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6:47 PM
Feb 21, 2019
 |  BC Innovations  |  Targets & Mechanisms

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 is required for production of S1P, and S1P induces HER2 expression.

In a study published on Feb. 6 in the Journal of the American Chemical Society, the Scripps team showed that decreasing miR-515 expression with TGP-515 increased expression of SK1, S1P and HER2 in breast cancer cell lines and sensitized the cancer cells to HER2-targeting therapies Herceptin trasuzumab and Kadcyla aldo-trastuzumab emtansine.

HER2 (EGFR2; ErbB2; neu) - Epidermal growth factor receptor 2; miR-515 - MicroRNA-515; S1P- Sphingosine-1-phosphate; SK1 - Sphingosine kinase 1

Triple-negative breast cancer (TNBC) is characterized by the absence of the estrogen receptor, progesterone receptor and HER2. The indication affects about 20% of breast cancer patients, but there are no targeted therapies specifically approved for the indication. AstraZeneca plc and Merck & Co. Inc.’s PARP inhibitor Lynparza olaparib was approved in 2018 to treat HER2-negative cancers, which includes TNBC.

However, in a Phase III trial, it showed only a modest effect on progression-free survival and no effect on overall survival in the subset of HER2-negative patients with TNBC. Standard of care for TNBC is a combination of taxanes and anthracyclines in the neoadjuvant setting for first-line patients.

In January, Phoenix Molecular Designs described a biomarker, RSK2, that is activated in about 80% of TNBC tumors, based on unpublished preclinical studies on 65 TNBC tumors. The company is developing the RSK2 inhibitor PMD-026, and has partnered with Roche to develop a companion diagnostic (see “Reducing the R(i)sk in TNBC”).

TNBC has also been a large focus among studies presented at...

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