Navigation Links
Preclinical data support ongoing clinical trials testing IDO inhibitors as a treatment for cancer
Date:7/19/2012

PHILADELPHIA Inhibitors of indoleamine 2,3-dioxygenase (IDO) are being assessed in clinical trials as a potential treatment for recurrent or refractory solid tumors. Clear genetic rationale for these trials, together with evidence that primary and metastatic lung tumors 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.

"Our data provide preclinical genetic validation for the ongoing clinical trials testing IDO inhibitors in cancer patients," said Alexander Muller, Ph.D., associate professor at Lankenau Institute for Medical Research in Wynnewood, Pa. "We also believe that our results indicate that these drugs could have particular impact in patients with lung adenocarcinoma and lung metastases, conditions for which there is an urgent, unmet 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 tumor development in mice.

"It was very important to us to use models of disease as physiologically relevant as possible," he said. "We chose the KRAS-induced lung carcinoma model as our model of primary disease since tumors can be induced selectively in the lung and are driven by mutations in a gene known to be affected in approximately 20 percent of nonsmall cell lung cancers. We modeled metastatic disease using the 4T1 mouse breast cancer cell line, which very efficiently metastasizes 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 metastasize efficiently to sites affected in human breast cancer patients."

Genetically-induced IDO deficiency reduced lung tumor burden and improved survival in both models.

"This genetic confirmation of the importance of IDO in lung tumor development is essential support for the clinical trials," said Muller. "However, we were also hoping to garner insight into the mechanisms by which IDO impacts tumor development. In this regard, our findings linking IDO to increased vascularization and modification of the inflammatory environment are critical. These data indicate that IDO has a far more expansive role in tumorigenesis than we might have thought."

Analysis of differences between the lungs of IDO-sufficient and -deficient tumor-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 tumor-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 (MDSCs). MDSCs are well-characterized, potent inhibitors of antitumor immune responses.

"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," said Muller. "We think that this mechanism might also link with the vascular effects of IDO. IDO promotes tumorigenesis in many different ways, and we are looking to see if we can take clinical advantage of some of these."

Muller has financial interests in the clinical development of IDO inhibitors for the purpose of treating cancer and other diseases.


'/>"/>

Contact: Jeremy Moore
Jeremy.Moore@aacr.org
215-446-7109
American Association for Cancer Research
Source:Eurekalert

Related medicine news :

1. Supporting LGB children may influence their long-term health, BU study finds
2. International breast health global summit will focus on supportive care and quality of life
3. Americans Support Medicare Reform, But Not on Their Dime: Poll
4. Decision support system translates into high percentage of positive chest CT examinations
5. More cutting-edge cancer research supported by industry
6. Study Supports Value of Sigmoidoscopy, an Alternative to Colonoscopy
7. Behavioral support from peers, staff lowers patients blood pressure
8. Study supports urate protection against Parkinsons disease, hints at novel mechanism
9. The W3 Project Receives Support from Doulton for Emergency Relief Efforts
10. Dietary fiber alters gut bacteria, supports gastrointestinal health
11. Narconon Louisiana Supports United Nations International Day Against Drug Abuse and Illicit Trafficking
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:1/16/2017)... , ... January 16, 2017 , ... Gym Source, America’s ... a new showroom in East Hanover, New Jersey. , “We are elated to be ... new innovative in-store concept is designed to give clients a seamless and motivating shopping ...
(Date:1/16/2017)... (PRWEB) , ... January 16, 2017 , ... ... office , Antoine Dental Center, is currently offering complimentary consultations and financing for ... their teeth examined for bite irregularities and learn about their orthodontic options. Walk-in, ...
(Date:1/16/2017)... ... January 16, 2017 , ... Atlanta-based incentive company ... in the wheelchair accessibility industry, BraunAbility . Incentive Solutions will provide BraunAbility ... accessible vehicles. With this new incentive plan, BraunAbility plans to continue their tradition ...
(Date:1/16/2017)... ... January 16, 2017 , ... In ... education and high-level training standards to an international multidisciplinary group of healthcare treatment ... As a way to further its mission at the grassroots level, iaedp launched ...
(Date:1/16/2017)... ... January 16, 2017 , ... NexTec Group has been ... of 100 organizations honored for their accomplishments in the field of midmarket financial software. ... leadership and recognition, and innovation. Selection is not based on revenue and those firms ...
Breaking Medicine News(10 mins):
(Date:1/17/2017)... , January 17, 2017 - First ... MENA healthcare market expected to grow by a CAGR of ... Holding, the Qatari holding company which operates globally across a number ... achieved a number of notable successes and is well-positioned for further ... ...
(Date:1/16/2017)... -- Summary GlobalData,s new report, "North ... market data on the North America Bone Densitometers market. ... volume (in units) and average prices (USD) within market ... Ultrasound (QUS). The report also provides company shares ... segements, and global corporate-level profiles of the key market ...
(Date:1/16/2017)... Derek H. Potts , founder and ... appointed Liaison Counsel in California,s ... In this role, Potts was assigned to serve as ... the Court and Co Lead Plaintiff,s Counsel. Co-Counsel includes ... Fairchild & Wade and Ruth Rizkalla ...
Breaking Medicine Technology: