BKM120, a pure PI3K inhibitor, demonstrates stronger anti tumoral effect than BEZ235, a dual PI3K-mTOR inhibitor, on rat prolactin secreting pituitary tumor SMtTW-3

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 88-111-Cushing's Disease & Non-Functioning Hypothalamus-Pituitary Tumors
Clinical
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-98
Carole Auger1, Pascale Chevallier2, Alexa Rachwan3, Veronique Raverot4, Marie Chanal5, Jacqueline . Trouillas6 and Gerald Raverot*7
1UniversitéLyon1-INSERM, UMR-S1028, Lyon, France, 2Université Lyon1- INSERM , UMR S1028, Lyon, France, 3Université Lyon1_ INSERM, UMR-S1028, LYON, France, 4Hospices Civils de Lyon, Lyon, France, 5Université Lyon1- INSERM, UMR-S1028, Lyon, France, 6Université Lyon1-INSERM, UMR-S1028, Lyon, France, 7Université Lyon1_ INSERM, UMR-S1028, Lyon,, France
Introduction: 15% of pituitary tumors are considered as aggressive based on resistance to conventional treatment. Less than 40% of these cases respond to temozolomide treatment underlining the need for new therapeutic options. The PI3K/Akt/mTOR pathway, upregulated in different pituitary tumors subtypes, can be targeted by different drugs in particular BKM 120, a pure PI3K inhibitor, and BEZ235, a dual PI3K/mTOR inhibitor.

Objective: To study the anti-tumoral effect of BKM120 and BEZ235, on a model of rat prolactin pituitary tumor SMtTW-3.

Method: One month after grafted SMtTW3 rats were treated via oral gavage 5 days/week with BKM120 (5mg/kg/day, 20 days; n=15) or BEZ235 (20mg/kg/day, 15 days (n=13) or 30 days (n=13)) or control (n=10 for each treatment). Antitumoral effect was evaluated by measuring tumor weigh at sacrificed and prolactin plasma level was measured before and after treatment. Ki67 index, mitosis were calculated on tumor section.

Results:

BKM120 treatment reduces significantly tumor growth and prolactin secretion compare to controls with a final tumor weight of 5.36 ± 2.27g vs  28.76 ± 7.50g  (p<0.001) and prolactin concentration of 1909 ± 234.6µg/L  vs 5465 ± 1026µg/L.

BEZ235 treatment was less efficient and reduced tumor growth only after 30 days compare to control (35.87±16.40g vs 47.52±8.69g; p <0.05) and did not significantly decrease tumor growth after 15 days (10.89 ± 4.06g vs11.86 ± 5.83g) or prolactin secretion after 15 or 30 days of treatment (respectively 6718 ± 3687 vs 7183 ± 4452µg/l and 6846 ± 3676 vs 8275 ± 4323 µg/L).

Both treatments were associated with a decrease of ki67 index and mitosis compared to tumors in control group.

Conclusion: BKM120, a pure PI3K inhibitor, present promising result for treating patient with aggressive pituitary tumor resistant to any conventional treatment. Differential effect between BKM120 and BEZ235 on tumor growth and PI3K/AKT/mTOR pathway is under investigation.

Disclosure: GR: Principal Investigator, Novartis Pharmaceuticals. Nothing to Disclose: CA, PC, AR, VR, MC, JT

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: BEZ235 and BKM210 were provide by NovartisPharma and this work was support by a research funding from Novartis Pharma.