Abstract 4521: P7170, a novel inhibitor of phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) and activin receptor-like kinase 1 (ALK1) shows anti-tumor activity in triple negative breast cancer
Authors: Agarwal Veena R. , Bhatia Dimple , Joshi Asavari , Mishra Prabha , Bharadwaj Kalyani G. , lobo Aurelio S. , Menon Pranoy , Dhar Payal , Pandey Prashant , Srinivasa Sreesha , sonawane vinay 
Published: May 2015

Abstract
Triple negative breast cancer (TNBC) lacks ER, PR and Her2 receptor expression & accounts for nearly 10-15% of all breast cancer. It is an aggressive disease with high risk for early relapse & visceral metastasis leading to poor survival as compared to other subtypes. Currently, there is no targeted therapy beyond cytotoxic chemotherapy for TNBC. PI3K-mTOR pathway is often dysregulated (via mutations in PI3K or PTEN) in TNBC and hence offers an opportunity to develop a therapeutic to address the high unmet medical need in this disease. P7170, a small molecule mTOR/PI3K/ALK1 inhibitor with potent antitumor activity in various cancer types {Cancer Res, April 15,2012; 72(8 Supplement): 3742 and 3759} is currently undergoing Phase 1 clinical trial. Here, we report the evaluation of anti-tumor activity and the identification of potential pharmacodynamic markers of P7170 in a TNBC model. P7170 inhibited proliferation (IC50 range 5 - 38 nmol/L) in TNBC cell lines as determined using propidium iodide (PI) assay. In addition, P7170 inhibited anchorage-independent growth of tumor cells isolated from patient derived tumor xenografts evaluated in a clonogenic assay. PI3K-mTOR pathway proteins pS6 and p4EBP1 were potently inhibited whereas pAkt was modestly inhibited by P7170 in MDA-MB-231 cells as assessed by Western blot. It also inhibited migration of MDA-MB-231 cells in a transwell migration assay. P7170 at 1/3rd dose of Maximum tolerated dose (5 mg/kg, po) as a single agent resulted in 63% (P&lt;0.05) tumor growth inhibition in MDA-MB-231 xenograft mouse model. Pharmacodynamic effects of P7170 were evaluated in the plasma, tumor and skin of MDA-MB-231 tumor bearing mice treated with
P7170 (5 and 15 mg/kg) orally for 3 days. Expression of target genes was measured by qRT-PCR, tumor and skin proteins were measured by immunohistochemistry, and plasma proteins by ELISA. P7170 significantly reduced pS6 protein in a dose-and time-dependent manner in the tumor and skin. P7170 significantly reduced tumor p4EBP1 protein at the highest dose and reduced tumor CDC25A gene by 2-fold. In addition, P7170 dose-dependently reduced plasma IGF1/IGFBP3 ratios compared to vehicle group. Conclusion: These data suggest that P7170 demonstrates robust antiproliferative activities in vitro and anti-tumor activity in vivo in TNBC. Tumor pS6 protein, CDC25A transcript levels and skin pS6 levels were identified as pharmacodynamic markers of P7170 activity. P7170 could be a therapeutic option for TNBC patients, and warrants testing in a clinical trial.
Citation Format: Veena R. Agarwal, Dimple Bhatia, Asavari Joshi, Prabha Mishra, Kalyani G. Bharadwaj, Aurelio S. lobo, Pranoy Menon, Payal Dhar, Prashant Pandey, Sreesha Srinivasa, vinay sonawane. P7170, a novel inhibitor of phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) and activin receptor-like kinase 1 (ALK1) shows anti-tumor activity in triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4521. doi:10.1158/1538-7445.AM2014-4521