Project Description Narrative:
Lung cancer stands as a global health concern, exerting a profound impact on mortality and morbidity across the world. It is the leading cause of cancer-related deaths, affecting both developed and developing nations. According to 2023 data from the American Cancer Society, lung cancer is the leading cause of cancer-induced mortality in Wisconsin, surpassing the combined fatalities attributed to pancreatic and colorectal cancers. This stark statistic underscores that despite strides in therapeutic advancement and the declining trend in lung cancer mortality, the need for more efficacious treatments remains unmet to alleviate the burden of lung cancer at local, national, and international levels. Small-cell lung cancer (SCLC), a highly aggressive neuroendocrine lung cancer, constitutes 13-15% of all lung cancers, with two-thirds diagnosed at the metastatic or extensive stage (ES).
Despite a robust initial treatment response, recurrence is inevitable, and five-year survival rates are less than 15% for limited stage (LS) and less than 2% for ES-SCLC. Limited therapeutic options exist due to the absence of oncogenic driver mutations, but SCLC often exhibits a significant tumor mutational burden, prompting consideration of combining immune checkpoint blockage with chemotherapy as a front-line approach. Clinical trials like CASPIAN and IMpower133 demonstrated improved survival with chemoimmunotherapy, but only a subset of patients benefited. In most SCLC, immunotherapy treatment leads to no clinical benefit due to lack of antigen presentation by tumor cells as well as an immune cold tumor microenvironment. This highlights the need to develop strategies to enhance immunotherapy efficacy in SCLC, including restoring antigen presentation. Genome-wide profiling studies have uncovered mutations in various histone-modifying proteins, including CREBBP, p300, and KMT2D, in primary SCLC. SCLC is distinguished by its characteristic low or absent MHC-I expression, and recent research has emphasized the involvement of epigenetic mechanisms in this phenomenon. Numerous epigenetic modifiers, such as EZH2, LSD1, and KDM6A, have been recognized as contributors to MHC-I silencing in SCLC. These findings collectively support the notion that epigenetic deregulation plays a pivotal role in driving the development and progression of SCLC. Enhancer of zeste homolog 2 (EZH2) is part of the Polycomb Repressive Complex 2 (PRC2), essential for chromatin modification and gene suppression through methylation of lysine 27 of histone H3 (H3K27me3). EZH1, a paralog of EZH2, forms an alternative PRC2 complex and likely exhibits functional redundancy with EZH2. EZH2 overexpression and mutations are linked to cancers like follicular lymphoma and sarcomas. Recent research has shown that targeted EZH2 inhibition enhances SCLC tumor immunogenicity by activating MHC-I genes expression.
Nevertheless, the function of EZH1 in this specific context remains unexplored. Therefore, this study will investigate the impact of dual EZH1/EZH2 inhibition on MHC-I genes and novel transcriptional programs influencing immunotherapy response in SCLC.