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Dinaciclib potential inhibitor of tumor growth in pancreatic cancer
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The novel agent dinaciclib demonstrated activity in xenographic models against the RAS pathway of the KRAS mutation associated with pancreatic cancer, according to study results presented at the International Congress on Molecular Targets and Cancer Therapeutics.
More than 90% of pancreatic cancer tumors exhibit mutated KRAS, although there is not yet a target active against this mutation, lead researcher Barry Nelkin, PhD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University said during a press conference.
“The primary strategy has been to target KRAS downstream signaling,” Nelkin said. “KRAS activates three major signaling pathways: RAF, PI3K and RAL. There are excellent inhibitors for the PI3K and MET pathways, and many of them are in clinical use or development. Unfortunately, there’ve been no effective inhibitors for RAL … [which is] centrally important for pancreatic cancer.”
Nelkin and colleagues found that by blocking the protein CDK5, they were able to also inhibit RAL activity.
They evaluated dinaciclib (SCH727965, Selleckchem) — a CDK5 inhibitor in clinical development — in combination with the pan-AKT inhibitor MK-2206 and the ERK inhibitor SCH772984 in two orthotopic patient-derived human pancreatic cancer xenograft models, Panc265 and Panc253.
Dinaciclib plus MK-2206 proved considerably more effective than controls at blocking tumor growth (Panc265, 90%; P<.001; Panc253, 93%; P<.001). The combination also reduced metastatic lesions (Panc265, 88.2%; P<.001; Panc253, 99%; P<.001).
Researchers reported three complete responses, one in the Panc265 tumor model and two in the Panc253 tumor model.
Combination treatment with dinaciclib and SCH772984 also inhibited tumor growth (Panc265, 82.5%; P<.001; Panc253, 95.7%; P<.001) and metastases (Panc265, 94.9%; P<.001; Panc253, 92.4%; P<.02). However, researchers observed no complete responses after this treatment.
“We found a therapeutically feasible way to inhibit the important RAL pathway downstream of KRAS by pharmacologic inhibition by dinaciclib,” Nelkin said. “The combinations of dinaciclib with either the AKT inhibitor MK2206 or ERK inhibitor SCH772984 were especially effective in xenograft models of pancreatic cancer.”
Based on these data, researchers have proceeded with a multicenter clinical trial designed to evaluate dinaciclib plus MK2206 in patients with pancreatic cancer, Nelkin said.
For more information:
Nelkin BD. Abstract #B263. Presented at: International Conference on Molecular Targets and Cancer Therapeutics; Oct. 19-23; Boston, Mass.
Disclosure: The researchers report no relevant financial disclosures.