Project Term
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Project Summary
While beta-catenin forms transcriptional complexes to activate MYC-expression and proliferation in other cell types, our studies in B-lymphoid cells revealed repressive beta-catenin complexes to suppress MYC. Unlike other cell types, B-lymphoid cells critically depend on high-efficiency beta-catenin protein degradation, which requires concerted activity of the GSK3B and CK1a kinases, NEDD8-activating enzyme (NAE1), and immunoproteasome subunits (PSMB8).
We propose three Aims, to evaluate the potency and safety of existing drugs targeting (1) phosphorylation by GSK3B and CK1a kinases, (2) NEDD8-connection by the NAE1 molecules and (3) the proteasome subunit PSMB8. The main impetus of this project is to compare these compounds against each other and then prioritize one of them for a systematic drug-repurposing effort for patients with refractory B-cell malignancies.
Lay Abstract
In solid cancers (e.g., colon, breast, lung cancer), beta-catenin pairs with TCF7-factors to activate MYC, a central driver of cell growth. beta-catenin accumulation is a frequent feature in cancer because it promotes MYC-dependent tumor growth.
Our expectation was that this also applies to leukemia and lymphoma, a blood cancer derived from B-cells that is particularly common in children and young adults. To our surprise, however, the beta-catenin protein was barely detectable in leukemia and lymphoma cells.
Mutations that prevent breakdown of the beta-catenin protein are very common in cancer. However, we found that these mutations were conspicuously absent in B-cell leukemia and lymphoma. Moreover, we found that B-cell cancers were surprisingly sensitive to accumulation of the beta-catenin protein. When we induced accumulation of beta-catenin in B-cell leukemia and lymphoma cells under experimental conditions, beta-catenin did not pair with TCF7 to activate MYC and tumor growth and instead coupled paired with a different partner, called Ikaros. In tandem with Ikaros, beta-catenin did not activate but instead suppressed MYC. As a consequence, when leukemia and lymphoma cells were forced to accumulate beta-catenin they acutely stopped growing and rapidly underwent cell death. This unusual behavior in B-cell leukemia and lymphoma is owing to the fact that these tumors express Ikaros instead of TCF7. Since only B-cell cancers express Ikaros and are uniquely sensitive to accumulation of beta-catenin protein, we propose here to target the beta-catenin protein degradation machinery as a previously unrecognized vulnerability of B-cell tumors. Since depletion of normal B-cells is well tolerated, we are expecting that this unusual approach will have few side effects.
Recent work in our laboratory showed that three classes of drugs that target the beta-catenin protein degradation machinery have already demonstrated safety in clinical trials for other diseases. These drugs target 3 distinct components of the beta-catenin protein breakdown machinery, namely when beta-catenin is (1) marked by phosphorylation by GSK3B and CK1a kinases, subsequently (2) connected with NEDD8 by the NAE1 enzyme and finally (3) moved to the proteasome for breakdown by PSMB8. Drugs that target these 3 pathway components were safe in previous clinical trials for a variety of diseases. Our results show that each of them is highly active in forcing accumulation of beta-catenin in B-cell cancers to stop growth and to induce cell death.
We propose three Aims, to evaluate the potency and safety of existing drugs targeting (1) phosphorylation by GSK3B and CK1a kinases, (2) NEDD8-connection by the NAE1 molecules and (3) the proteasome subunit PSMB8. The main impetus of this project is to compare these compounds against each other and then prioritize one of them for a systematic drug-repurposing effort for patients with refractory B-cell leukemia and lymphoma.
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