# New Therapeutics for Post-Transplant Lymphoproliferative Disorder

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $398,138

## Abstract

7. PROJECT SUMMARY/ABSTRACT
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.

## Key facts

- **NIH application ID:** 9942385
- **Project number:** 5R01AI113130-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Olivia M Martinez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $398,138
- **Award type:** 5
- **Project period:** 2016-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942385

## Citation

> US National Institutes of Health, RePORTER application 9942385, New Therapeutics for Post-Transplant Lymphoproliferative Disorder (5R01AI113130-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9942385. Licensed CC0.

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