20%が100日(人間に換算すると10年)の間生存したとのこと。

もちろん人間でまったく同様の効果が得られるかはこれからの検証が必要ですが、もしラットと同様の効果があるとすれば、生存率は2倍以上にまで高められることになります。

膠芽腫の治療は患者にとっても非常に辛いものとなります。この新しい治療法の実用化にはまだ長い道のりがあるものの、今後の進捗に期待したいところです。 

Via: EurekAlert

Source: Duke University

Tumor-seeking salmonella treats brain tumors

New approach produces 20 percent survival rate in rat model where few typically live

Duke University

DURHAM, N.C. -- Biomedical engineers at Duke University have recruited an unlikely ally in the fight against the deadliest form of brain cancer -- a strain of salmonella that usually causes food poisoning.
Clinicians sorely need new treatment approaches for glioblastoma, the most aggressive form of brain cancer. The blood-brain barrier -- a protective sheath separating brain tissue from its blood vessels -- makes it difficult to attack the disease with drugs. It's also difficult to completely remove through surgery, as even tiny remnants inevitably spawn new tumors. Even with the best care currently available, median survival time is a dire 15 months, and only 10 percent of patients survive five years once diagnosed.
The Duke team decided to pursue an aggressive treatment option to match its opponent, turning to the bacterium Salmonella typhimurium. With a few genetic tweaks, the engineers turned the bacterium into a cancer-seeking missile that produces self-destruct orders deep within tumors. Tests in rat models with extreme cases of the disease showed a remarkable 20 percent survival rate over 100 days -- roughly equivalent to 10 human years -- with the tumors going into complete remission.
The results appeared online on December 21, 2016, 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 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, quite accidentally, that the presence of bacteria can cause the immune system to recognize and begin attacking tumors. However, 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.
Tumors just so happen to be an excellent source of purine, causing the bacteria to flock to them in droves.
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.
"A major challenge in treating gliomas is that the tumor is dispersed with no clear edge, making them difficult to completely surgically remove. So designing bacteria to actively move and seek out these distributed tumors, and express their anti-tumor proteins only in hypoxic, purine rich tumor regions is exciting," said Ravi Bellamkonda, Vinik Dean of Duke's Pratt School of Engineering and corresponding author of the paper. "And because their natural toxicity has been deactivated, they don't cause an immunological response. At the doses we used in the experiments, they were naturally cleared once they'd killed the tumors, effectively destroying their own food source."
The researchers tested the modified bacteria by injecting them directly into the rats' brains. While this may sound like an extreme delivery option, the first course of action usually performed with glioblastoma is to surgically remove the primary tumor, if possible, leaving the opportunity to directly deliver therapeutics.
The treatment worked in 20 percent of the rats, causing complete tumor regression and extending their lives by 100 days, which translates to roughly 10 human years.
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. "However, this was our first attempt at designing such a therapy, and there is some nuance to the specific model we used, thus more experiments are needed to know for sure."
The researchers now plan to program their bacteria to produce different drugs that cause stronger reactions in the tumors. These will be more difficult to implement, however, as other drugs are not as specific to tumor cells as those used in this study, making potential side effects more of a concern.

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This research was supported by the Ian's Friends Foundation, Ann Rankin Cowan, Children's Healthcare of Atlanta and Georgia Research Alliance.

"Bacterial Carriers for Glioblastoma Therapy." Nalini Mehta, Johnathan G. Lyon, Ketki Patil, Nassir Mokarram, Christine Kim, Ravi V. Bellamkonda. Molecular Therapy - Oncolytics, 2016. DOI: 10.1016/j.omto.2016.12.003