Wednesday, April 2, 2025
4/2/2025
A Novel Approach to Enhance Therapeutic Efficacy of Tarlatamab for Small Cell Lung Cancer Treatment - PROJECT SUMMARY Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer with a dismal survival rate. The response of SCLC to current therapies is short-lived and the disease progression is inevitable in most patients. Furthermore, unlike other lung cancer types, there is a notable scarcity of targeted therapies in SCLC. The bispecific T-cell engager (BiTE) antibodies represent a transformative new approach in cancer therapy that facilitates T-cell-mediated eradication of cancer cells. Due to their effectiveness the U.S. FDA has approved several BiTE antibodies for treating various cancers. Delta-like ligand 3 (DLL3) is overexpressed in most SCLCs, which prompted the development of a novel BiTE antibody, Tarlatamab. Tarlatamab specifically targets DLL3 on SCLC cells and CD3 on T-cells, leading to T-cell mediated tumor lysis. In the recent Phase II clinical trial DeLLphi-301, Tarlatamab demonstrated potent anti-tumor activity, achieving durable objective responses in 40% of previously treated SCLC patients and showing encouraging survival outcomes. The Phase III clinical trial (ClinicalTrial.Gov ID# NCT05740566) is underway and its clinical approval in the third-line (3L) setting for SCLC is expected to occur this year. However, the median progression-free survival benefit with Tarlatamab is limited to approximately 4.9 months, highlighting the need to identify molecular drivers of response, which will allow more effective use of Tarlatamab in SCLC patients. We performed a CRISPR-based gene activation (CRISPR- a) screen by activating the expression of over 350 human genes encoding epigenetic regulators. This screen and subsequent analyses identified EZH2 overexpression as a key event that drives Tarlatamab resistance in SCLC. Our overall objective is to determine the in vivo role of EZH2 in conferring resistance to Tarlatamab in SCLC and evaluate pharmacological inhibition of EZH2 for enhancing the efficacy of Tarlatamab in SCLC. In Aim 1 studies, we will model the in vivo impact of genetic and pharmacological inhibition of EZH2 in forestalling and reversing the resistance to Tarlatamab in SCLC. To test this, we will use human SCLC cells and T-cell admixture mouse model and a novel immunocompetent humanized mouse model with a human immune system. To pharmacologically inhibit EZH2, we will use a U.S. FDA approved EZH2 inhibitor Tazemetostat, and test if treatment of SCLC cells with Tazemetostat can forestall and/or reverse the resistance to Tarlatamab in SCLC. In Aim 2 studies, we will elucidate the role of canonical and non-canonical functions of EZH2 in driving resistance to Tarlatamab in SCLC. First, we will determine the role of EZH2-mediated transcriptional repression of DLL3 and other DLL3-independent mechanisms in conferring resistance to Tarlatamab. Next, we will utilize the EZH2 degrader, MS1943, and a catalytically inactive mutant of EZH2 to probe the non-canonical functions of EZH2 in determining resistance to Tarlatamab in SCLC. Collectively, these studies will identify a novel therapeutically targetable pathway to enhance the efficacy of Tarlatamab in SCLC.
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