Survival Pathways in Multiple Myeloma

ASPIRE Award (2023-Present)

David Allman, PhD; Dan Vogl, MD, MSCE, University of Pennsylvania

David Allman, PhD

Dan Vogl, MD, MCSE

Multiple myeloma (MM) is a challenging and incurable cancer that affects plasma cells, specialized blood cells responsible for antibody production. Despite current therapies reducing tumor burden, relapse remains a significant concern. Plasma cells, both normal and malignant, have high demands for protein production due to continuously synthesizing and secreting antibodies. To meet this demand, the cells rely on pathways that optimize endoplasmic reticulum (ER) function and prevent apoptosis induced by ER stress.

David Allman aims to explore the metastable state of plasma cells as a potential avenue for therapeutic intervention. His preliminary data suggests that normal and malignant plasma cells utilize purinergic receptors to enhance ER function and evade apoptosis. Purinergic stimulation plays a critical role in promoting antibody secretion and sustaining plasma cell survival. Inhibiting purinergic receptor function could activate an ER-centered death mechanism in plasma cells, including those in multiple myeloma.

To test this hypothesis, Allman and his team will employ various experimental systems, including a novel and highly tractable patient-derived xenograft model. They will investigate the impact of inhibiting purinergic receptor function on the growth and survival of primary human multiple myeloma cells. Additionally, they aim to uncover the specific mechanisms by which purinergic receptors regulate ER-centered death in multiple myeloma cells. This innovative research seeks to establish a new connection between microenvironmental and cell-intrinsic factors that influence plasma cell function. The findings have the potential to provide valuable mechanistic insights and open new avenues for therapy in relapsed multiple myeloma and other plasma cell neoplasms.

published research

Ishikawa M, Hasanali ZS, Zhao Y, Das A, Lavaert M, Roman CJ, Londregan J, Allman D, Bhandoola A. Bone marrow plasma cells require P2RX4 to sense extracellular ATP. Nature. 2024.

Hasanali ZS, Garfall AL, Burzenski L, Shultz LD, Tang Y, Kadu S, Sheppard NC, Liu W, Dopkin D, Vogl DT, Cohen AD, Waxman AJ, Susanibar-Adaniya SP, Carroll M, Stadtmauer EA, Allman D. Human IL-6 fosters long-term engraftment of patient derived disease-driving myeloma cells in immunodeficient mice. JCI Insight. 2024.