Research We Fund

RNA splicing is a central metabolic pathway that is frequently perturbed in hematopoietic malignancies (HMs) that harbor mutations in spliceosome components (most commonly affecting SRSF2, SF3B1, U2AF1, or ZRSR2). These mutations are particularly prevalent in myeloid malignancies (e.g., MDS, MDS/MPN, sAML), but recent pan-cancer studies have implicated aberrant splicing in >30 tumor types. The Project Leaders have probed the molecular consequences of aberrant splicing and identified critical pathways that are amenable to targeted inhibition, including the DNA damage response (Graubert/Walter), the nonsense-mediated RNA decay (NMD) pathway (You/Walter), the spliceosome itself (Abdel-Wahab/Walter/Graubert), and others. To date, effective therapies for HMs have not capitalized on these unique vulnerabilities. The goal of this SCOR is to generate testable clinical hypotheses based on careful mechanistic studies in pre-clinical models and to rapidly move these ideas into the clinic in the near term.

We focus on blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive blood cancer with limited treatment options and poor outcomes. We want to understand what causes the disease, develop laboratory tools, and identify new treatments and ways to overcome therapy resistance. We have translated our discoveries to clinical trials. Our goal is to continue this bench to beside approach to develop the next generation of BPDCN therapies that improve survival and minimize treatment toxicity.

In previous studies of recurrently amplified 1q21 genes in myeloma, we identified ILF2 as a modulator of the DNA repair pathway, which promotes adaptive responses to genotoxic stress. Thus, ILF2 may have clinical utility as a biomarker of aggressive myeloma and blocking the ILF2-mediated repair signaling may enhance the effectiveness of current DNA-damaging agent-based therapies. We are seeking to determine the feasibility of therapeutically targeting ILF2 with antisense nucleotides and identify DNA repair effectors whose loss of function induces synthetic lethality in ILF2-depleted myeloma.

In February 2021, LLS made an equity investment in Caribou Biosciences to support "A Phase 1, Multicenter, Open-Label Study of CB-011, a CRISPR-Edited Allogeneic Anti-BCMA CAR-T Cell Therapy in Patients With Relapsed/Refractory Multiple Myeloma." 

Caribou is a leading clinical-stage biotechnology company, co-founded by CRISPR pioneer and Nobel Prize winner Jennifer Doudna, Ph.D., using next-generation CRISPR genome-editing technology to develop “off-the-shelf” (allogeneic) CAR therapies for hard-to-treat blood cancers.

CB-011, Caribou’s second allogeneic CAR-T cell therapy, targets BCMA for the treatment of relapsed/refractory multiple myeloma and is immunologically cloaked for enhanced persistence. The CaMMouflage Phase 1 clinical trial, a multicenter, open-label study to evaluate the safety and efficacy of a single dose of CB-011 in adult patients with relapsed or refractory multiple myeloma (r/r MM), is currently enrolling (NCT05722418).