Mechanistic studies of high-dose irradiation are important to improve our understanding on how the efficacy of stereotactically delivered high-dose irradiation can be enhanced by therapeutics such as ataxia-telangiesctasia–mutated (ATM) inhibitors. In this issue of Cancer Research, Torok and colleagues found that a single 15 Gy radiation dose eliminated lung tumor growth in mice when ATM was deleted in cancer cells versus when deleted in endothelial cells. These data support the establishment of clinical trials testing ATM inhibitors in combination with highly conformal radiotherapy or high-dose rate brachytherapy.
See related article by Torok et al., p. 773
In this issue of Cancer Research, Torok and colleagues (1) used dual recombinase technology in mouse lung cancer models to delete ataxia-telangiesctasia mutated (ATM), an enzyme involved in DNA damage repair following radiation. They found a substantial reduction in the growth of lung tumors treated with 15 Gy radiation when ATM was deleted compared with tumors without ATM deletion. Using the same approach, they deleted ATM in the tumor endothelium to determine whether this would yield similar results as those observed by deleting ATM in cancer cells. ATM deletion in the endothelium increased radiation-induced endothelial cell death; however, this did not result in a significant reduction of lung tumor growth. These findings indicate that deletion of ATM in cancer cells significantly impacts lung tumor growth compared with deletion of ATM in the tumor endothelium. It is important to note that in the mouse model used by Torok and colleagues, the tumors developed in both lungs, therefore the entire thorax was irradiated; the mice, however, did not die as a result of whole thorax irradiation (1). In addition, because both lungs required treatment, stereotactically delivered (precisely targeted) high-dose irradiation was not used in these experiments.
The dose of radiation used in this study is a single 15 Gy dose, which is an appropriately high-dose irradiation. The clinical significance of this high dose is that doses in the range of 10 to 20 Gy are commonly used to treat primary or metastatic lung cancer. Stereotactic body radiation therapy (SBRT), defined as the precise delivery of high doses of radiation treatment to a tumor, is highly effective in controlling lung cancer (2). Stage I lung cancer shows better local tumor control with stereotactically delivered high-dose irradiation compared with metastatic cancers, therefore metastatic cancers might benefit from the combination of high-dose irradiation with radiation-sensitizing drugs.
In a prior study, using a sarcoma model, the Kirsch lab showed a similar radiation-sensitizing effect following ATM deletion. Similar to the results in the current publication, in the sarcoma model, ATM deletion in the endothelium enhanced radiation-induced cytotoxicity in the endothelium but did not enhance tumor control. Utilizing an ATM-specific inhibitor, BEZ235, they showed that ATM inhibition enhanced the tumor growth delay following a single 20 Gy dose irradiation. The enhanced radiosensitivity was more specific to cancer as BEZ235 had minimal effect on normal tissue such as the heart (3).
The biological importance of the study by Torok and colleagues is that it further assesses the hypothesis that the microvasculature is a biological target of high-dose irradiation. There has been considerable debate in the literature regarding the importance of endothelial destruction following high-dose radiation (4). It should be noted that in the Torok and colleagues’ study, ATM deletion in the endothelium did not result in the complete absence of tumor growth delay; however, it was not significantly different from tumors without ATM deletion. The tumor growth delay observed with endothelium ATM deletion was less substantial compared with studies of radiation with antiangiogenic agents (5–7). Many molecular targets within the endothelium have been shown to enhance tumor growth delay; examples of radiosensitizers for the tumor endothelium include the VEGF receptor and Tie2 (8).
Torok and colleagues studied CD31, a specific endothelium marker (1). They did not study tumor perfusion or blood flow; therefore, it is unclear whether blood flow in these tumors was diminished following high-dose irradiation. In comparison, studies of antiangiogenic agents with radiation have shown reduced blood flow. Studies that have explored the importance of tumor vasculature during the radiation response have taken two other approaches; use of acid sphingomyelinase (ASMASE) and VEGF receptor inhibitors. ASMASE is an enzyme in the endothelium that contributes to cell death following radiation doses above 13 Gy (4). Mice lacking ASMASE had a lower tumor response to high-dose irradiation compared with wild-type mice, indicating that the endothelial response plays an important role in tumors treated with radiation. Importantly, ASMASE studies did not add radiation-sensitizing agents such as ATM inhibitors, but studied the effects of high-dose radiation alone. Other studies have utilized VEGF receptor inhibitors and demonstrated enhanced tumor control in mouse cancer models treated with low-dose irradiation (5).
Torok and colleagues demonstrated that deletion of ATM in the endothelium resulted in vascular destruction (1). Concerns about destruction of tumor blood vessels are related to tumor blood perfusion including reduced drug and oxygen delivery to the tumor during radiotherapy. One other consideration is a reduction in the ability of immune effector cells to access irradiated tumors. This is important given that clinical trials of SBRT combined with immunotherapy have shown promising results (9). It is not known whether the destruction of tumor vascular endothelium by inhibiting ATM would impede the efficacy of combined SBRT and immunotherapy.
High doses of radiation are administered to a large percentage of patients with cancer. The clinical success has been due to the accuracy and conformality of newer radiotherapy procedures that limit the dose of radiation to surrounding normal tissues. The study by Torok and colleagues supports an exciting new strategy for the development of molecularly targeted radiation sensitizers when high-dose irradiation is administered (1). Examples of conditions where high-dose radiation is used include oligometastases, defined as few metastatic sites (10). These are treated with high single dose stereotactic irradiation, and could benefit from radiosensitizing ATM inhibition. Another example is high-dose rate brachytherapy, which is given to many cancer subtypes such as cervical cancer. Brachytherapy delivery of radiation requires the placement of high-dose rate radiation devices into the center of the cancer, thereby limiting the dose to the surrounding tissues. This very brief pulse of radiation is well-suited for intravenous administration of radiation-sensitizing drugs such as ATM inhibitors.
Disclosure of Potential Conflicts of Interest
D.E. Hallahan is a department head at Washington University, reports receiving a commercial research grant from Pfizer, and has ownership interests in MedGYde and Cumberland Pharmaceuticals.