Abstract 3742: P7170: A potent and oral phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) and activin receptor-like kinase 1 (ALK1) inhibitor with anti-tumor and anti-angiogenic activity

Abstract

The PI3K/mTOR pathway plays an important role in regulating cancer cell proliferation, growth, survival and metabolism. Activation of the PI3K/mTOR pathway by multiple mechanisms is one of the most frequently observed defects in human malignancies. The objective of these studies was to identify a small molecule that has anti-angiogenic activity in addition to PI3K and mTOR activity. P7170, a novel small molecule, inhibits PI3Kα and mTOR enzyme activity with IC50 value of 2.2 nM and 4.4 nM respectively. P7170 also inhibits a number of PI3Kα mutants. The Inhibition of PI3K-mTOR pathway in different cancer cell lines was demonstrated by 80 to 100% inhibition of the expression of phosphorylated AKT (pAKT), S6 ribosomal protein (pS6), and 4EBP1 (p4EBP1) upon treatment with P7170 in a western blot assay. P7170 also inhibited ALK1, an important enzyme involved in angiogenesis, and DNA-PK, an enzyme involved in DNA repair with the IC50 values of 47 and 1.5 nM, respectively. P7170 exhibited potent cytotoxic activity with IC50 values ranging from 2 to 22 nM in a number of cancer cell lines eg. ovarian (A2780), prostate (PC3), triple negative breast (MDA-MB-231 and MDA-MB-468), ER positive breast (MCF7), hepatocellular (HuH-7), renal (786-O), pancreatic (Panc1, AsPC1, and BxPC3), and colon (HCT116, HCT115, SW480) cancer cell lines. More interestingly, P7170 inhibited pAKT and pS6 in stem-like cells isolated from tumor samples of colon, breast, and head and neck cancer patients. P7170 also inhibited anchorage independent colony formation of tumor cells isolated from 39 different human tumor xenografts derived from tumors of patients with different cancers. In addition, P7170 inhibited angiogenesis in vitro in a tube formation assay, and in a matrigel plug assay in animals. It also inhibited metastasis of breast cancer cells. P7170 demonstrated significant in vivo efficacy when administered orally in three human xenograft tumor models. Tumor growth inhibition of 79% at 15 mg/kg in prostate (PC3), 78% at 10 mg/kg in ovarian (A2780), and 64% at 10 mg/kg in triple negative breast (MDA-MB-231) xenografts. Conclusion: P7170 has a unique profile of PI3K-mTOR pathway inhibition along with anti-angiogenic and anti- DNA repair activities. Combined with its effect on stem-like cells, P7170 may prove to be an effective anti-cancer drug. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3742. doi:1538-7445.AM2012-3742

The PI3K/mTOR dual inhibitor P7170 demonstrates potent activity against endocrine-sensitive and endocrine-resistant ER+ breast cancer

“…S1), we did not observe drug-induced changes in P-Smad1/5/8 in MCF-7 tumors by immunoblot or IHC (data not shown). Given the order-of-magnitude difference in P7170 IC 50 values between PI3K/mTOR and ALK1 [16], and the finding that P7170 only modestly inhibits PI3K in vivo at the doses tested (Fig. 3B), we speculate that the concentrations of P7170 achieved in vivo did not adequately inhibit ALK1 to affect P-Smad1/5/8 levels.…”

“…P7170 inhibits the in vitro enzymatic activity of the p110 isoforms of Class IA PI3K and mTOR with IC 50 values of 2.2-203 nM and 4.4 nM, respectively [16]. We tested the effects of treatment with P7170 for 16-24 h on PI3K/AKT/mTOR pathway activation over a range of concentrations in a panel of anti-estrogen-sensitive ER+ breast cancer cell lines.…”

“…P7170 also inhibits the in vitro enzymatic activity of transforming growth factor-β (TGF-β) type I receptor activin receptor-like kinase (ALK1) with an IC 50 value of 47 nM [16]. ALK1 can drive oncogenic phenotypes (reviewed in ref.…”

“…Herein, we evaluated the efficacy the novel ATP-competitive PI3K/mTOR dual inhibitor P7170 [16,17] as a single agent and in combination with the anti-estrogen fulvestrant in preclinical models of ER+ breast cancer.…”