Abstract 3931: TGN-1062 inhibits CDK7 and augments the effects of gemcitabine and nab-paclitaxel in pancreatic cancer models

Abstract

Abstract Purpose: Overexpression of Cyclin-Dependent Kinase 7 (CDK7) is linked to poor clinical outcomes in a variety of cancer types including AML, breast, ovarian, pancreatic, and lung cancers. CDK7 plays a dual role in tumor progression by regulating the cell cycle via phosphorylation of members of the CDK family and stimulation of transcription via phosphorylation of RNA Polymerase II. CDK7 has also been shown to be associated with super-enhancers which can lead to overexpression of oncogenic driver genes such as BCL2, GFI1, and MYC. The development of a selective inhibitor of CDK7 is a promising strategy to control expression of these oncogenic genes in patients’ tumors. Previously, we described the design and synthesis of a potent and selective small molecule inhibitor of CDK7, TGN-1062, which was designed to bind to the catalytic ATP pocket. We showed efficacy in both AML and ovarian in vitro and in vivo models with correlative biomarker data. Here, we have generated further data on the effect and safety of TGN-1062 in pancreatic cancer cell line (CDX) and patient derived xenograft (PDX) models, both as a single agent and in combination with standard of care (SOC) therapies. Methods: In vivo efficacy studies were conducted in mice engrafted with pancreatic CDX and PDX tumors and treated with TGN-1062 with and without SOC therapies. Tumors were measured to determine tumor growth inhibition (TGI) and correlating drug accumulation levels were measured in both tumors and plasma using mass spectrometry. Immunohistochemistry (IHC) was performed on tumors to determine changes in cleaved Caspase-3, MYC, Ki67, and RNA Pol II. Rats were dosed with TGN-1062 to assess plasma exposures and preliminary tolerability. Results: In a pancreatic CDX model (MIA PaCa-2), TGN-1062 showed 38% TGI as a single agent and 121% TGI when in combination with gemcitabine and nab-paclitaxel, which on its own showed 37% TGI. In a pancreatic PDX model, TGN-1062 did not exhibit single agent effect, but combination with gemcitabine and nab-paclitaxel showed 95% TGI compared to 79% TGI with gemcitabine/nab-paclitaxel alone. Drug accumulation, biomarker analysis, and IHC from CDX and PDX tumors, showed that TGN-1062 treatment decreased RNA Pol II phosphorylation and MYC expression, and induced apoptosis. Rat pharmacokinetics indicated 100% oral bioavailability. Conclusion: Our potent and selective small molecule inhibitor of CDK7, TGN-1062, shows promise in pancreatic cancer models as a single or in combination with SOC. Preliminary data suggests that TGN-1062 can be developed further in multiple cancer indications. Citation Format: Alexis Weston, Trason Thode, Ryan Rodriguez del Villar, Serina Ng, Samuel Sampson, Shelby Rheinschmidt, Tithi Ghosh Halder, Raffaella Soldi, Mohan Kaadige, Srinivas Kasibhatla, Haiyong Han, Justin Moser, Vincent Chung, Joseph Chao, Victoria Villaflor, Daniel Von Hoff, Sunil Sharma. TGN-1062 inhibits CDK7 and augments the effects of gemcitabine and nab-paclitaxel in pancreatic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3931.