Recent studies suggest a positive correlation between glycogen synthase kinase-3 (GSK-3) activation and tumor growth. Currently, it is unclear how both Akt that inhibits GSK-3 and active GSK-3 are maintained concurrently in tumor cells. We investigated the role of GSK-3 and the existence of an Akt-resistant pathway for GSK-3 activation in prostate cancer cells. Our data show that Src, a non-receptor tyrosine kinase is responsible for Y216GSK-3 phosphorylation leading to its activation even when Akt is active. Experiments involving mouse embryonic fibroblasts lacking cSrc, Yes and Fyn, as well as Src activity modulation in prostate cancer cells with constitutively active (CA-Src) and dominant negative Src (DN-Src) plasmids demonstrated the integral role of Src in Y216GSK-3 phosphorylation and activity modulation. Inhibition of GSK-3 with SB415286 in PC3 cells resulted in impaired motility, proliferation and colony formation. Treatment of PC3 cells with the Src inhibitor dasatinib reduced Y216GSK-3 phosphorylation and inhibited proliferation, invasion and micrometastasis in vitro. Dasatinib treatment of athymic nude mice resulted in impaired growth of PC3 cell tumor xenograft. Together, we provide novel insight into the Src-mediated Y216GSK-3 phosphorylation and activation in prostate cancer cells and reveal the potential benefits of targeting Src-GSK-3 axis using drugs such as dasatinib.

Romiplostim, a thrombopoietin mimetic, is FDA approved for the treatment of thrombocytopenia in patients with refractory immune thrombocytopenia. Given the success of thrombopoietin agonists in the treatment of immune thrombocytopenia, data in other clinical settings are emerging. In the bone marrow transplant setting, secondary failure of platelet recovery and persistent thrombocytopenia are associated with increased mortality. In this case, romiplostim was attempted in a chronic lymphocytic leukemia patient who underwent a matched, unrelated donor, non-myeloablative stem cell transplant. This patient experienced profound thrombocytopenia despite dose escalation. Anti-thrombopoietin or anti-romiplostim antibodies were not detected by specific assays. Furthermore, the patient remains in disease remission with full chimerism. This case demonstrates that heavily pre-treated patients with limited bone marrow reserve may not respond to thrombopoietin agonists.

The development of imatinib has revolutionized the treatment of chronic myeloid leukemia. Follow-up analysis of IRIS trial participants continues to demonstrate durable responses for imatinib at 400 mg/day. However, 10%–15% of patients with chronic myeloid leukemia will become imatinib-resistant or intolerant of adverse events. Phase II studies have shown that most of these patients will respond to second-generation tyrosine kinase inhibitors, such as nilotinib, dasatinib, and bosutinib. Both nilotinib and dasatinib have recently demonstrated clinical efficacy as frontline therapy in Phase III studies. In the ENESTnd trial, nilotinib 600–800 mg/day produced significantly higher major molecular rates and complete cytogenetic response rates in comparison with imatinib at 12 months. Recently, 18-month follow-up analysis of this trial continues to demonstrate superiority for nilotinib. It is unknown whether this will ultimately translate into improved long-term outcomes, such as event-free survival or overall survival. Nilotinib continues to be generally well tolerated and tends to produce less Grade 3/4 toxicity in frontline therapy when compared with its use following imatinib failure. With three tyrosine kinase inhibitors for potential frontline therapy and an active drug discovery pipeline, treatment for chronic myeloid leukemia is still subject to change with time as clinical algorithms continue to evolve.

Abstract:The development of imatinib has revolutionized the treatment of chronic myeloid leukemia. Follow-up analysis of IRIS trial participants continues to demonstrate durable responses for imatinib at 400 mg/day. However, 10%-15% of patients with chronic myeloid leukemia will become imatinib-resistant or intolerant of adverse events. Phase II studies have shown that most of these patients will respond to second-generation tyrosine kinase inhibitors, such as nilotinib, dasatinib, and bosutinib. Both nilotinib and dasatinib have recently demonstrated clinical efficacy as frontline therapy in Phase III studies. In the ENESTnd trial, nilotinib 600-800 mg/day produced significantly higher major molecular rates and complete cytogenetic response rates in comparison with imatinib at 12 months. Recently, 18-month follow-up analysis of this trial continues to demonstrate superiority for nilotinib. It is unknown whether this will ultimately translate into improved long-term outcomes, such as event-free survival or overall survival. Nilotinib continues to be generally well tolerated and tends to produce less Grade 3/4 toxicity in frontline therapy when compared with its use following imatinib failure. With three tyrosine kinase inhibitors for potential frontline therapy and an active drug discovery pipeline, treatment for chronic myeloid leukemia is still subject to change with time as clinical algorithms continue to evolve.