Josie Ursini-Siegel, PhD

Targeted therapies offer little to no survival benefit for individuals with hard-to-treat cancers, including metastatic and drug-resistant disease. The greatest hurdle to developing life-extending therapies for such hard-to-treat malignancies is the enormous amount of genetic diversity in each tumor, making “personalized” approaches targeting individual mutations next to impossible.

My research team addresses this unmet need by first interrogating the adaptive stress responses that all cancer cells must overcome to survive even under the harshest of conditions, making them more aggressive. Subsequently, we leverage this information to develop rational combination therapies that target these essential vulnerabilities with a goal to evoke potent anti-tumorigenic and anti-metastatic responses irrespective of the mutational landscape and heterogeneity of individual cancers. We focus on four such adaptive stress responses:

• We seek to understand how the mRNA translation machinery is dysregulated in cancer cells and then to attenuate protein synthesis, representing a universal requirement for cancer cell growth, survival and metastasis.
• We seek to understand how cancer cells adapt to and exploit reactive oxygen species (ROS) production, which are highly unstable oxygen containing molecules. We study the mechanisms by which chronic and moderate oxidative stress increases the aggressive properties of cancers. Leveraging this information, we seek to identify novel strategies to potentiate a more severe and acute oxidative stress, which instead confers tumoricidal responses.
• We seek to understand how chronic inflammation increases the tumor- and metastasis-promoting properties of cancers and how we can reprogram these inflammatory responses to instead acquire tumor killing properties, focusing on novel innate immune cell subsets with tumoricidal functions.
• We seek to understand how immune suppression leads to the emergence of aggressive cancers and then devise strategies to re-activate anti-tumor immune responses that sensitize tumors to immunotherapies.

To achieve these objectives, our highly collaborative team employs multi-disciplinary in vivo and in vitro approaches including mouse genetics, molecular biology studies, flow cytometry, confocal microscopy and several -omics based technologies (transcriptomics, proteomics, metabolomics). We focus primarily on aggressive breast cancer and melanoma.