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. IRE1 is amplified in ~10% 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 first-in-class 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 and complete eradication 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. Non-human primate toxicology testing showed that 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.
In Aim 1, we will establish diagnostic tests to determine eligibility for a clinical trial of ORIN1001 plus taxane combination therapy.
Aim 2 will exploit the immunomodulatory effects of ORIN1001 plus docetaxel therapy in breast cancer by testing the addition of anti-PD-L1 immunotherapy.
In Aim 3, we will conduct a phase I dose escalation study of ORIN1001 alone, then in combination with paclitaxel, followed by expansion cohorts in 4 subsets of breast cancer. 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.

Public Health Relevance

After the introduction of successful HER2 directed therapeutics, most fatal cases of breast cancer are associated with chemotherapy-insensitive triple-negative or luminal B breast cancer. Our research will establish endoplasmic reticulum stress sensor IRE1-targeted therapy as a novel therapeutic approach to enhance chemotherapy sensitivity and reverse the immunosuppressive microenvironment in the presence of chemotherapy that sensitizes MYC-driven breast cancers to immune checkpoint intervention. !

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National Cancer Institute (NCI)
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Baylor College of Medicine
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Zhao, Na; Cao, Jin; Xu, Longyong et al. (2018) Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer. J Clin Invest 128:1283-1299
Bhat, Raksha R; Yadav, Puja; Sahay, Debashish et al. (2018) GPCRs profiling and identification of GPR110 as a potential new target in HER2+ breast cancer. Breast Cancer Res Treat 170:279-292
Guarducci, Cristina; Bonechi, Martina; Benelli, Matteo et al. (2018) Cyclin E1 and Rb modulation as common events at time of resistance to palbociclib in hormone receptor-positive breast cancer. NPJ Breast Cancer 4:38
Johnston, A N; Bu, W; Hein, S et al. (2018) Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions. Breast Cancer Res 20:42
Dasgupta, Subhamoy; Rajapakshe, Kimal; Zhu, Bokai et al. (2018) Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature 556:249-254
Rimawi, Mothaffar F; De Angelis, Carmine; Contreras, Alejandro et al. (2018) Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer. Breast Cancer Res Treat 167:731-740
Bajgain, Pradip; Tawinwung, Supannikar; D'Elia, Lindsey et al. (2018) CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation. J Immunother Cancer 6:34
Niravath, Polly; Chen, Bingshu; Chapman, Judy-Anne W et al. (2018) Vitamin D Levels, Vitamin D Receptor Polymorphisms, and Inflammatory Cytokines in Aromatase Inhibitor-Induced Arthralgias: An Analysis of CCTG MA.27. Clin Breast Cancer 18:78-87
Mohammed, Somala; Sukumaran, Sujita; Bajgain, Pradip et al. (2017) Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer. Mol Ther 25:249-258
Hertz, D L; Kidwell, K M; Hilsenbeck, S G et al. (2017) CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study. Breast Cancer Res Treat 166:277-287

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