Poster Presentation 26th Lorne Cancer Conference 2014

BL-011256 is a novel VEGFR3 selective inhibitor, which suppresses tumour lymphatics and lymph node metastasis in an animal model of melanoma (#193)

Annabell Leske 1 2 , Richard Foitzik 2 3 , Donna Beaumont 1 2 , John Bentley 2 4 , Ylva Bergman 2 3 , Chloe Brown 1 2 , Michelle Camerino 2 3 , Susan Charman 2 5 , Neil Choi 2 3 , Matthew Chung 2 6 , Melanie De Silva 2 7 , Hendrik Falk 2 7 , Daniel Ganame 2 7 8 , Alison Gregg 2 5 , Julian Grusovin 2 4 , Andrew Harvey 1 2 , Catherine Hemley 2 3 , Ian Holmes 2 , Belinda Huff 1 2 , Daniel Inglis 1 2 , Wilhelmus Kersten 2 7 8 , Tina Lavranos 1 2 , Romina Lessene 2 7 8 , Gillian Lunniss 2 3 , Brendon Monahan 2 4 , Benjamin Morrow 2 3 , Marica Nikac 2 3 , George Nikolakopoulos 2 7 8 , Dharam Paul 1 2 , Tom Peat 2 4 , Justin Ripper 1 2 , Michaela Scherer 1 2 , Paul Stupple 2 7 8 , Karen White 2 5 , Ian Street 2 , Gabriel Kremmidiotis 1 2
  1. Bionomics Limited, Thebarton, SA, Australia
  2. Cancer Therapeutics CRC, Bundoora, Vic, Australia
  3. Monash Institute of Pharmaceutical Sciences, Parkville, Vic, Australia
  4. CSIRO Materials Science and Engineering, Parkville, Vic, Australia
  5. CDCO, Monash Institute of Pharmaceutical Sciences, Parkville, Vic, Australia
  6. St Vincent's Institute, Fitzroy, Vic, Australia
  7. Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia
  8. Department of Medicinal Biology, The University of Melbourne, Parkville, Vic, Australia

The role of VEGFR3 in lymphangiogenesis has been well established. Targeting VEGFR3 has been shown to curtail tumour progression mediated via lymphatic dissemination. Recently VEGFR3 was shown to play an important role in the mediation of tumour-induced immune cell tolerance. We have identified BL-011256, a novel inhibitor of VEGFR3 that exhibits 17-fold selectivity over VEGFR2 and a narrow tyrosine kinase inhibition spectrum. A 7-day b.i.d repeat oral dose study showed that BL-011256 is well tolerated in mice. Mouse plasma exposure demonstrated that BL-011256 attains free drug plasma levels that exceed the concentration required for IC50 activity on VEGFR3 in vitro but are considerably lower than the in vitro IC50 required for activity on VEGFR2. In the B16F10 mouse melanoma model, animals bearing melanoma tumours displayed attenuated signs of tumour progression when treated. BL-011256 caused a 70% reduction in primary lesion growth and a 50% reduction in metastasis to the draining lymph node. Furthermore, BL-011256 was active in reducing the number of satellite in-transit metastases. Immunohistochemical whole mount analyses on ears with primary tumour lesions from BL-011256 and vehicle treated mice using Lyve-1 for identification of lymphatic vessels and CD31 for identification of blood vessels was conducted. Tumours in vehicle-treated mice displayed a peri-tumoural area densely populated by lymphatic vessels. In contrast, tumours derived from BL-011256 treated mice were devoid of peri-tumoural lymphatic vessels. Notably, both vehicle-treated and BL-011256-treated animals displayed similar staining for peri-tumoural blood vessels, suggesting no effect on blood vessels (consistent with no activity on VEGFR2). Furthermore, PK sampling during the last day of dosing in a 14-day dosing schedule demonstrated no compound accumulation during the repeat dosing schedule utilised in the B16F10 tumour efficacy experiment. In conclusion BL-011256 has been identified as a selective inhibitor of VEGFR3 that supresses both primary tumour growth and lymph node metastasis.