The B-cell receptor (BCR) pathway is an excellent new therapeutic target in lymphoma (Schatz et al. 2013). Our study addresses the following points: 1) We wish to define exactly how the BCR pathway is activated in follicular lymphoma (FL). Point mutations in the canonical pathway are rare in FL and we hypothesize that genomic aberration (chromosomal gains/losses) target key regulators of BCR signaling in FL. Using a functional genomics approach we have already identified EPHA7 as a regulator of BCR that is targeted by 6q deletions in FL, and recently identified additional genes. Our data reveal new and known regulators of BCR signaling and provide potential therapeutic opportunities (Oricchio et al. 2011). 2) We have already identified EPHA7 as a BCR regulator and developed a therapeutic strategy to restore EPHA7 to lymphomas. We now wish to preform proof-of-concept studies to investigate the therapeutic potential of this specific BCR regulator. The strategy is a bi-functional Rituxan/EPHA7 fusion antibody and our preliminary data show that this construct is superior to Rituxan alone. Further work is needed to define pharmacological parameters, distributions, toxicity etc. 3) New small molecule inhibitors of BCR signaling show great promise (e.g. inhibitors of BTK (Ibrutinib) and PI3Kdelta (e.g. Idealsib and others). These drugs are not yet approved but show clinical activity in follicular lymphoma. However, the response rates and durability are limited. We speculate that rational combinations of small molecule BCR inhibitors, BCL2 antagonists and antibodies (Rituxan/EPHA7) will improve outcomes. Our preliminary data show synergy between ibrutinib and the BCL2 inhibitor ABT199. We wish to test these strategies in xenografts and our new murine FL model. The goal of this application is to provide strong preclinical data to enable clinical trials in follicular lymphoma. We focus on Follicular Lymphoma (FL) because it is the most common form of indolent B-cell lymphoma and remains incurable with current therapy (chemotherapy plus Rituxan). The disease has been somewhat neglected compared to other lymphomas owing to a lack of experimental models. We developed a new mouse model of FL (Oricchio et al. 2011; Schatz et al. 2011)and this model for the first time enables genetic and therapeutic studies on non-transformed FLs. Together our application is a multipronged approach to fully exploit the therapeutic potential of BCR pathway inhibition and bring new therapeutic strategies that will minimize cytotoxic exposure. Oricchio, E., G. Nanjangud, et al. (2011). The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma. Cell 147(3): 554-564. Schatz, J. H., E. Oricchio, et al. (2013). Progress against follicular lymphoma. Curr Opin Hematol. Schatz, J. H., E. Oricchio, et al. (2011). Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma. J Exp Med 208(9): 1799-1807.

Public Health Relevance

Follicular lymphoma (FL) is the most common form of indolent B-cell lymphoma and incurable with standard chemo and antibody treatment. The causes of treatment failure are the cumulative toxicity of cytotoxic treatment and transformation into aggressive disease (tFL). The B-cell receptor (BCR) pathway is a rational target in FL and our overall hypothesis rational combinations including BCR inhibitors will outperform current therapies for FL. However, at this time it is not yet clear how the pathway is activated in FL, and moreover we need to learn how to use small molecule and biological inhibitors to their maximum effectiveness. The goal of our study is to provide new insight into BCR signaling biology and preclinical data to inform clinical trials that seek to minimize exposure to cytotoxic chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA183876-05
Application #
9477484
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Chen, Weiwei
Project Start
2014-05-05
Project End
2019-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Oricchio, Elisa; Katanayeva, Natalya; Donaldson, Maria Christine et al. (2017) Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma. Sci Transl Med 9:
Jiang, Yanwen; Ortega-Molina, Ana; Geng, Huimin et al. (2017) CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas. Cancer Discov 7:38-53
Boice, Michael; Salloum, Darin; Mourcin, Frederic et al. (2016) Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells. Cell 167:405-418.e13
Mets, E; Van der Meulen, J; Van Peer, G et al. (2015) MicroRNA-193b-3p acts as a tumor suppressor by targeting the MYB oncogene in T-cell acute lymphoblastic leukemia. Leukemia 29:798-806
Ortega-Molina, Ana; Boss, Isaac W; Canela, Andres et al. (2015) The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. Nat Med 21:1199-208
Oricchio, Elisa; Papapetrou, Eirini P; Lafaille, Fabien et al. (2014) A cell engineering strategy to enhance the safety of stem cell therapies. Cell Rep 8:1677-1685
Mavrakis, Konstantinos J; Van Der Meulen, Joni; Wolfe, Andrew L et al. (2011) A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL). Nat Genet 43:673-8