Targeting the ALT Pathway to Induce Synthetic Lethality and Treat Poor Outcome Pediatric Tumors
The fundamental paradigm of cancer therapy is moving from conventional therapies that poorly differentiate cancer cells from normal cells to targeting biological processes that are unique to cancer cells in a specific patient. This strategy, termed personalized or precision medicine, targets a tumor-specific Achilles heel creating a situation that kills only tumor cells, but not normal (non-tumor) cells. We have identified such a tumor-specific vulnerability in a significant fraction of pediatric brain and bone cancers and propose to isolate inhibitors of the target MUS81 to exploit this tumor liability. Moreover, the normal function of MUS81 suggests that its inhibition will make conventional chemotherapy used to treat these cancers more effective. High-grade brain cancers or bone cancers of children that have spread from the primary tumor site are in desperate need of more effective treatment options.
Our project represents the earliest steps in drug development and we have two experienced pediatric oncologists on our team who will offer specific clinical perspectives and expertise right at the earliest stage. Drug development is a long-term project, but through a serendipitous finding, we also have the potential to repurpose an existing approved drug to significantly speed up the process. One specific attraction of our approach is that the treatment we envision is designed to be specific for the tumor cells and sparing of normal cells, which should lead to fewer side effects and less long-term adverse consequences, which are important considerations in particular for young cancer survivors and their quality of life.
Project Update - June 2020
We are trying to exploit such a tumor-specific vulnerability in a significant fraction of pediatric brain and bone cancers by isolating inhibitors of an enzyme that is specifically required in these tumors but not in healthy tissue. Towards this goal, we have screened a large chemical library for compounds that inhibit our enzyme and identified promising candidates, which we are currently trying to validate and develop further into leads for initial drug development.