Presenter:
Olivia Amodeo
Prostate cancer (Pca) is one of the most common types of cancers and accounts for the second- largest number of cancer-related deaths in men. Most therapeutic strategies target the androgen receptor in PCa; however, PCa often adapts and becomes resistant to treatment. The latter has led to the emergence of neuroendocrine prostate cancer (NEPC), a lethal histological subtype that is resistant to AR-targeted treatments, characterized by high proliferation and poor prognosis. A critical knowledge gap remains regarding actionable molecular targets that drive NEPC progression that could be therapeutically exploited. Using publicly available RNA- seq cancer datasets, we found that Tyrosine Threonine Kinase (TTK), a mitotic checkpoint kinase, is upregulated in NEPC. We believe that TTK is essential for tumor growth and can be targeted to improve treatment outcomes. To test this, we employed genetic and pharmacological approaches in NEPC cell lines to determine if targeting TTK resulted in reduced proliferation. In addition, we conducted phospho-proteomic analysis to identify TTK- NEPC phospho-targets. RABL6, a member of the Ras family of small GTPases, was identified as a putative TTK phospho-target. Our studies have shown that TTK inhibition significantly impairs the growth of NEPC cells. Combining the TTK inhibitor, CFI-402257, with a commonly used chemotherapy drug, docetaxel, resulted in a synergistic inhibitory effect on NEPC cell growth. Furthermore, our data shows that RABL6 is also elevated in advanced PCa, and genetic depletion slows NEPC cell growth. Cumulatively, our data suggest that the TTK-RABL6 pathway plays a role in the development of NEPC tumor cells. Further studies are warranted to determine if TTK is a promising therapeutic target in NEPC and provide a rationale for future clinical exploration of the clinical compound CFI-402257. A GIANT Step for Glioblastoma Research: Characterization of T Cell Activation and Expansion with anti-PD1 and anti-Lag3 Immune Checkpoint Therapy
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Presenter: Olivia Amodeo
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Glioblastoma is the most aggressive brain tumor, notorious for its therapeutic resistance, immunosuppressed tumor microenvironment (TME), and paucity of active tumor-infiltrating lymphocytes (TILs) capable of triggering an antitumoral response. Immune checkpoint blockers (ICB) targeting suppressive molecules such as programmed cell death protein 1 (PD- 1) and lymphocyte activation gene 3 (LAG-3) have shown efficacy in melanoma treatment. In preclinical studies, combination anti-PD-1 and anti-LAG-3 treatment has been shown to enhance immune activation and increase TILs in the TME. It is hypothesized that this co- inhibition is also associated with phenotypic changes observed in T cells, shifting to a natural killer (NK) / natural killer T (NKT) cell signature. NK/NKT cells interact with other cells in an HLA-independent manner, so the T cell adoption of a NK-like phenotype could improve immune activation and cancer cell killing. To investigate T cell reprogramming, we expanded T cells from peripheral blood mononuclear cells (PBMCs) of a glioblastoma patient (under a Duke IRB-approved protocol) using anti-CD3/anti-CD28 stimulation with anti-PD1 (nivolumab) or anti-PD1 + anti-Lag3 (relatlimab) over a 14-day period. We aimed to characterize the phenotypic expression of T cell and NK cell signatures at different timepoints throughout treatment based on growth kinetics, spectral flow cytometry, and bulk RNA sequencing on days 0, 3, 7, 10, and 14. Data from these in vitro studies will help demonstrate if this shift occurs simultaneously with T cell activation and to what degree phenotypic changes are observed. This pre-clinical study is conducted in parallel with our upcoming clinical trial of PD-1/LAG-3 co-inhibition in newly diagnosed glioblastoma (NCT06816927). Mechanistic studies will complement analyses of human biospecimens to better understand the effects of nivolumab and relatlimab on T cell activation, proliferation, exhaustion, and memory formation, as well as generate new insights into the role of NK/NKT cells.
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Duke University / 2025
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Presenter: Olivia Amodeo