Poster Presentation 28th Lorne Cancer Conference 2016

TRXE-009-1, an investigational small molecule, significantly inhibits tumour growth and extends survival in vivo (#102)

Eleanor I Ager 1 , Dhanalakshmi Sivanandhan 2 , Ram Sudheer Adluri 3 , Alex Stevenson 4 , Eleanor Eiffe 1 , Andrew Heaton 1 , Brain Gabrielli 4 , David Brown 1
  1. Novogen, Hornsby, NSW, Australia
  2. Jubilant LifeSciences, Bangaluru
  3. GVK Bio, Hyderabad
  4. University of Queensland Diamantina Institute, Woolloongabba

TRXE-009-1 is a novel small molecule identified using Novogen’s proprietary VAL-ID – Versatile Approach to Library-based Iterative Design – medicinal chemistry program, which has proven to be a rapid and robust method of identifying lead oncology compounds. Here, we investigated the efficacy of TRXE-009-1 in vitro and in vivo against multiple cancer types. Viability assays indicated sub-micromolar IC50s against prostate, lung, ovarian, and brain cancer (glioblastoma [GBM]) cell lines. A screen of over 15 melanoma cell lines grown as 3D spheres indicated sensitive and resistant populations, but resistance did not reflect BRAF, PTEN, or p53 status. We next tested TRXE-009-1 in vivo. Treatment was initiated at an average tumour volume of ~100mm3. Both DU145 and PC3 subcutaneous (s.c.) xenograft prostate cancer models demonstrated decreased tumour volume from day 7 (P ≤0.0136) and 74% (PC3) or 67% (DU145) inhibition in final tumour volume (P <0.0001) with TRXE-009-1 monotherapy compared to vehicle control. Survival following 15 days of TRXE-009-1 monotherapy was also significantly improved compared to control in a s.c. PC3 model (median survival 18 days control vs. 33 days treatment, P <0.0001). We next tested the ability of TRXE-009-1 to combine with Dabrafenib against melanoma using a xenograft A375 model and, in an immunocompetent model, we tested TRXE-009-1 against B16-F10 melanoma allografts in C57BL/6 mice. These studies indicated significant tumour growth inhibition with single-agent TRXE-009-1 treatment against both A375 and B16 (P <0.0001). Against A375, the combination of Dabrafenib and TRXE-009-1 was significantly more effective than either monotherapy (P ≤0.0003). Additional survival studies utilising orthotopic cancer models and in vitro studies investigating cell death pathways initiated by TRXE-009-1 are currently ongoing. Our existing pre-clinical data indicate the potential for TRXE-009-1 to provide clinical benefit with subsequent studies designed to further identify appropriate target populations for clinical development.