QSP programs

Metastatic Breast Cancer

 

In collaboration with the Lee, Oesterreich, and Pulhalla laboratories we have implemented a QSP program for metastatic breast cancer to understand how tumors coevolve with their microenvironment.   Our goal is to identify pathway dependencies and mechanisms of resistance that inform novel robust therapeutic strategies. In estrogen receptor positive (ER+) patients who are undergoing estrogen deprivation therapy (i.e., aromatase inhibitors) the allele frequency of mutations within the ER-encoding gene (ESR1) increase in metastases compared to the primary tumor. Functional genomic studies demonstrate that these mutations confer both constitutive activity and partial resistance to ER antagonists consistent with clinical outcomes.  We have developed sensitive methods for detecting ESR1 mutants in liquid biopsies using digital droplet PCR and will use this approach to prospectively determine the relevance of these mutations in an upcoming clinical trial. In parallel we are advancing our functional genomic studies using iterative computational and experimental systems pharmacology approaches to design and validate therapeutic strategies to treat metastases harboring these ESR1 mutants.  (Wang et al. Sensitive detection of mono- and polyclonal ESR1 mutations in primary tumors, metastatic lesions, and cell-free DNA of breast cancer patients. Clinical Cancer Research 2016; 22:1130-1137.)