Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970.

Platinum-based DNA-damaging chemotherapy is standard-of-care for most patients with lung cancer but outcomes remain poor. This has been attributed, in part, to the highly effective repair network known as the DNA-damage response (DDR). ATR kinase is a critical regulator of this pathway, and its inhibition has been shown to sensitize some cancer, but not normal, cells in vitro to DNA damaging agents. However, there are limited in vivo proof-of-concept data for ATR inhibition. To address this we profiled VX-970, the first clinical ATR inhibitor, in a series of in vitro and in vivo lung cancer models and compared it with an inhibitor of the downstream kinase Chk1. VX-970 markedly sensitized a large proportion of a lung cancer cell line and primary tumor panel in vitro to multiple DNA damaging drugs with clear differences to Chk1 inhibition observed. In vivo VX-970 blocked ATR activity in tumors and dramatically enhanced the efficacy of cisplatin across a panel of patient derived primary lung xenografts. The combination led to complete tumor growth inhibition in three cisplatin-insensitive models and durable tumor regression in a cisplatin-sensitive model. These data provide a strong rationale for the clinical evaluation of VX-970 in lung cancer patients.

Combination of radiation and burn injury alters [¹8F] 2-fluoro-2-deoxy-D-glucose uptake in mice.

Radiation exposure and burn injury have both been shown to alter glucose utilization in vivo. The present study was designed to study the effect of burn injury combined with radiation exposure on glucose metabolism in mice using [¹8F] 2-fluoro-2-deoxy-D-glucose (¹8FDG). Groups of male mice weighing approximately 30 g were studied. Group 1 was irradiated with a ¹³7Cs source (9 Gy). Group 2 received full thickness burn injury on 25% TBSA followed by resuscitation with saline (2 ml, IP). Group 3 received radiation followed 10 minutes later by burn injury. Group 4 were sham-treated controls. After treatment, the mice were fasted for 23 hours and then injected (IV) with 50 µCi of ¹8FDG. One hour postinjection, the mice were sacrificed, and biodistribution was measured. Positive blood cultures were observed in all groups of animals compared to the shams. Increased mortality was observed after 6 days in the burn plus radiated group as compared to the other groups. Radiation and burn treatments separately or in combination produced major changes in ¹8FDG uptake by many tissues. In the heart, brown adipose tissue, and spleen, radiation plus burn produced a much greater increase (P < .0001) in ¹8FDG accumulation than either treatment separately. All three treatments produced moderate decreases in ¹8FDG accumulation (P < .01) in the brain and gonads. Burn injury, but not irradiation, increased ¹8FDG accumulation in skeletal muscle; however, the combination of burn plus radiation decreased ¹8FDG accumulation in skeletal muscle. This model may be useful for understanding the effects of burns plus irradiation injury on glucose metabolism and in developing treatments for victims of injuries produced by the combination of burn plus irradiation.