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A Phase I Study of Dinaciclib in Combination With MK-2206 in Patients With Advanced Pancreatic Cancer
Adrian G Murphy1, Marianna Zahurak2, Mirat Shah1
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Abstract:
The combination of drugs targeting Ral and PI3K/AKT signaling has antitumor efficacy in preclinical models of pancreatic cancer. We combined dinaciclib (small molecule cyclin dependent kinase inhibitor with MK-2206 (Akt inhibitor) in patients with previously treated/metastatic pancreatic cancer. Patients were treated with dinaciclib (6-12 mg/m2 i.v.) and MK-2206 (60-135 mg p.o.) weekly. Tumor biopsies were performed to measure pAKT, pERK, and Ki67 at baseline and after one completed cycle (dose level 2 and beyond). Thirty-nine patients participated in the study. The maximum tolerated doses were dinaciclib 9 mg/m2 and MK-2206 135 mg. Treatment-related grade 3 and 4 toxicities included neutropenia, lymphopenia, anemia, hyperglycemia, hyponatremia, and leukopenia. No objectives responses were observed. Four patients (10%) had stable disease as their best response. At the recommended dose, median survival was 2.2 months. Survival rates at 6 and 12 months were 11% and 5%, respectively. There was a nonsignificant reduction in pAKT composite scores between pretreatment and post-treatment biopsies (mean 0.76 vs. 0.63; P = 0.635). The combination of dinaciclib and MK-2206 was a safe regimen in patients with metastatic pancreatic cancer, although without clinical benefit, possibly due to not attaining biologically effective doses. Given the strong preclinical evidence of Ral and AKT inhibition, further studies with better tolerated agents should be considered.
Insights
This study combined dinaciclib and MK-2206 for pancreatic cancer, finding the regimen safe but lacking clinical benefit. Further research with better tolerated agents is recommended for Ral and AKT pathway inhibition.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Preclinical models show that combining drugs targeting Ral and PI3K/AKT signaling pathways yields antitumor effects in pancreatic cancer.
- Pancreatic cancer remains a significant health challenge with limited effective treatment options.
Purpose of the Study:
- To evaluate the safety and efficacy of combining dinaciclib (a cyclin-dependent kinase inhibitor) with MK-2206 (an Akt inhibitor) in patients with previously treated or metastatic pancreatic cancer.
Main Methods:
- A phase I/II clinical trial involving 39 patients with metastatic pancreatic cancer.
- Patients received weekly intravenous dinaciclib and oral MK-2206.
- Tumor biopsies were analyzed for pAKT, pERK, and Ki67 expression at baseline and after treatment.
Main Results:
- The maximum tolerated doses were determined to be dinaciclib 9 mg/m² and MK-2206 135 mg.
- The combination was generally safe, with toxicities including neutropenia, lymphopenia, and hyperglycemia.
- No objective responses were observed; the best response was stable disease in 10% of patients. Median survival was 2.2 months.
Conclusions:
- The combination of dinaciclib and MK-2206 is a safe regimen for metastatic pancreatic cancer but did not demonstrate clinical benefit.
- Lack of clinical benefit may be due to insufficient biologically effective doses.
- Further investigation with more tolerable agents targeting Ral and AKT pathways is warranted based on preclinical data.
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