Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

The highly selective focal adhesion kinase inhibitor CTx-0294945 reduces tumour cell growth in an experimental metastasis model. (#73)

J Doherty 1 2 , A Natoli 1 2 , J Schreuders 1 2 , L Allan 2 3 , R Anderson 1 2 , Y Bergman 2 4 , M Camerino 2 3 , S Charman 2 4 , N Choi 2 4 , T Connor 2 3 , M de Silva 2 3 , H Falk 2 3 , R Foitzik 2 4 , D Ganame 2 3 , M Gorman 2 5 , A Gregg 2 4 , C Hemley 2 3 , G Holloway 2 3 , W Kersten 2 3 , K Lackovic 2 3 , R Lessene 2 3 , K Leuchowius 2 3 , G Lovrecz 2 6 , G Lunniss 2 4 , G McArthur 1 2 , N McKern 2 5 , B Monahan 2 4 , B Morrow 2 4 , M Nikac 2 4 , P Novello 2 3 , M Parker 2 5 , T Peat 2 6 , C Scott 2 7 , M Tiong 2 3 , K Visser 1 2 , S Walker 2 4 , H Yang 2 3 , I Holmes 2 , M Devlin 1 2 , I Street 2 3
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Cancer Therapeutics CRC Pty Ltd, Melbourne, Vic, Australia
  3. The Walter & Eliza Hall Institute of Medical Research, Melbourne, Vic, Australia
  4. Monash Institute of Pharmaceutical Sciences, Parkville, Vic, Australia
  5. SYNthesis Research, Melbourne, Vic, Australia
  6. CSIRO , Parkville, Victoria, Australia
  7. Griffith Institute for Drug Discovery , Griffith University , Nathan, Qld, Australia

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that represents a central point of convergence for many signalling pathways implicated in cancer progression and metastasis. Evidence from pre-clinical models suggests that inhibition of FAK activity in both stromal and tumour cells will aid in the prevention of the growth and metastasis of human cancers.
CTx-0294945 is an orally bioavailable small molecule ATP competitive inhibitor of focal adhesion kinase (FAK KD=0.21 nM). It exhibits high selectivity against a diverse panel of 125 kinases including the closely related Pyk2 (Pyk2 IC50=550 nM). CTx-0294945 inhibits autophosphorylation of 397Y-FAK in MDA-MB-231 cells with an IC50 = 7 nM. The compound exhibits low general cellular toxicity (IC50 = 6.6 µM) against MDA-MB-231 cells grown under standard conditions. CTx-0294945 is suitable for oral administration (%F=58 and t1/2=5.1 h at 20 mg/Kg in rat).
The ability of CTx-0294945 to prevent the outgrowth of micro metastases was assessed in a model of disseminated basal breast cancer. Luciferase tagged MDA-MB-231 cells (105) were injected into the left ventricle of the heart of BalbC SCID mice (n = 9 per group) and treatment with vehicle (hydroxypropylmethylcellulose), or CTx-0294945 (20 mg/kg, 40 mg/kg or 80 mg/kg p.o. QD) was commenced the day after injection of cells. The distribution and growth of metastatic lesions was quantitated by bioluminescent imaging over the course of the experiment. The model exhibited prominent metastasis to the jaw as well as knee joints and internal organs and mice exhibited marked body weight loss that correlated with the strength of the whole body BLI signal. Mice were euthanized when weight loss was ≥ 20% of starting weight or when they displayed overt signs of metastatic disease. CTx-0294945 dose-dependently decreased the rate of metastasis growth based on whole body BLI and increased survival in this aggressive model of tripe-negative breast cancer metastasis. The results recommend further investigation of CTx-0294945 alone and in combination with other targeted and chemotherapeutic agents for the prevention and treatment of breast cancer metastasis.