Lgr5-mediated self-renewal in B cell selection and leukemia-initiation

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Grant Award Details

Grant Type:

Quest – Discovery Stage Research Projects

Grant Number:

DISC2-10061

Investigator(s):

Name:

Markus Müschen

Institution:

City of Hope, Beckman Research Institute

Type:

Disease Focus:

B cell cancers, Blood Cancer, Cancer, Leukemia

Human Stem Cell Use:

Cancer Stem Cell

Award Value:

$2,183,223

Status:

Closed

Progress Reports

Reporting Period:

Year 2

In a comprehensive analysis of signaling characteristics that define self-renewal and positive selection in B-cells, we identified LGR5 as a common denominator of stemness in B-ALL.

The following aspects of this CIRM-funded work will contribute to conceptual innovation in the field of self-renewal mechanisms in normal and malignant B-cells and therapeutic targeting of refractory B-LIC in B-lymphoid malignancies.

• Novel concept of antigen-driven stemness -rather than determined by a developmental hierarchy- in B-cell tumors that is marked by transient LGR5-surface expression and dependent on LGR5-mediated feedback control of WNT/b-catenin.

• Finding that B-cell malignancies, unlike the vast majority of myeloid- and T-cell leukemia and solid tumors, are exempt from activating lesions of the WNT/b-catenin pathway.

• Discovery of Lgr5 as previously unrecognized critical negative regulator of WNT/b-catenin signaling and self-renewal in normal and malignant B-cells

• LGR5 as novel predictor of relapse and poor clinical outcome in multiple B-cell malignancies.

• LGR5 is induced upon engagement of high-affinity BCRs by antigen during normal B-cell selection in germinal centers. Likewise, oncogenic BCR-mimics induce LGR5 expression.

• Lgr5 is critical for tumor-initiation and stemness of B-ALL and B-cell lymphoma. Collaboration with Dr. Hans Clevers (Lgr5fl/fl and Lgr5-eGFP reporter mice) for the development of genetic B-ALL, MCL and DLBCL models to test Lgr5 function in LIC.

• Identification of the GSK3b-inhibitor LY2090314 as an FDA-approved drug that selectively kills B-LIC, at >300-fold lower dose levels than myeloid and epithelial tumor cells. LY2090314 met safety criteria in a recent clinical trial (NCT01632306) for patients with pancreatic cancer but was not pursued further because of low efficacy and slow enrollment.

• Development and validation of two new LGR5 CAR-T cell therapeutics.

Grant Application Details

Application Title:

Lgr5-mediated self-renewal in B cell selection and leukemia-initiation

Public Abstract:

Research Objective

LGR5-antibody drug conjugate to target LIC in B cell tumors that undergo self-renewal

Impact

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.

Statement of Benefit to California:

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.

Publications

Nat Rev Cancer (2018): Autoimmunity checkpoints as therapeutic targets in B cell malignancies. (PubMed: 29302068)
Cell (2018): B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies. (PubMed: 29551267)
Nature (2017): Metabolic gatekeeper function of B-lymphoid transcription factors. (PubMed: 28192788)