While the use of immunosuppression is crucial to the success of solid organ transplantation, it also predisposes patients to an increased incidence of infection and malignancy. Epstein Barr virus (EBV) B cell lymphomas associated with post-transplant lymphoproliferative disorder (PTLD) represent one of the most challenging, and serious, complications in transplant recipients. Currently, there is no consensus on treatment strategies for patients with PTLD, in part because the approaches utilized vary in their efficacy and because we cannot predict which therapy will best benefit a given patient. Furthermore, relapse and treatment-related mortality are major concerns. Our laboratory has worked to elucidate the underlying pathogenesis of EBV+ PTLD as a strategy to identify novel therapeutic targets. We have discovered that the PI3K/Akt/mTOR pathway is constitutively active in EBV+ B cell lymphomas from patients with PTLD and that EBV contributes to dysregulation of this pathway. We have also shown that survival and proliferation of EBV+ B cell lymphomas depends upon the PI3K/Akt/mTOR pathway because small molecule inhibitors, or siRNA, that target pathway constituents significantly inhibit lymphoma growth. In this proposal we will 1) determine the role of the PI3K/Akt/mTOR pathway in survival and growth of EBV+ B cell lymphomas, and apply rational therapeutics for targeting key nodes in the pathway; 2) define the mechanisms underlying PI3K/Akt/mTOR dysregulation in EBV+ B cell lymphomas and 3) determine if targeting the PI3K/Akt/mTOR pathway prolongs graft survival and can simultaneously inhibit lymphoma growth. To accomplish Aim 1 we will target mTOR in combination with PI3K or Akt proteins in EBV+ B cell lymphomas, both in vitro and in a mouse model of PTLD, to exploit our biochemical studies that revealed dysregulation of PI3K/Akt/mTOR is a common feature of EBV+ B cell lymphomas.
In Aim 2 we will determine whether deficiencies in negative regulatory proteins plays a role in constitutive signaling of the PI3K/Akt/mTOR pathway in EBV+ B cell lymphomas. We will also evaluate how diversity in the LMP1 gene affects pathway activation and assess whether LMP1 coopts the host cell microRNA network to undermine regulation of PI3K/Akt/mTOR in infected B cells.
In Aim 3 we characterize the effect of PI3K/Akt/mTOR small molecule inhibitors on alloactivation of T cells and graft survival. We also utilize an LMP1 transgenic mouse model to investigate how modulation of specific nodes in the PI3K/Akt/mTOR pathway alters B cell lymphoma growth in transplant recipients. These studies will create new opportunities for improving the treatment of EBV+ PTLD, and will also increase our basic understanding of EBV+ B cell lymphoma biology and the immune response to the allograft.
Post-transplant malignancies continue to be a major complication of solid organ and bone marrow transplantation. B cell lymphomas associated with the Epstein Barr virus (EBV) comprise a large proportion of these malignancies. At present there is no consensus on how to best treat patients with post-transplant EBV+ B cell lymphomas in part because of the variable efficacy of current treatment strategies, the significant rate of relapse, and of treatment-related mortality. Furthermore, we do not understand how to determine which therapies will benefit individual patients. The studies proposed here will define the mechanisms underlying the lack of regulation of the PI3K/Akt/mTOR signal transduction pathway in B cell lymphomas as well as the role of the pathway in B cell lymphoma survival and graft survival with the goal of identifying novel treatment approaches for post-transplant EBV+ B cell lymphomas.
| Sang, Adam X; McPherson, Marla C; Ivison, Geoffrey T et al. (2018) Dual blockade of the PI3K/Akt/mTOR pathway inhibits post-transplant Epstein-Barr virus B cell lymphomas and promotes allograft survival. Am J Transplant : |
| Martinez, Olivia M; Krams, Sheri M (2017) The Immune Response to Epstein Barr Virus and Implications for Posttransplant Lymphoproliferative Disorder. Transplantation 101:2009-2016 |
| Krams, S M; Schaffert, S; Lau, A H et al. (2017) Applying Mass Cytometry to the Analysis of Lymphoid Populations in Transplantation. Am J Transplant 17:1992-1999 |
