A Small Molecular Inhibitor of TGFß Protects Against the Development of Radiation Induced Lung Injury
Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 30, 2007
Presenter: Mitchell S. Anscher, MD Presenter's Affiliation: Virginia Commonwealth University Medical Center, Richmond, VA Type of Session: Plenary
One of the primary limitations that inhibits dose escalation in the treatment of lung cancer is the risk of pulmonary toxicity, such as pulmonary fibrosis. Finding new agents to prevent or treat pulmonary fibrosis could mitigate this dose limiting toxicity perhaps improving outcomes by allowing more dose to be given.
Transforming Growth Factor b (TGFb) is a key cytokine which appears to be involved in the development of pulmonary fibrosis.
TGFb is known to play a role in promoting deposition of connective tissue and inhibiting the break down of connective tissues. It has also been linked to immunosupression and to promote angiogenesis and metastasis.
TGFb is secreted in an inactive form and can be activated by proteases, integrins and free radicals (such as those created by radiation).
The present study examines whether the use of an inhibitor to bind TGFb can inhibit pulmonary fibrosis in a mouse model.
Materials and Methods
112 Sprague-Dawley rats were divided into eight groups of 14. The groups were as follows:
Low dose chow
High dose chow
Low dose chow
High dose chow
Radiation with 3 weeks of SM16
The TGFb inhibitor SM16 was mixed into the rat chow at doses of 0.07 g/kg (low dose) and 0.15 g/kg (high dose). Rats were started on the SM16 chow seven days prior to radiation. SM16 was given ad libitum aside from those in the group with short term SM16 treatment (3 week group).
On days seven and 14 plasma levels of SM16 were checked.
All rats received 28 Gy of radiation to the right hemithorax or sham radiation using 135 kV x-rays.
In each group seven animals were sacrificed at 6 weeks and seven at 26 weeks after radiation.
Toxicity was assessed by:
Body weight every two weeks
Breathing rate every two weeks
Assay for inflammatory cells
Expression and activation of TGFb
There was a significantly lower body weight in mice treated with radiation alone compared with those treated with the indefinite high dose SM16 with radiation (p<0.05 for weeks 3-26) and those receiving the high dose SM16 for 3 weeks after radiation (p<0.05 for weeks 1-26).
There was no significant difference in body weight for the remaining groups.
Average breathing frequency:
The average breathing frequencies of irradiated rats in the indefinite high dose SM16 group was significantly lower than the rats which received radiation alone for weeks 10-22 (p<0.05).
Average breathing frequency for rats treated with indefinite low dose SM16 demonstrated significantly lower breathing frequency than rats receiving radiation alone on weeks 10, 14, and 22 (p<0.05).
Histology specimens collected at 26 weeks demonstrated:
Irradiated rats treated with indefinite high dose SM16 had significantly less lung fibrosis (p=0.016), TGFb activity (p=0.011) and inflammatory response (p=0.006).
The low dose SM16 group and rats only treated for three weeks of high dose SM16 therapy had significant differences compared with the radiated controls in some histological categories such as TGFb pathway activation, macrophage activity, and free radical production. However none of these differences were as significant as those mice treated with the indefinite high dose SM16 therapy.
Oral administration of SM16 decreased all measures of lung damage and there appears to be a dose response.
The length of administration appears to be important with longer treatment leading to better outcomes.
SM16 has the potential to be an agent for the use of prevention and treatment of pulmonary fibrosis.
The authors are interested in conducting clinical trials with this agent. However, the number of patients who would have to take the drug to demonstrate a difference in pulmonary fibrosis rates would be large (due to the infrequent incidence of pulmonary fibrosis). Therefore the authors purpose that SM16 be used to treat patients who already have pulmonary fibrosis.
Because prognosis is so grim in advanced lung cancer, dose escalation is of great interest. However, often times the volumes that need to be treated are large and the patients have poor lung function impairing the ability to treat these patients definitively. This compound may prevent pulmonary fibrosis, allowing more dose and larger areas of lung to be treated.
Plasma levels of TGFb may be a useful marker to determine the risk of developing pulmonary fibrosis. The authors state that it appears to be a difficult marker to use, however, if the TGFb level is high and the patient is symptomatic, they may be most likely to benefit from TGFb treatment.
Clearly further clinical trials are needed prior to this compound playing a role in the clinic. Further preclinical studies to clarify whether the drug is preventing or treating the pulmonary fibrosis would help define how to use this drug better in a clinical trial.
Partially funded by an unrestricted educational grant from Bristol-Myers Squibb.