Abstract 3534: PBI-1402, a first-in-class erythropoiesis regulating agent, possesses differentiation properties and demonstrates synergistic anticancer activity in combination with chemotherapy

Abstract

Abstract Background: PBI-1402 reduces the need for transfusion and increases hemoglobin (Hb) level and red blood cell count (RBC) in chemotherapy-induced anemia (CIA) patients by a mechanism of action which is distinct from erythropoietin (EPO). The PBI-1402 receptor is also expressed on certain cancer cells such as leukemia (K562), lung (LL-2), prostate (PC-3) and pancreas (Panc-02). Aim: The objective of this study was to determine the role of the PBI-1402 receptor on tumor growth. Methods: Cell proliferation and differentiation of K562 (human erythroleukemia) was studied in presence of PBI-1402 or EPO using 2,7-diaminofluorene for hemoglobin quantification. The effect of oral administration of PBI-1402 in combination with chemotherapy agents (gemcitabine or cyclophosphamide) was studied in subcutaneous syngeneic Panc02, LL-2 and xenogeneic PC-3 models. Results: PBI-1402 inhibits proliferation of K562 cells and promotes differentiation of the remaining cells. K562 cells express both EPO and PBI-1402 receptors. EPO increases phosphorylation of ERK1/2 and Stat3 (linked to cell proliferation) while PBI-1402 decreases it in a dose dependent manner. The antitumor efficacy of oral administration of PBI-1402 was studied in combination with gemcitabine in subcutaneous LL2 and Panc02 as well as in orthotopic Panc02 cancers. In subcutaneous Panc02, gemcitabine induced a significant inhibition (p<0.05) of tumor growth from day 27 to 34 with T/C from 55% to 78%. PBI-1402 induced a significant inhibition (p<0.05) of tumor growth from day 23 to 44 with T/C from 26% to 58%. The combination therapy induced a significant (p<0.05) inhibition of tumor growth and T/C<40% from day 23 to 37 when compared to control and at day 23, 25 and 30 to 39 when compared to gemcitabine alone. In orthotopic Panc02, mice treated with gemcitabine or a combination of gemcitabine and PBI-1402 displayed prolonged survival (71 and 88 days, respectively) compared to control (48 days). In LL-2 cancer, at day 25, mice treated with PBI-1402 or gemcitabine alone had a T/C of 94% and 72%, respectively. Mice treated with a combination of gemcitabine plus PBI-1402 displayed a significant (synergistic) reduction of tumor growth (T/C: 33%). The effect of PBI-1402 alone or in combination with cyclophosphamide was also studied in a xenograft prostate PC-3 tumor. Mice treated with PBI-1402 or cyclophosphamide alone have a significant T/C<40% from day 21 to 56 and day 35 to 56, respectively. Mice treated with a combination of cyclophosphamide plus PBI-1402 displayed tumor regression from day 21 to 56. Conclusion: These results suggest that PBI-1402 has the potential to inhibit the growth of lung, prostate and pancreatic cancer by induction of cell differentiation. PBI-1402-differentiated cancer cells appear to be more susceptible to chemotherapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3534. doi:10.1158/1538-7445.AM2011-3534