Abstract 5718: TGN-1062, a dual CDK7 and FLT3 Inhibitor, shows potent anti-AML activity and synergizes with Venetoclax
Authors: Thode Trason , Nguyen Le Xuan Truong , Durbin Brian , Weston Alexis , Ng Serina , Halder Tithi Ghosh , Bargenquast Taylor , Soldi Raffaella , Kasibhatla Srinivas , Chung Vincent , Villaflor Victoria , Kaadige Mohan , Marcucci Guido , Sharma Sunil 
Published: March 2024

Abstract
Purpose: Acute Myeloid leukemia (AML) is an aggressive malignancy of the hematopoietic system with poor survival rates. The best responses to treatment are achieved for young and fit patients who can tolerate chemotherapy followed by stem cell transplantation compared to older patients unfit to take intense chemotherapy. Since its approval venetoclax, a BCL2 inhibitor, has been the standard treatment for older patients in combination with a hypomethylating agent (HMA), such as azacitidine or decitabine, with a 76% complete response (CR). Despite this success as a frontline treatment, there is limited response for patients with relapse and refractory (r/r) and development of novel agents is required to improve overall therapeutic response. MYC has been shown to be frequently activated in AML and plays an important role in the induction of leukemogenesis and leukemic progression. While BCL2 inhibition via venetoclax has, in part, been shown to control c-MYC activation, the addition of another inhibitor which controls MYC may prove beneficial. CDK7 plays a dual role in tumor progression by regulating the cell cycle and transcription. CDK7 has also been shown to be associated with the overexpression of oncogenic driver genes such as BCL2 and MYC. Previously, we have presented the development of a potent and reversible CDK7 inhibitor, TGN-1062. Here, we have generated data supporting the potential benefit of CDK7 inhibition in combination with standard of care therapy for AML.
Methods: AML lines were co-treated with TGN-1062, venetoclax, and/or an HMA, assessed for viabilities with CellTiter-Glo, and analyzed with the Bliss synergy model. AML CDX or PDX cells were implanted subcutaneously or transplanted via tail vein, respectively, and treated with TGN-1062 and/or venetoclax. Subcutaneous tumors were measured to determine tumor growth inhibition (TGI) and correlating drug accumulation levels were measured in tumors and plasma using mass spectrometry. Leukemic burden and survival were evaluated at the end of treatment for transplanted models. Immunohistochemistry (IHC), Western blotting, and RT-PCR were performed to determine changes in relevant biomarkers in tumors and/or AML cell lines.
Results: Previously we have reported that TGN-1062 was effective in suppressing the growth of MV4-11 AML model. We extend these studies and show that TGN-1062 has activity at lower doses in both in vitro and in vivo AML models. In addition, we show synergy between TGN-1062 and other agents for AML treatment, including venetoclax or an HMA. Western blotting demonstrated significant changes in apoptotic markers. Survival of mice bearing AML was significantly increased with TGN-1062 treatment and combination treatment with venetoclax produced the longest survival.
Conclusion: Targeting CDK7 with TGN-1062 in combination with venetoclax or an HMA is a promising therapeutic approach for treatment of AML and needs further investigation.
Citation Format: Trason Thode, Le Xuan Truong Nguyen, Brian Durbin, Alexis Weston, Serina Ng, Tithi Ghosh Halder, Taylor Bargenquast, Raffaella Soldi, Srinivas Kasibhatla, Vincent Chung, Victoria Villaflor, Mohan Kaadige, Guido Marcucci, Sunil Sharma. TGN-1062, a dual CDK7 and FLT3 Inhibitor, shows potent anti-AML activity and synergizes with Venetoclax [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5718.