Grant Award Details
Lgr5-mediated self-renewal in B cell selection and leukemia-initiation
Grant Application Details
- Lgr5-mediated self-renewal in B cell selection and leukemia-initiation
LGR5-antibody drug conjugate to target LIC in B cell tumors that undergo self-renewal
LIC were only defined in myeloid leukemia, while LIC populations in B cell tumors remain elusive. LICs give rise to drug-resistance and relapse and remain unsolved clinical problems in B cell tumors.
Major Proposed Activities
- Proof of concept studies- Positive selection by antigen-receptor (BCR) signals drives self-renewal in normal B cell development and leukemia and lymphoma.
- Define patient groups and B cell leukemia and lymphoma subtypes that will benefit from LGR5-ADC mediated eradication of LIC.
- Safety and efficacy profiles - choice of LGR5-ADC based on safety and efficacy profiles in quiescent Lgr5+ populations
- In vivo testing platform –optimizing LGR5-ADC efficacy and therapeutic window
- IND-enabling studies, concept for multicenter phase 1 clinical trial to test safety and tolerability of LGR5-ADC in patients woth pre-B ALL and mature B cell lymphoma.
B cell tumors account for an estimated ~129,000 newly diagnosed patients in 2015 in the US and California. Despite improvements, survival rates recently leveled off near 60%. 40,000 patients are expected to die from B cell tumors in the US and California this year. 1.2 million people are currently living with or recovering from B cell tumors. Therefore, stem cell-based efforts to reduce toxicity and minimize late effects are an important aspect in the development of new therapy strategies.
- Cell (2018) B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies. (PubMed: 29551267)
- Nat Rev Cancer (2018) Autoimmunity checkpoints as therapeutic targets in B cell malignancies. (PubMed: 29302068)
- Nature (2017) Metabolic gatekeeper function of B-lymphoid transcription factors. (PubMed: 28192788)