Targeted therapy of cancer typically focuses on agents that suppress oncogenic signaling below a minimum threshold needed for survival and proliferation. Here, we propose a novel strategy to overcome drug-resistance in B cell malignancies based on targeted activation of an autoimmunity checkpoint (AIC) for removal of autoreactive B cells. Owing to the necessity of the B cell repertoire to censor autoreactive clones, B cells fundamentally differ in their signaling requirements from other cell types. Unlike other types of cancer, B cell malignancies are uniquely susceptible to clonal deletion induced by hyperactive signaling from an autoreactive B cell receptor (BCR). Three recent studies from our group showed that targeted AIC-activation is achievable by pharmacological hyperactivation of BCR-signaling above a maximum threshold (Chen et al., Nature 2015; Shojaee et al., Cancer Cell 2015; Shojaee et al., Nature Med 2016). Hence, targeted AIC-activation can be leveraged for eradication of drug-resistant B cell leukemia and lymphoma clones. Based on these and other findings, we propose three Aims to validate targeted autoimmunity checkpoint (AIC)- activation as new concept for the treatment of human B cell malignancies: 1. This proposal includes a mechanistic Aim based on the novel observation that checkpoints to safeguard from autoimmunity disease are still functional in B cell malignancies.
This Aim explores how AIC-activation can be reliably achieved in B cell malignancies and how AIC-activation leads to cell death. 2. The stratification Aim will identify disease subtypes and groups of patients that may be most responsive to AIC-activation and elucidate the biological basis of different treatment responses. 3. A therapeutic Aim will refine the treatment concept by prioritizing targeted hyperactivation of specific components of the BCR pathway and by exploring combinations with established treatment agents.

Public Health Relevance

Targeted therapy of cancer typically focuses on agents that suppress oncogenic signaling below a minimum threshold needed for survival and proliferation. Here, we propose a novel strategy to overcome drug-resistance in B cell malignancies based on targeted activation of an autoimmunity checkpoint (AIC) for removal of autoreactive B cells. Unlike other types of cancer, B cell malignancies are uniquely susceptible to clonal deletion induced by hyperactive signaling from an autoreactive B cell receptor (BCR). Three recent studies from our group showed that targeted AIC-activation is achievable by pharmacological hyperactivation of BCR-signaling above a maximum threshold (Chen et al., Nature 2015; Shojaee et al., Cancer Cell 2015; Shojaee et al., Nature Med 2016). Hence, targeted AIC-activation can be leveraged for eradication of drug-resistant B cell leukemia and lymphoma clones.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA157644-09
Application #
9404975
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Jhappan, Chamelli
Project Start
2017-04-04
Project End
2021-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
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