Details

Autor(en) / Beteiligte

• Segatto, I
• Massarut, S
• Boyle, R
• Baldassarre, G
• Walker, D
• Belletti, B

Titel

Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer

Ist Teil von

• European journal of cancer (1990), 2016-12, Vol.69, p.S36-S36

Ort / Verlag

Oxford: Elsevier Science Ltd

Erscheinungsjahr

2016

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Background: Triple Negative Breast Cancer (TNBC) is an aggressive malignancy with dismal prognosis owing to high levels of recurrence. It has been shown that p7036 kinase (p7056K) is activated via post-surgical inflammation and can mediate recurrence in a mouse model of TNBC. The purpose of the current study is to validate whether a novel p70S6K1 inhibitor, FS115, can control the formation of recurrence and metastasis in pre-clinical models of TNBC. Material and Methods: FS115 was synthesized by Sentinel Oncology. IC50s were determined via radiometric kinase assays. Cell colony assay: MDA-MB-231 cells (basal, TNBC) were treated with FS115 or vehicle then seeded onto plates and incubated for 14 d prior to colony counting. The pharmacokinetic (PK) profile was determined in two separate cohorts of CD-i mice (dosed P0 or IV with FSI15). Pharmacodynamics (PD) were determined as follows: nude mice bearing MDA-MB-231 tumours were dosed with FS115 (125mg/kg BID x 3 P0) or vehicle, then 12 h after the last dose mice were sacrificed and tumour ELISA carried out to measure levels of p-S6 240/244, t-S6, p-AKT 473 and t-AKT. Local recurrence was modelled in vivo: MDA-MB-231 orthotopic primary tumors were first grown in nude mice. The mice were treated with FS115 or vehicle in a pen-operative schedule (day -1, day 0, day +1; surgery on day 0) then monitored for recurrence for 56 d. Metastasis was modelled in vivo as follows: On day -1, nude mice were assigned to treatment groups. On day 0, mice were given an intracardiac injection of MDA-MB-231-Iuc cells (luciferase-expressing). Mice were dosed for a further 68 days and were then imaged for total photon flux to show metastatic spread. Results: In vitro, FS1 15 potently inhibits p70S6K1 (IC50 0.035 μM) with high selectivity over P13K pathway kinases (AKT2 IC50 23.8 μM). In MDA- MB-231, a TNBC cell line, FS115 inhibits p70S6K activity in a dose- dependent manner (optimal effect at 10 μM) and suppresses colony growth in the range 1-10μm. The PK profile of FS115 in mice shows high oral bioavailability (>95%) and favorable brain penetration (4:1 B:P). PD studies reveal that FS115 inhibits phosphorylation of p70S6K substrate S6 in tumour by 55% without concomitant AKT activation. In mouse models of TNBC, FS115 was found to inhibit multiple facets of the disease including (a) tumor take rate and growth, (b) local recurrence and (c) metastasis, including brain metastasis. Conclusions: Here, we show that a small molecule oral inhibitor of p70S6K1, FS115, dosed to mice in a pen-operative schedule was effective in decreasing local recurrence of breast cancer and in long-term treatment schedule was well-tolerated and efficiently suppressed distant metastasis formation. Altogether, these findings suggest that an inhibitor of p70S6K1 could provide a targeted treatment option for TNBC patients at high risk of recurrence.