Waldenstrom Macroglobulinemia (WM) remains incurable with a median overall survival of 5-6 years, and most patients succumb to disease progression. Therefore, there is a strong rationale for novel therapies that target aberrant molecular pathways in WM. The PI3K/AKT pathway acts as a critical regulator of apoptosis, cell cycle regulation, and tumor proliferation in many lymphoproliferative malignancies. In addition, the PI3K pathway regulates migration and trafficking in lymphocytes indicating that it may regulate homing in WM. Our preliminary data demonstrate that members of the PI3K pathway are upregulated in WM cells as compared to normal control. Downregulation of AKT by a novel therapeutic agent, Perifosine leads to significant inhibition of proliferation and induction of apoptosis in WM cells in vitro. In addition, our data demonstrate that perifosine inhibits migration and adhesion of WM cells in vitro and homing in vivo. Based on these findings, we propose to study this novel agent in a phase II study along with carefully designed translational research studies. We hypothesize that the AKT inhibitor perifosine will increase the overall response rate in patients with relapsed/refractory WM, and have a significant inhibitory effect on homing and adhesion of WM cells to the bone marrow microenvironment. We will study this hypothesis in 3 specific aims.
Aim 1 is to determine the safety, tumor response rate, and duration of response for the AKT inhibitor, perifosine in patients with relapsed/refractory WM.
Aim 2 is to determine the mechanisms of response/resistance to perifosine in vivo, and Aim 3 is to determine the role of the PI3K/AKT pathway in the regulation of migration and adhesion in WM. These studies will help define the role of the PI3K/AKT pathway in WM and allow the design of future therapeutic trials targeting this pathway, and combinations of agents with other novel targeted agents. ? ? ?
| Agarwal, Amit; Ghobrial, Irene M (2013) The bone marrow microenvironment in Waldenstrom macroglobulinemia. Clin Lymphoma Myeloma Leuk 13:218-21 |
| Leblebjian, Houry; Agarwal, Amit; Ghobrial, Irene (2013) Novel treatment options for Waldenstrom macroglobulinemia. Clin Lymphoma Myeloma Leuk 13 Suppl 2:S310-6 |
| Issa, Ghayas C; Ghobrial, Irene M; Roccaro, Aldo M (2011) Novel agents in Waldenstrom macroglobulinemia. Clin Investig (Lond) 1:815-824 |
| Ghobrial, Irene M; Zhang, Yong; Liu, Yang et al. (2011) Targeting the bone marrow in Waldenstrom macroglobulinemia. Clin Lymphoma Myeloma Leuk 11 Suppl 1:S65-9 |
| Sacco, Antonio; Leleu, Xavier; Rossi, Giuseppe et al. (2010) Novel agents in Waldenstrom Macroglobulinemia. Open J Hematol 1: |
| Ghobrial, Irene M; Roccaro, Aldo; Hong, Fangxin et al. (2010) Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia. Clin Cancer Res 16:1033-41 |
| Roccaro, Aldo M; Sacco, Antonio; Aujay, Monette et al. (2010) Selective inhibition of chymotrypsin-like activity of the immunoproteasome and constitutive proteasome in Waldenstrom macroglobulinemia. Blood 115:4051-60 |
| Roccaro, Aldo M; Sacco, Antonio; Husu, Emanuel N et al. (2010) Dual targeting of the PI3K/Akt/mTOR pathway as an antitumor strategy in Waldenstrom macroglobulinemia. Blood 115:559-69 |
| Stedman, Jennifer; Roccaro, Aldo; Leleu, Xavier et al. (2010) New Therapeutic Approaches for Waldenstrom Macroglobulinemia. Drugs Future 35:53-58 |
| Ghobrial, Irene M; Gertz, Morie; Laplant, Betsy et al. (2010) Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenstrom macroglobulinemia. J Clin Oncol 28:1408-14 |
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