Expansion into TNBC
How RNA-binding small molecules could sensitize TNBC to targeted therapies
With an RNA-binding small molecule that sensitizes HER2-negative cancers to Herceptin, Matt Disney’s latest study adds to the growing arsenal of preclinical therapies against triple-negative breast cancer. The only problem is the molecule may run the risk of worsening a patient’s cancer before making it better.
Disney has been a pioneer in the growing field of RNA-binding small molecules, a technology that takes on the long-standing dogma that RNA is poorly druggable by conventional modalities. Disney spun out Expansion Therapeutics Inc. from The Scripps Research Institute, where he is a professor of chemistry and neuroscience, to develop treatments for RNA-expansion diseases. Last year, Expansion raised $55.3 million in a series A round co-led by 5AM Ventures, Kleiner Perkins, Novartis Venture Fund and Sanofi Ventures.
Disney’s Scripps lab focuses on designing selective therapeutic RNA-binding molecules based on gene sequences.
In a study published in the Journal of the American Chemical Society on Feb. 6, Disney’s team designed a molecule that converts HER2-negative cancers to HER2-positive, sensitizing them to Roche’s anti-HER2 mAb Herceptin trastuzumab, but driving up invasiveness in the process.
The study throws a new strategy into an indication that, by definition, is hard to treat.
Figure: HER2 conversion
The Scripps Research Institute identified a new RNA-binding small molecule, Targaprimir-515 (TGP-515), that converts HER2-negative breast cancer cells into HER2-positive cells. TGP-515 could offer a new mechanism to treating triple-negative breast cancer (TNBC) by sensitizing TNBC tumors to HER2-targeted therapies.
Targarprimir-515 works by binding miR-515’s hairpin precursor (pri-miR-515) to block production of the miRNA, resulting in upregulation of HER2. miR-515 is a suppressor of SK1 expression, which