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Principal Investigator: CHRISTINE M. EISCHEN
Organization: THOMAS JEFFERSON UNIVERSITY
Fiscal Year: 2024
Award: $355,240
Funding agency: National Cancer Institute
Summary
A prerequisite for tumor development is acquiring resistance to apoptosis. This can be accomplished through
multiple mechanisms, but a frequent alteration in human cancers that protects from apoptosis is the
overexpression of one or more of the anti-apoptotic BCL2 family members. BCL2 itself is frequently
overexpressed in multiple types of B cell lymphomas and many other lymphoid and non-lymphoid malignancies.
Because of the perceived reliance of cancer cells on BCL2 for survival, a targeted specific BCL2 inhibitor was
developed, ABT-199 (venetoclax). Although, venetoclax has been FDA approved for the treatment of specific
leukemias, clinical trials with venetoclax have not been successful for B cell lymphomas with high levels of BCL2,
such as follicular lymphomas and diffuse large B cell lymphomas (DLBCL) that have translocated or amplified
BCL2. The results indicate these lymphomas do not require BCL2 for their continued survival, revealing a
significant gap in knowledge of what lymphomas use to protect themselves from apoptosis. Recently, we made
the unexpected discovery that BCLW, an unexplored anti-apoptotic BCL2 family member that was only thought
to be important in spermatogenesis, was overexpressed in six different types of B cell lymphomas, including
follicular lymphoma and DLBCL. We determined patients with DLBCL containing higher levels of BCLW had
reduced survival, and BCLW was more highly expressed than BCL2 in higher grade follicular lymphoma. We
also showed BCLW was necessary for the survival of Burkitt lymphoma cells, and increased levels of BCLW
provided resistance to Burkitt lymphoma cells to an inhibitor that targets three anti-apoptotic BCL2 family
members. Therefore, we hypothesize BCLW overexpression is necessary for the survival of multiple types of B
cell lymphomas and confers resistance to lymphoma cells to venetoclax and other BCL2 family inhibitors. We
propose two Aims to test this hypothesis. In Aim 1, we propose to evaluate the requirements of BCLW in multiple
different B cell lymphomas in relationship to other BCL2 family members and mechanisms for its overexpression.
In Aim 2, we propose to determine the contribution of BCLW to resistance to inhibitors of anti-apoptotic BCL2
family members and ways to overcome this resistance. Completion of these Aims will significantly increase
knowledge into the BCL2 family of proteins and the contribution of BCLW to B cell lymphomas and resistance to
targeted inhibitors of BCL2 family members. Results are also likely to lead to improved lymphoma clinical trials,
diagnostics, prognostics, and therapeutic interventions with knowledge based treatment combinations.
Terms: <Apoptosis><Apoptosis Pathway><Apoptotic><B blood cells><B cell><B cell lymphoma 2><B cells><B lymphoma><B-Cell CLL/Lymphoma 2 Gene><B-Cell Leukemia><B-Cell Lymphomas><B-Cells><B-Lymphocytes><B-cell><B-cell lymphoma-extra large><B-cell lymphoma/leukemia-2><BCL-XL><BCL2><BCL2 gene><BCL2-Like 1><BCL2-Related Gene><BCL2-Related Protein, Long Isoform><BCL2-Related Protein, Short Isoform><BCL2L1><BCL2L1 gene><BCLX><BCLXL><BCLXS><Bcl-2><Biological Markers><Brill-Symmers Disease><Burkitt Lymphoma><Burkitt Tumor><Burkitt's Lymphoma/Leukemia><Burkitt's Type Small Non-Cleaved Cell Lymphoma><Cancer Cause><Cancer Etiology><Cancer Treatment><Cancers><Cell Line><Cell Survival><Cell Viability><CellLine><Clinic><Clinical Trials><Combined Modality Therapy><DLBCL><Development><Diagnostic><Diffuse Large B-Cell Lymphoma><FDA approved><Family><Family Therapy><Family member><Family psychotherapy><Follicle Center Lymphoma><Follicular Lymphoma><Follicular Non-Hodgkin's Lymphoma><Genomic approach><Genomics><Germinoblastic Sarcoma><Germinoblastoma><Giant Follicular Lymphoma><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Human><Human Cell Line><Investigation><Knowledge><Link><Lymphoid><Lymphoma><Lymphoma cell><Lymphomagenesis><MCL-1><MCL1><MCL1 gene><Malignant Cell><Malignant Hematologic Neoplasm><Malignant Lymphoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mice><Mice Mammals><Modern Man><Molecular><Monitor><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Nodular Lymphoma><Oncogenesis><PDX model><Pathway interactions><Patient derived xenograft><Patients><Population><Programmed Cell Death><Protein Family><Proteins><Resistance><Reticulolymphosarcoma><Role><Sampling><Scientist><Spermatogenesis><Strains Cell Lines><System><Testing><Therapeutic><Therapeutic Intervention><anti-cancer therapy><bcl-2 Genes><bio-markers><biologic marker><biomarker><biomarker identification><cancer cell><cancer therapy><cancer-directed therapy><ced9 homolog><combination therapy><combined modality treatment><combined treatment><cultured cell line><developmental><experiment><experimental research><experimental study><experiments><genomic effort><genomic strategy><identification of biomarkers><identification of new biomarkers><improved><inhibitor><innovate><innovation><innovative><intervention therapy><large cell Diffuse non-Hodgkin's lymphoma><leukemia><malignancy><marker identification><mouse model><multi-modal therapy><multi-modal treatment><murine model><myeloid cell leukemia 1><myeloid cell leukemia sequence 1><myeloid leukemia cell differentiation protein><neoplasm/cancer><non-genomic><nongenomic><novel><overexpress><overexpression><pathway><patient derived xenograft model><pressure><prognostic><prognostic indicator><resistance mechanism><resistance to therapy><resistant><resistant mechanism><resistant to therapy><response to therapy><response to treatment><single cell analysis><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapeutic response><therapeutic target><therapy resistant><therapy response><treatment resistance><treatment response><treatment responsiveness><tumor><tumorigenesis>