Publication Date

2018-07-15

Availability

Open access

Embargo Period

2018-07-15

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2018-06-07

First Committee Member

Jonathan Schatz

Second Committee Member

Wasif Khan

Third Committee Member

Stephen Lee

Fourth Committee Member

Francisco Vega

Fifth Committee Member

Marzenna Blonska

Abstract

Despite decades of research identifying molecular drivers of cancer, targeted therapies fail to provide long-term survival benefits for cancer patients much of the time, primarily due to tumor heterogeneity and redundancies of signaling pathways. In the most common lymphoma, diffuse large B-cell lymphoma (DLBCL), malignant activation of B-cell receptor (BCR) signaling drives cancer cell growth. Expression of the PIM kinases downstream of this signaling is a common feature of the Activated B-cell like (ABC) subtype of DLBCL, and a target of interest for therapy. We found the sensitivity of ABC DLBCL to pan-PIM kinase inhibition by the clinical compound PIM447 to be dependent on mutational activation of BCR signaling. Cell lines with mutations downstream that directly activated NF-kB signaling through the CARD11, BCL10, MALT1 protein complex where dependent on PIM for activation of protein translation, while cell lines lacking those downstream mutations had multiple avenues for activation of translation and thus were resistant to PIM447 treatment. Importantly, all cell lines were sensitive to direct inhibition of translation through the RNA helicase eIF4A1, regardless of mutational status, highlighting the advantage of directly targeting translation in cancer to avoid these resistance mechanisms. Because there is currently an unmet need for eIF4A1 inhibitors in the clinic, we performed a novel screen for inhibitors of eIF4A1’s ATPase activity. We discovered the natural compound elatol, which in a 2:1 stoichiometry interacts with two key lysines in eIF4A1 to prevent ATP hydrolysis. Elatol shows antitumor activity in a wide range of cancer cell lines, but as our studies with PIM in DLBCL suggested, lymphoma is a particularly sensitive cancer type. Elatol induces apoptosis in DLBCL cells by inhibiting cap-dependent protein expression of key cancer drivers including c-MYC, Cyclin D3 and MCL1. Surprisingly, elatol treatment induces expression of stress response factor ATF4, but this is not important for elatol’s antitumor activity, which are driven by its action against eIF4A1. Elatol is tolerated at high doses in vivo, and significantly delayed tumor progression in an ABC DLBCL xenograft model. Together these studies emphasize the inhibition of translation as a therapeutic option in DLBCL and provide a pipeline for the development of eIF4A inhibitors.

Keywords

Cancer; eIF4A; protein translation; therapy

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