Kinase inhibitor may prevent RT-induced lung injury

December 1, 2007

A new oral kinase inhibitor that targets the transforming growth factor-beta (TGF-b) receptor reduced radiation-induced lung injury in a preclinical model

LOS ANGELES—A new oral kinase inhibitor that targets the transforming growth factor-beta (TGF-b) receptor reduced radiation-induced lung injury in a preclinical model, Mitchell S. Anscher, MD, reported at the plenary session of this year's ASTRO meeting (abstract 5).

TGF-b has multiple activities that may promote the development of lung injury after radiation therapy, and these activities are initiated by binding of the molecule to its receptors, said Dr. Anscher, a radiation oncologist at Virginia Commonwealth University.

Animal study of SM16

The study tested the effectiveness of SM16, a novel oral kinase inhibitor that interferes with the binding of TGF-b to its type 1 receptor. The agent is under development by Biogen Idec. The researchers divided 112 Sprague-Dawley rats into 8 groups of 14 rats each:

• Three groups did not receive any radiation; according to group, these rats were fed control chow, chow with low-dose SM16, or chow with high-dose SM16 for their lifespan.

• Five groups received a single fraction of 28 Gy to the right hemithorax; according to group, these rats were fed control chow; chow with low-dose or high-dose SM16 for their lifespan; or chow with low-dose or high-dose SM16 for 3 weeks, with a return to control chow thereafter. The drug-containing chow was started 7 days before radiation.

Body weight over time, a measure of drug toxicity, was similar across groups, with the exception of a lower weight in irradiated rats fed control chow, Dr. Anscher said.

Breathing frequency, a measure of impaired lung function, was significantly lower, by about 15%, between weeks 10 and 22 after radiation in the irradiated rats fed high-dose SM16 than in their irradiated counterparts fed control chow; short-term feeding with the high dose was associated with a smaller, nonsignificant reduction.

In addition, at 6 months, compared with the irradiated control rats, the irradiated rats fed high-dose SM16 for the long term had levels of lung injury and TGF-b activation that were significantly lower, by roughly 35% to 50%.

Specifically, the high-dose SM16 group had less lung damage as assessed by architecture and collagen deposition in histologic sections; less macrophage activity, as assessed by ED1 staining; less TGF-b-1 activity; less staining for integrin (an activator of TGF-b in the lung); less free radical production, as assessed by 8-hydroxyguanosine staining; and less activation of TGF-b signaling, whether assessed by smad 3 staining or by staining for the active (phosphorylated) form, p-smad 2/3.

Rats fed SM16 for the long term but with the low dose had smaller reductions in these measures of lung injury and TGF-b activation, and most of the differences compared with controls were not significant.

Similarly, rats fed SM16 for the short term only, regardless of whether they received the high dose or the low dose, had smaller and generally nonsignificant reductions in these measures.

Does not promote tumor growth

Research thus far suggests that SM16 does not promote tumor cell growth, Dr. Anscher said. "Most tumor epithelial cells are no longer responsive to the growth inhibitory effects of TGF-b, so that the presence of TGF-b in most cell types actually is a growth stimulatory phenomenon," he explained. "We have observed that SM16 actually has a growth inhibitory effect on the tumor cell lines we've tested."

Summing up, Dr. Anscher said, "Oral administration of the anti-TGF-b type 1 receptor kinase SM16 reduces all measures of lung injury in this animal model—there is less lung damage, there is less fibrosis, there is less of an inflammatory response, less activation of TGF-b, and less transduction of the signaling pathway." He added that the data also suggest that response varies with both dose and duration of treatment.

"I hope you'll all agree with me that targeting the TGF-b pathway may be an effective strategy to try to either prevent or ameliorate radiation-induced lung injury," he commented.

Clinical development

Clinical development of SM16 is planned, Dr. Anscher said. However, he noted that studies of radiation-induced lung injury in the lung cancer population can be difficult, while the incidence of this outcome in the non-lung-cancer population is so low that many patients would be needed.

"I think one of the ways that this might be moved forward into the clinic is to try to identify whether it could be used once people become symptomatic, and that may alleviate the need for such an enormous study with a large group of patients," he said.

In the end, he noted, "that is really the group we want to try and help, the ones we think may be developing symptoms from radiation injury."