AACR 2017 | Poster 5179/22 – TK-216, the first in class FLI1 inhibitor, demonstrates in vivo and in vitro anti-tumor activity in Lymphoma

At the American Association for Cancer Research (AACR) annual meeting in Washington, DC, USA, on Wednesday 5^th April, a poster session titled “Oncogenes and Tumor Suppressors as Therapeutic Targets” took place.

One of the posters on display (5179 / 22) was titled “The first in class FLI1 inhibitor TK-216 presents both in vitro and in vivo anti-tumor activity in lymphoma” by Filippo Spriano from the Institute of Oncology Research, Bellinzona, Switzerland, and colleagues.

This poster presented extensive preclinical results obtained with TK-216 in in vitro and in vivo lymphoma models. TK-216 is a clinical derivative of YK-4-279, which is a small molecule that inhibits the EWS1-FLI1 fusion protein binding to RHA resulting in reduced growth and increased apoptosis in Ewing sarcoma cells.

In total, in vitro studies were carried out using 56 cell lines (n = 27 DLBCL; n = 10 MCL; n = 6 MZL; n = 5 T-cell ALCL; n = 8 others), which were given TK-216 at increasing doses for 72 hours. DLBCL TMD8 xenografts in NOD-SCID mice were used for the in vivo studies and treatment was administered at approximately SC 60mm³ tumor volumes. Lastly, using DLBCL cell lines, TK-216 was tested in combination with other targeted agents.

Key Highlights:

• TK-216 displayed high activity: median IC₅₀ = 449nM (95%CI, 367–506)
• Sensitivity was not affected by cell of origin (B vs T; ABC vs GC DLBCL) or MYC and TP53 status
• Non-statistically significant trend reported for lower sensitivity in cell lines harboring BCL2 chromosomal translocation (P = 0.07, DLBCL only; P = 0.06, all cell lines)
• Cell cycle analysis found that anti-tumor activity was mainly cytotoxic; time-dependent apoptosis came after G2/M arrest
• In vivo, compared with control group (n = 10), administration of TK-216 (100mg/Kg, BID; n = 9) reduced tumor growth, observed as early as day 3 and becoming much stronger with time (D3, D5, D8, D11: P < 0.01)
• A 4-fold reduction in tumor volume was reported at D11 (P < 0.01)
• Benefit was reported when combining TK-216 with:
  • Lenalidomide: synergism in 2/2 ABC DLBCL
  • OTX015 (MK-8628): synergism in 2/4 cells and additive effect in 1/4
  • Rituximab: synergism in 2/3 cells
  • Venetoclax: synergism in 3/4 cells (could be related to the negative trend between TK-216 IC₅₀ values and the presence of BCL2 translocation)

In conclusion, TK-216 demonstrated strong preclinical anti-tumor activity in Lymphoma, providing a rationale for further investigation in preclinical and clinical settings as monotherapy and in combination regimens.