Project 3: Targeting Endoplasmic Reticulum Stress Sensor IRE1 to Enhance Chemotherapy Sensitivity in MYC-driven Breast Cancer

Limited sensitivity to chemotherapy and an immunosuppressive tumor microenvironment drives breast cancer mortality in HER2 negative breast cancer. We have identified the IRE1/XBP1 branch of the Unfolded Protein Response (UPR) or endoplasmic reticulum (EnR) stress response as a previously unexplored therapeutic vulnerability in MYC-driven breast cancer that enhances chemotherapy sensitivity and reverses the immunosuppressive tumor microenvironment. I

RE1 is amplified in ~10 percent of human breast cancer, and frequently co-amplified with the MYC oncogene. Activation of MYC is synthetic lethal with IRE1/XBP1 pathway inhibition. We found that inhibition of the IRE1/XBP1 pathway with a highly selective IRE1 RNase inhibitor ORIN1001 suppresses MYC-high-expressing (MYChigh), but not MYC-low-expressing (MYClow), tumor growth in patient-derived xenograft (PDX) models. ORIN1001 substantially enhances the docetaxel efficacy, resulting in rapid tumor regression of the MYChigh PDX tumors. Furthermore, the ORIN1001 plus docetaxel therapy triggers massive cytotoxic T-cell infiltration, depletion of immunosuppressive myeloid-derived suppressor cells (MDSCs) and substantial upregulation of PD-L1 in the tumor microenvironment. ORIN1001 has excellent safety profile and is well-tolerated.

These preclinical data prompt us to hypothesize that inhibition of the IRE1/XBP1 pathway with the IRE1 inhibitor ORIN1001 compromises MYChigh breast cancers by inhibiting obligatory UPR stress adaptation required for cellular viability. This therapeutic effect of ORIN1001 is associated with a marked increase in taxane sensitivity. In addition, MDSCs are also selectively depleted by ORIN1001 in the presence of a taxane, thus reversing immunosuppression and potentially sensitizing MYChigh breast cancers to immune checkpoint intervention. A pre-clinical phase study in breast cancer models will be conducted in parallel with a Phase 1 clinical trial.

The overarching objective of this proposal is to design and open a Phase 2 clinical trial in MYC-positive metastatic breast cancer with eligibility and endpoints to be defined by the execution of the research aims.