Sorafenib and radiation: A promising combination in colorectal and pancreas cancer

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Author(s): G. D. Wilson, A. Suen, J. Robertson, S. Galoforo, B. Marples; William Beaumont Hospital, Royal Oak, MI
Background: Sorafenib inhibits both RAF kinase, a critical component of the RAS/RAF/MEK/ERK signaling pathway that controls cell proliferation, and VEGFR-2/PDGFR-beta signaling cascade, blocking tumor angiogenesis; this dual activity has great potential for radiosensitization. This study examines the effectiveness of radiation and sorafenib in a series of human colorectal and pancreatic cell lines and xenografts with differing ras mutational status.
Methods: Three colorectal cell lines were selected. HT29 and SW48 are wild-type ras whilst SW480 has a mutation in codon 12 . Two pancreatic cancer cell lines were selected, Panc 03.27 is wild-type ras whilst Panc 02.03 has a mutation in codon 12. MTT assays were used to find the best drug concentration and timing to combine with radiation. Radiosensitization was assayed using clonogenic assays with either 5 or 10µg/ml sorafenib. Xenografts were established and randomized to control, sorafenib at 20mg/kg daily (5 days/week) for 3 weeks, radiation given as 2.5 Gy daily fractions (5 days/week) for 3 weeks or a combination of the two with sorafenib administered immediately after radiation
Results: The MTT data suggested that sorafenib given immediately after or at least within 2 hours of radiation appeared to give the greatest growth inhibition. Sorafenib had no effect on cell survival in the colorectal cell lines but showed a modest radiosensitization, the surviving fractions at 2 Gy alone or with 5 or 10 µg/ml sorafenib were 34%, 26% and 23% (p=0.0018) in SW48 cells. In pancreatic cells, sorafenib was toxic at 10 µg/ml and reduced survival by 30% at 5 µg/ml without sensitization The endpoint in the xenograft studies was tumor growth to 2000mm3 within a period of 120 days. In SW48 tumors, the number of days to grow to 2,000 mm3 was 13.6 ± 2.2 in the control arm, 37.0 ± 21.2 in the radiation alone arm, 17.0 ± 8.2 in the sorafenib arm and100.8 ± 28.0 in the combined arm (2 of the 5 animals were 'cured'). The respective data in the HT29 xenografts was13.2 ± 2.1, 62.6 ± 9.8, 38.2 ± 26.5 and106.2 ± 36.2 days (3 of 5 animals were 'cured'.
Conclusions: Sorafenib and radiation are a promising combination. Phase I studies are under development in both pancreatic and colorectal cancer at our Instittution.