T-cell lymphomas display shorter relapse intervals and poor overall survival. Targeted therapies for T-cell lymphomas are lacking, and there is no established standard of care for patients at relapse. The limited information on the specific molecular signals that are activated in T-cell lymphomas hampers the development of effective therapies. Emergent research has demonstrated that aberrant activation of proteins involved in actin organization is critical for cancer metastasis and tumor growth. The candidate preliminary studies demonstrate that a large network of actin organizing proteins is activated during the development of T-cell lymphoma. Also, the major actin regulatory protein Wiskott-Aldrich syndrome protein (WASp) increases the dissemination and growth of a subtype of T-cell lymphoma, anaplastic large cell lymphoma (ALCL). These preliminary findings are very exciting, as identified a major actin regulatory protein as key determinant for lymphoma development. However, whether WASp also plays a role in lymphoma development in more common and aggressive types of T-cell lymphomas needs to be determined. The candidate novel preliminary findings demonstrate that WASp is expressed and activated in the most common type of T-cell lymphoma in the United States, peripheral T- cell lymphoma, non-otherwise specified (PTCL-NOS). In addition, WASp expression decreases the sensitivity of primary T-cell lymphoma cells to available chemotherapeutics, suggesting a role of WASp in chemotherapy resistance. Moreover, WASp can activate downstream proteins known to increase tumor proliferation and dissemination. Among these proteins, activation of lymphocyte specific protein 1 (LSP1) and extracellular signal-regulated kinase (ERK) in T-cell lymphomas has been validated. Importantly, ERK pathway can be inhibited with drugs that are currently in clinical trials for other types of cancer. The central hypothesis is that WASp and its downstream signals (ERK and LSP1) are therapeutic targets for patients with a diagnosis of T-cell lymphoma. In this proposal, I will evaluate 1) the role of WASp and its downstream signals (ERK and LSP1) during lymphoma growth, 2) the role of WASp dependent actin re-organization during T-cell lymphoma dissemination, 3) the signaling pathways that mediate WASp-dependent chemotherapy resistance, and 4) the oncogenic role of WASp in-vivo using a mice model of T-cell lymphoma with knock-down expression of WASp. The candidate long term career goal is to develop as a successful independent physician-scientist with a research focus in the pathobiology of T-cell lymphomas. The candidate career development plan is structured in three main components to help achieve its goals; 1) Gain technical and clinical skills for translational studies on T-cell lymphomas, 2) Expand its knowledge related to tumor progression and 3) Develop skills to become an independent scientist and write an R01 application to the NCI.
Non-Hodgkin lymphoma is the seventh most common cancer in the US, and 10% to 15% of these cases are T-cell lymphomas. Only 30% of patients with T-cell lymphoma will survive after three years of diagnosis. Knowledge of the pathobiology of this tumors is required to overcome chemotherapy resistance, and develop novel targeted therapies.
| Murga-Zamalloa, Carlos; Polk, Avery; Hanel, Walter et al. (2017) Polo-like-kinase 1 (PLK-1) and c-myc inhibition with the dual kinase-bromodomain inhibitor volasertib in aggressive lymphomas. Oncotarget 8:114474-114480 |
