Targeting contexts of synthetic lethality in acute lymphoblastic leukemia

Project: Research project

Project Details

Description

Acute lymphoblastic leukemia (ALL) is a highly aggressive blood cancer afflicting children and adults. Up to 25% pediatric ALL patients fail or relapse post-frontline chemoradiation and face dismal prognosis. Certain high-risk disease subsets have poor outcomes and toxicities, stemming from direct inhibition of the oncogenes, are often debilitating. We hypothesize that the process of oncogenic transformation is driven by aberrant activity of oncogene-associated chromatin (epigenetic) modifying partners. These changes create a chromatin environment unique to the malignant state, and therefore disruption of critical oncogenic nuclear environment critical for oncogenesis would likely not affect healthy tissues. Along those lines, we have strong evidence for the intertwined roles of two chromatin oncogenic partners in ALL, JMJD3 and USP7. USP7 controls tumor growth through JMJD3-dependent and independent activities and it potentially regulates transcriptional elongation. Small molecule inhibitors against USP7 significantly affect expression of oncogenic targets and inhibit growth of leukemia cells in vitro. In this proposal we plan to further characterize these pro-oncogenic roles as well as target them using a combination of small molecule inhibitors in primary patient samples, mouse and xenograft models of disease. This approach can lead to clinical trials for the treatment of high-risk disease in the foreseeable future.
StatusFinished
Effective start/end date7/1/166/30/17

Funding

  • St. Baldrick's Foundation (429654)

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.