Preclinical efficacy of GPR56 antibody-drug conjugates and combination therapies for triple-negative breast cancer - ABSTRACT: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poorer prognosis. As therapy resistance, metastasis of tumor to distant organs, and tumor relapse frequently occur; there is an urgent need to identify new targets and therapeutic strategies to treat and eliminate TNBC tumors with reduced side-effects. Antibody-drug conjugates (ADCs) are one of the fastest growing classes of anticancer drugs and have demonstrated a recent upsurge in success, particularly for breast cancer treatment. The ADC approach combines the high specificity of tumor-targeting antibodies with a potent cytotoxic drug to generate “armed” antibodies that can act as target-guided missiles to directly deliver drug into tumor cells, while sparing normal tissues. Thus, identifying new ADC targets for the treatment of TNBC could have promising clinical potential. GPR56, an adhesion receptor, is highly expressed at the tumor cell surface in various cancers, including TNBC, and correlates with poor patient survival. Importantly, GPR56 is found at lower levels on normal healthy tissues, suggesting a GPR56-targeted therapy would be well-tolerated in patients. We developed GPR56 ADCs that showed promising safety and preclinical efficacy in patient-derived tumor models of colorectal cancer. Moreover, our preliminary data show GPR56 ADCs have higher cell-killing potency in TNBC cells and enhanced efficacy when treated in combination with a poly (ADP-ribose) polymerase (PARP) inhibitor currently in clinical trials. We hypothesize GPR56 ADCs will be highly effective in treating GPR56-high TNBC tumors with minimal to no toxicity to normal tissues. We further hypothesize combination of GPR56 ADCs with PARP inhibitors will have enhanced efficacy and eliminate tumors, regardless of tumor mutational status. In Aim 1, we will generate GPR56 ADCs by attaching different cytotoxic drugs and evaluate cell-killing efficacy in TNBC cell lines expressing different levels of GPR56. In Aim 2, the lead GPR56 ADCs that exhibit highest specificity and cell-killing potency for GPR56-high TNBC cells will then be tested for any toxicity in normal healthy mice. We will then evaluate GPR56 ADCs in mouse models using human TNBC cell lines and patient-derived tumors with or without BRCA1/2 mutations. In Aim 3, we will test if GPR56 ADCs in combination with PARP inhibitors augments antitumor efficacy and prevents metastasis in a model of mouse mammary carcinoma using non-invasive imaging. Importantly, this study will provide a preclinical evaluation of unique GPR56 ADCs as a single-targeted therapy and in combination with PARP inhibitors for the improved treatment of TNBC patients that otherwise have limited targeted therapeutic options.
