Program: Oral and Poster Abstracts
Session: 615. Acute Myeloid Leukemia: Commercially Available Therapy, excluding Transplantation: Poster II
We next investigated the effects of ONC212 in vivo in a systemic AML xenograft model using OCI-AML3 cells expressing luciferase. Biweekly oral administration of 50 mg/kg ONC212 markedly inhibited AML expansion and prolonged overall survival (p = 0.0003). Median survival increased from 43 d in controls to 49 d in the ONC212-treated group (+14%). For in vivo functional assessment of ONC212’s anti-tumor effects against leukemia stem and progenitor cells, we utilized our patient-derived xenograft (PDX) mouse model. We treated primary PDX cells with ONC212 (250 nM, 36 hr) ex vivo, and then injected identical numbers of viable cells (treated or untreated) into recipient NSG mice. After one month, the percentages of human CD45+ cells in the peripheral blood, spleen, and BM were significantly decreased in the ONC212-treated group. The median survival in this group was remarkably different: 82 d compared to 36 d for controls (+128%, p<0.0001). These results indicated that ONC212 targets AML stem cells with potential to eradicate the disease.
Because BCL-2 is generally considered protective against ISR-mediated apoptosis and ONC212 induced p53-mediated apoptosis as demonstrated above, we hypothesized that the BCL-2 inhibitor ABT-199 or the p53 activator nutlin-3a could further sensitize AML cells to ONC212. Indeed, the in vitro combination of ONC212 plus ABT-199 or nutlin-3a synergistically induced apoptosis in AML cells. Furthermore, the combination of ONC212 and ABT-199 showed highly significant synergistic anti-leukemia effects in vivo in a MOLM-13 xenograft mouse model. The combinatorial treatment prolonged overall median survival from 20 d for untreated controls to 21 d for each agent as monotherapy to 30 d for the combination.
Since the G-protein-coupled receptor (GPCR) dopamine receptor D2 is the putative target of first-generation imipridone ONC201, we performed a PathHunter β-arrestin screening to determine if ONC212 also bound GPCRs. ONC212 did not engage DRD2 but instead specifically engaged the orphan GPCR GPR132, which is a putative tumor suppressor when activated. Interestingly, expression of GPR132 mRNA was highly correlated with sensitivity to ONC212. Furthermore, GPR132 overexpression induced cell death and ONC212 treatment induced GPR132 mRNA expression in AML cell lines, suggesting that GPR132 could be a potential therapeutic target in hematological malignancies.
Taken together, ONC212, and its putative target GPR132, represent a promising novel anti-cancer strategy for AML therapy that warrants further development.
Disclosures: Prabhu: Oncoceutics: Employment, Equity Ownership. Allen: Oncoceutics: Employment, Equity Ownership, Patents & Royalties. Oster: Oncoceutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Stogniew: Oncoceutics: Employment. Andreeff: Daiichi Sankyo: Consultancy.
See more of: Acute Myeloid Leukemia: Commercially Available Therapy, excluding Transplantation
See more of: Oral and Poster Abstracts