On January 29, 2021 BostonGene Corporation, a biomedical software company committed to defining optimal precision medicine-based therapies for cancer patients, reported the publication of two manuscripts furthering our understanding of heterogeneity in diffuse large B-cell lymphoma (DLBCL) (Press release, BostonGene, JAN 29, 2021, View Source [SID1234574426]). "A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications" was published in Cancer Cell while the Journal of Experimental Medicine published "Compromised Counterselection by FAS Creates an Aggressive Subtype of Germinal Center Lymphoma". The studies were completed in collaboration with researchers from the National Cancer Institute, part of the National Institutes of Health.
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A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications – Cancer Cell
In this research study, the NCI team developed a probabilistic algorithm that classifies individual patient DLBCL into one of seven genetic subtypes. The novel DLBCL classification tool, termed LymphGen, promises significant clinical utility and applicability to precision oncology. BostonGene supported the NCI in this endeavor by conducting B-cell receptor (BCR) repertoire analysis in the different genetic subtypes of DLBCL to further uncover the underlying BCR-mediated signaling mechanisms distinct to each genetic subtype. Overall, analysis of the genetic subtypes highlight distinct vulnerabilities to targeted therapy, supporting the use of this classification in precision medicine trials.
"The classification of DLBCL into seven genetic subtypes that differ with respect to oncogenic pathway engagement, gene expression phenotype, immune microenvironment, survival rates, and potential therapeutic targets will ultimately aid in the development of targeted therapy for patients with DLBCL," said Louis M. Staudt, MD, PhD, National Cancer Institute.
"We are honored to support NCI in their work on understanding genetic features of DLBCL," said Nathan Fowler, MD, Chief Medical Officer at BostonGene. "Ultimately, if a DLBCL genetic subtype is enriched for therapeutic responses, it could be used as a selection criterion for an expansion cohort in a subsequent clinical trial."
Compromised Counterselection by FAS Creates an Aggressive Subtype of Germinal Center Lymphoma – Journal of Experimental Medicine
The research study, led by NCI in collaboration with BostonGene, investigated the role of fas on germinal center (GC) B cells and fas mutations in DLBCL, identifying a unique DLBCL subgroup. Results showed that the absence of fas produced a strong cell-intrinsic survival advantage of GC B cells caused by decreased cell death in the light zone of the GC. Fas alterations occurred more commonly in GC-derived DLBCL and were associated with inferior survival of DLBCL patients and an altered tumor microenvironment (TME) enriched with T follicular helper (Tfh) cells. BostonGene provided insights into how fas-deficient DLBCL cells interact with the Tfh-enriched microenvironment, particularly through a co-deficiency with Herpes virus entry mediator (HVEM), a member of the tumor necrosis factor receptor superfamily. This work reveals that fas is a critical component involved in GC homeostasis, which may act as a molecular basis of differential responses to therapy observed in DLBCL patients.
"The results underscore the critical role of Fas in germinal center homeostasis and the importance of determining cell intrinsic and extrinsic factors to positively impact patient clinical outcomes," said Jagan R. Muppidi, MD, PhD at National Cancer Institute.
"The data published in the Journal of Experimental Medicine supports the need to fully understand the immune cell composition and spatial distribution of an altered TME," said Nathan Fowler, MD, Chief Medical Officer at BostonGene. "An integrated analysis into the architecture of the TME will improve treatment outcomes for individual DLBCL patients."