Regulation of the P13K/AKT pathway in Waldenstrom Macroglobulinemia

Summary

Principal Investigator: Irene M Ghobrial
Abstract: [unreadable] DESCRIPTION (provided by applicant): 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. [unreadable] [unreadable] [unreadable]
Funding Period: 2007-06-01 - 2009-05-30
more information: NIH RePORT

Top Publications

  1. pmc The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia
    Xavier Leleu
    Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
    Blood 110:4417-26. 2007
  2. pmc Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenstrom macroglobulinemia
    Irene M Ghobrial
    Dana Farber Cancer Center, Boston, MA, USA
    J Clin Oncol 28:1408-14. 2010
  3. pmc Dual targeting of the PI3K/Akt/mTOR pathway as an antitumor strategy in Waldenstrom macroglobulinemia
    Aldo M Roccaro
    Medical Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA
    Blood 115:559-69. 2010
  4. pmc Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia
    Irene M Ghobrial
    Dana Farber Cancer Institute, Boston, MA, USA
    Clin Cancer Res 16:1033-41. 2010
  5. pmc Targeting the bone marrow in Waldenstrom macroglobulinemia
    Irene M Ghobrial
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA
    Clin Lymphoma Myeloma Leuk 11:S65-9. 2011
  6. pmc The bone marrow microenvironment in Waldenström macroglobulinemia
    Amit Agarwal
    Division of Hematology Oncology, University of Arizona, Tucson, AZ, USA
    Clin Lymphoma Myeloma Leuk 13:218-21. 2013
  7. pmc Selective inhibition of chymotrypsin-like activity of the immunoproteasome and constitutive proteasome in Waldenstrom macroglobulinemia
    Aldo M Roccaro
    Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
    Blood 115:4051-60. 2010
  8. pmc Src tyrosine kinase regulates adhesion and chemotaxis in Waldenstrom macroglobulinemia
    Hai T Ngo
    Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA
    Clin Cancer Res 15:6035-41. 2009
  9. pmc Update on therapeutic options in Waldenström macroglobulinemia
    Xavier Leleu
    Kirsch Laboratory for Waldenström macroglobulinemia, Department of Medical Oncology, Dana Farber Cancer Institute DFCI and Harvard Medical School, Boston, MA, USA
    Eur J Haematol 82:1-12. 2009
  10. pmc Waldenstrom macroglobulinemia
    Xavier Leleu
    Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
    Cancer Lett 270:95-107. 2008

