Nuclear Functions of BCL10 and MALT1 and Their Potential for Therapeutic Intervention in Non-Hodgkins Lymphoma
Abstract
Objective and Rationale: Non-Hodgkin s lymphomas are the fifth most common cancer. Among those, some respond well to therapy and can be cured while some remain incurable even after a good initial response to therapy. Consequently, new approaches are needed. We have worked in therapeutic targeting of the protein complex CARMA1/BCL10/MALT1 involved in the activated B-cell like (ABC) subtype of Diffuse Large B-cell lymphoma, which has a less favorable prognosis with standard chemoimmunotherapy. We have shown that MALT1 inhibition by a small molecule inhibitor is effective against a series of activated B-cell like (ABC) subtype of Diffuse Large B-cell lymphoma (DLBCL). However, another CBM component, BCL10 is aberrantly expressed and localized to the nucleus independent of MALT1 in several non-Hodgkin s lymphomas and pancreatic cancer. Not many data are available about the role of nuclear BCL10 in cancer. However, nuclear BCL10 participates in DNA damage repair and has been suggested to activate the expression of other genes. Moreover, nuclear localization is associated with poor prognosis in MALT lymphomas and pancreatic cancer. We have detected BCL10 in the nucleus of DLBCL cell lines, but its significance for DLBCL survival is unknown. Consequently, we hypothesize that BCL10 binds to proteins other than MALT1 in the nucleus of DLBCL cells promoting enhanced cell growth or survival of cells and ultimately lymphoma. Our objective is to establish which proteins interact with BCL10, how they promote lymphomagenesis, and whether nuclear BCL10 is a marker for prognosis in DLBCL. Principal Investigator (PI) Career Goals in Cancer Research: Dr. Fontan has been working in non-Hodgkin s lymphoma and the CARMA1/BCL10/MALT1 complex for 8 years. Initially, she was able to show the driver oncogenic role of MALT1 using a transgenic mouse model. The last 4 years she has been focused in Experimental Therapeutics, involved in the development of inhibitors and the therapeutic targeting of MALT1 in DLBCL with the mentorship of Dr. Melnick. Dr. Fontan will continue focusing on new and different aspects of BCL10 and MALT1 proteins biology and on how these can be leveraged for the treatment of hematologic malignancies. Obtaining this award will greatly benefit the PI s career advance by allowing the PI to branch out and start her own line of research. This award will allow the PI to hire a research technician who will work under her direct supervision to advance this project. Moreover, it will allow the PI to do several training activities including courses in Protein Purification and Proteomics that will be good complements for the PI s instruction and will greatly advance this project. Ultimate Applicability of Research: The ultimate applicability of the research coming from this project will be (i) to determine if nuclear BCL10 localization can be used as a marker for disease prognosis and/or response to treatment in DLBCL patients and (ii) to determine which are the nuclear BCL10 partners and functions, which will be the basis to develop new therapeutical approaches by targeting nuclear BCL10 partners or functions. How Will Benefit Military: Non-Hodgkin s lymphoma incidence has steadily grown over the last 35 years to duplicate its prevalence. Moreover, patients treated with chemo and/or radiotherapy for this or other malignancies have an increased risk to develop non-Hodgkin s lymphoma because of the side effects of these treatments. Additionally, military personnel are at greater risk for developing non-Hodgkin s lymphoma because of professional exposure to cytotoxins and chemicals, including solvents. For example, exposure to the Agent Orange during the Vietnam War has been connected to the development of all B-cell neoplasms, including DLBCL, one of the most aggressive and chemoresistant forms of non-Hodgkin s lymphoma. Consequently, an expansion on the knowledge and treatment options for non-Hodgkin s ly
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510418
Entities
People
- Lorena Fontán
Organizations
- United States Army
- Weill Cornell Medicine