Preclinical data supports ongoing clinical trials testing IDO inhibitors as a treatment for lung tumours
Genetically-induced IDO deficiency reduced lung tumour burden and improved survival
- Date : 08 Aug 2012
- Topic : Lung and other thoracic tumours
Inhibitors of indoleamine 2,3-dioxygenase (IDO) are being assessed in clinical trials as a potential treatment for recurrent or refractory solid tumours. Clear genetic rationale for these trials, together with evidence that primary and metastatic lung tumours might be particularly susceptible to the drugs, is now reported in a preclinical study published in Cancer Discovery, a journal of the American Association for Cancer Research.
The reported data provide preclinical genetic validation for the ongoing clinical trials testing IDO inhibitors in cancer patients, according to Alexander Muller, PhD, associate professor at Lankenau Institute for Medical Research in Wynnewood, USA. The researchers also believe that their results indicate that these drugs could have particular impact in patients with lung adenocarcinoma and lung metastases, conditions for which there is a need for new therapeutic options.
The ongoing clinical trials were initiated based on pharmacological studies that indicated that IDO inhibitors can enhance the effectiveness of other therapies in mouse models of cancer. Genetic evidence to support the concept was lacking. Muller and his colleagues, therefore, set out to determine the effect of disrupting the IDO gene on tumour development in mice.
It was very important to use models of disease as physiologically relevant as possible. The researchers chose the KRAS-induced lung carcinoma model as a model of primary disease since tumours can be induced selectively in the lung and are driven by mutations in a gene known to be affected in approximately 20% of non-small cell lung cancers. They modelled metastatic disease using the 4T1 mouse breast cancer cell line, which very efficiently metastasises to the lung after being engrafted in the mammary glands of mice. This is one of only a few breast cancer models with the capacity to metastasise efficiently to sites affected in human breast cancer patients.
Genetically-induced IDO deficiency reduced lung tumour burden and improved survival in both models.
The genetic confirmation of the importance of IDO in lung tumour development is essential support for the clinical trials
The researchers are also hoping to garner insight into the mechanisms by which IDO impacts tumour development. In this regard, their findings linking IDO to increased vascularisation and modification of the inflammatory environment are critical. These data indicate that IDO has a far more expansive role in tumorigenesis than they might have thought.
Analysis of differences between the lungs of IDO-sufficient and -deficient tumour-bearing mice in the KRAS-induced lung carcinoma model revealed that levels of the pro-inflammatory molecule IL-6 were markedly lower in the absence of IDO. Levels of this known tumour-promoting factor were also lower in the model of metastasis when IDO was absent.
Additional work in the model of metastasis indicated that IDO-potentiated IL-6 production and promoted metastasis to the lung by driving the expansion and immunosuppressive function of a population of cells known as myeloid-derived suppressor cells. These cells are well-characterised, potent inhibitors of antitumour immune responses.
For the study team, it was very satisfying to be able to experimentally close the loop and clearly define a mechanism by which IDO promotes metastatic outgrowth to the lung, at least in the 4T1 breast cancer model. This mechanism might also have link with the vascular effects of IDO, since it promotes tumorigenesis in many different ways.
Muller has financial interests in the clinical development of IDO inhibitors for the purpose of treating cancer and other diseases.
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