Mutations in BCL10 as a Biomarker for Precision Therapy in DLBCL

Background & Unmet Need

• Diffuse large B-Cell Lymphoma (DLBCL) is the most common hematological malignancy
• DLBCL is classified into three subgroups, of which Activated B Cell-like (ABC) DLBCL is the most aggressive and has the poorest outcomes
• Constitutive activation of NF-kB signaling is a hallmark of ABC-DLBCL, which is largely mediated by B Cell Receptor (BCR) signaling
• BTK inhibitors have had a large impact on treatment of other lymphomas and act downstream of BCR, but show only modest effects in DLBCL
• There are several targets along the BCR signaling pathway, including within the CARD11—BCL10—MALT1 (CBM) complex which can be mutated and may mediate BTK resistance
• Unmet Need: Better understanding of somatic mutations in ABC DLBCL to guide precision treatment selection

Technology Overview

• The Technology: Use of BCL-10 as a biomarker to guide precision therapy for ABC DLBCL
• The Discovery: Genome sequencing revealed that mutations in BCL10 are most common in ABC-DLBCLs
• BCL10 is a part of the CBM complex, which activates NF-kB signaling downstream of BCR
• Biochemical, structural, and functional analysis demonstrated that BCL10 mutations fall into two distinct classes: a)Missense mutations in the CARD domain b)Truncating mutations in the C-terminal
• PoC Data: Both BCL10 mutants with truncating and with missense mutations demonstrate resistance to BTK inhibitors
• Mutants with BCL10 truncating mutations are hypersensitive to MALT1 inhibitors, whereas missense BCL10 mutants are not

Technology Applications

• Supplement traditional methods of embryo selection and prioritization by assigning ploidy predictions to embryos in a high throughput and unbiased manner
• Assist embryologists in determining on which embryos the more invasive and costly PGT-A should be performed in IVF cases that are complex and/or unlikely to be successful (advanced maternal age, low embryo count, etc.)

Technology Advantages

• Determines which patients may benefit from alternatives to BTK inhibitors
• Identifies patients which would be most likely to respond to MALT1 inhibitor therapy

Figure 1: Two categories of BCL10 mutations in DLBCL were identified: Missense mutations in the CARD domain and truncating mutations in the C-terminal.