Abstract B263: Combined inhibition of cyclin-dependent kinases (Dinaciclib) and AKT (MK-2206) or ERK (SCH772984) dramatically blocks pancreatic tumor growth and metastases in patient-derived orthotopic xenograft models.
Authors: Hu Chaoxin , Dadon Tikva , Chenna Venugopal , Yabuuchi Shin , Bannerji Rajat , Booher Robert , Strack Peter , Samatar Ahmed , Azad Nilofer , Nelkin Barry D. , Maitra Anirban 
Published: August 2014

Abstract
Pancreatic cancer is among the deadliest of all solid malignances. The 5-year survival rate of pancreatic cancer remains below 5%, mainly due to a lack of early detection and the highly metastatic properties that make surgery impossible in most cases. Therefore, it is urgent to find effective systemic therapies to treat this highly metastatic cancer. KRAS is activated in the vast majority of cases of pancreatic cancer; unfortunately, therapeutic attempts to inhibit KRAS directly have been unsuccessful. Our previous studies showed that inhibition of cyclin-dependent kinase 5 (CDK5), using genetic manipulation or the CDK inhibitor Dinaciclib, reduces pancreatic cancer growth and progression, through blockage of the Ral effector pathway, downstream of KRAS. Since Ral has been shown to be a centrally important effector of KRAS signaling in pancreatic cancer, we hypothesized that simultaneous blockage of two major downstream KRAS effectors may further inhibit the growth and metastasis of pancreatic cancer and provide an effective therapeutic strategy for this disease.
In the current study, the therapeutic effects of combining the CDK inhibitor Dinaciclib with inhibitors of either the PI3K/AKT effector pathway (pan-AKT inhibitor MK2206) or the RAF/MEK/ERK effector pathway (ERK inhibitor SCH772984) were evaluated using two orthotopic patient-derived human pancreatic cancer xenograft models (Panc253 and Panc265). These models closely resemble the physiological and pathological conditions of pancreatic cancer in humans. A 2-3 mm3 tumor explant was implanted into the pancreas of nude mice and ultrasound imaging was used to measure the tumor size (3D) before randomization and treatment, which began when tumors grew to 50-100 mm3. The combination of Dinaciclib (20 mg/kg, i.p., t.i.w.) and MK2206 (60 mg/kg, p.o., t.i.w.) dramatically blocked tumor growth in the orthotopic Panc265 (90.0%, p&lt;0.001) and Panc253 (93.0%, p&lt;0.001) models versus control. It also significantly reduced the number of metastatic lesions in both Panc265 (88.2%, p&lt;0.001) and Panc253 (99.0%, p&lt;0.001) tumor models. Remarkably, complete responses were induced by the combination treatment of Dinaciclib and MK2206 in one mouse in the Panc265 tumor model, and in two mice in the Panc253 tumor model.
Similarly, the combination of Dinaciclib (20 mg/kg, i.p., t.i.w.) and SCH772984 (25 mg/kg, i.p., b.i.d.) dramatically inhibited the growth of primary orthotopic Panc265 (82.5%, p &lt; 0.001) and Panc253 (95.7%, p &lt;0.001) versus control, and also the number of metastatic lesions of both Panc265 (94.9%, p &lt;0.001) and Panc253 (92.4%, p &lt;0.02).
The striking results obtained in these models appear to validate our hypothesis that blocking multiple effector pathways downstream from KRAS, including the Ral effector pathway, may provide increased efficacy in pancreatic cancer. Thus, the combinations of Dinaciclib with the pan-AKT inhibitor MK2206 or the ERK inhibitor SCH772984 are novel, highly promising potential therapies against pancreatic cancer. Based on these data, an NCI-CTEP approved Phase I clinical trial for pancreatic cancer of the combination of Dinaciclib and MK2206 has now opened here at Johns Hopkins.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B263.
Citation Format: Chaoxin Hu, Tikva Dadon, Venugopal Chenna, Shin Yabuuchi, Rajat Bannerji, Robert Booher, Peter Strack, Ahmed Samatar, Nilofer Azad, Barry D. Nelkin, Anirban Maitra. Combined inhibition of cyclin-dependent kinases (Dinaciclib) and AKT (MK-2206) or ERK (SCH772984) dramatically blocks pancreatic tumor growth and metastases in patient-derived orthotopic xenograft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B263.