Detail Information

Publications21

  1. pmc The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia
    Xavier Leleu
    Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
    Blood 110:4417-26. 2007
    ..These results provide understanding of biological effects of Akt pathway in WM and provide the framework for clinical evaluation of perifosine in WM patients...
  2. pmc Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenstrom macroglobulinemia
    Irene M Ghobrial
    Dana Farber Cancer Center, Boston, MA, USA
    J Clin Oncol 28:1408-14. 2010
    ..CONCLUSION Everolimus has high single-agent activity with an overall response rate of 70% and manageable toxicity in patients with relapsed WM and offers a potential new therapeutic strategy for this patient group...
  3. pmc Dual targeting of the PI3K/Akt/mTOR pathway as an antitumor strategy in Waldenstrom macroglobulinemia
    Aldo M Roccaro
    Medical Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA
    Blood 115:559-69. 2010
    ..These studies therefore show that dual targeting of the PI3K/mTOR pathway is a better modality of targeted therapy for tumors that harbor activation of the PI3K/mTOR signaling cascade, such as WM...
  4. pmc Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia
    Irene M Ghobrial
    Dana Farber Cancer Institute, Boston, MA, USA
    Clin Cancer Res 16:1033-41. 2010
    ..Based on preclinical studies, we conducted a phase II clinical trial testing the efficacy and safety of the Akt inhibitor perifosine in patients with relapsed/refractory WM...
  5. pmc Targeting the bone marrow in Waldenstrom macroglobulinemia
    Irene M Ghobrial
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA
    Clin Lymphoma Myeloma Leuk 11:S65-9. 2011
    ..These include chemokines, adhesion molecules, Src/PI3K/Akt/mTOR signaling, NF-kB activation, and micro-RNA regulation in WM. Targeting these pathways in clinical trials could lead to significant responses in this rare disease...
  6. pmc The bone marrow microenvironment in Waldenström macroglobulinemia
    Amit Agarwal
    Division of Hematology Oncology, University of Arizona, Tucson, AZ, USA
    Clin Lymphoma Myeloma Leuk 13:218-21. 2013
    ..A better understanding of the role of the BM microenvironment in the pathogenesis of WM can help guide better therapeutic strategies that can target the tumor clone and also regulate the BM microenvironment...
  7. pmc Selective inhibition of chymotrypsin-like activity of the immunoproteasome and constitutive proteasome in Waldenstrom macroglobulinemia
    Aldo M Roccaro
    Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
    Blood 115:4051-60. 2010
    ..These findings suggest that targeting i20S and c20S CT-L activity by ONX0912 represents a valid antitumor therapy in WM...
  8. pmc Src tyrosine kinase regulates adhesion and chemotaxis in Waldenstrom macroglobulinemia
    Hai T Ngo
    Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA
    Clin Cancer Res 15:6035-41. 2009
    ..We sought to determine whether the protein tyrosine kinase Src regulates adhesion, migration, and survival in Waldenstrom macroglobulinemia...
  9. pmc Update on therapeutic options in Waldenström macroglobulinemia
    Xavier Leleu
    Kirsch Laboratory for Waldenström macroglobulinemia, Department of Medical Oncology, Dana Farber Cancer Institute DFCI and Harvard Medical School, Boston, MA, USA
    Eur J Haematol 82:1-12. 2009
    ..This report provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM...
  10. pmc Waldenstrom macroglobulinemia
    Xavier Leleu
    Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
    Cancer Lett 270:95-107. 2008
    ..This report provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM...
  11. pmc SDF-1/CXCR4 and VLA-4 interaction regulates homing in Waldenstrom macroglobulinemia
    Hai T Ngo
    Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
    Blood 112:150-8. 2008
    ..Together, these studies demonstrate that the CXCR4/SDF-1 axis interacts with VLA-4 in regulating migration and adhesion of WM cells in the bone marrow microenvironment...
  12. pmc Dual targeting of the proteasome regulates survival and homing in Waldenstrom macroglobulinemia
    Aldo M Roccaro
    Medical Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA
    Blood 111:4752-63. 2008
    ..Theses studies enhance our understanding of the biologic role of the proteasome pathway in WM, and provide the preclinical basis for clinical trials of combinations of proteasome inhibitors in WM...
  13. pmc Advances in the treatment of monoclonal gammopaties: The emerging role of targeted therapy in plasma cell dyscrasias
    Aldo M Roccaro
    Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
    Biologics 2:419-31. 2008
    ....
  14. pmc Targeting NF-kappaB in Waldenstrom macroglobulinemia
    Xavier Leleu
    Medical Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA
    Blood 111:5068-77. 2008
    ..Moreover, a combination of these drugs with the CD20 monoclonal antibody rituximab further increased their cytotoxic activity. Thus, effective WM therapy may require combination regimens targeting the NF-kappaB pathway...
  15. pmc Clinical challenges associated with bortezomib therapy in multiple myeloma and Waldenströms Macroglobulinemia
    Jacob P Laubach
    Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
    Leuk Lymphoma 50:694-702. 2009
    ....
  16. pmc microRNA expression in the biology, prognosis, and therapy of Waldenström macroglobulinemia
    Aldo M Roccaro
    Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
    Blood 113:4391-402. 2009
    ..These data indicate that microRNAs play a pivotal role in the biology of WM; represent important prognostic marker; and provide the basis for the development of new microRNA-based targeted therapies in WM...
  17. pmc Novel therapeutic agents in Waldenström's macroglobulinemia
    Irene M Ghobrial
    Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA
    Clin Lymphoma Myeloma 9:84-6. 2009
    ..In this review, we summarize the current understanding of the clinical development of these agents in WM...
  18. pmc Novel treatment options for Waldenström macroglobulinemia
    Houry Leblebjian
    Pharmacy Department, Dana Farber Cancer Institute, Boston, MA
    Clin Lymphoma Myeloma Leuk 13:S310-6. 2013
    ..We finally focus on some agents that have shown preclinical efficacy and might be available in the near future. ..