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Andrea Miyahara: Hi everyone. I'm Andrea Miyahara at the Prostate Cancer Foundation. Here with me today is Dr. Sheng-Yu Ku of Dana-Farber Cancer Institute. He will present his recent paper, Notch Signaling Suppresses Neuroendocrine Differentiation and Alters the Immune Microenvironment in Advanced Prostate Cancer. This is published in Journal of Clinical Investigation. Dr. Ku, thanks so much for joining us today.

Sheng-Yu Ku: Thank you for having me, and this opportunity to share our recent work. I'm Sheng-Yu Ku, an instructor at Dana-Farber Cancer Institute in Dr. Himisha Beltran's laboratory.

In this study, we aim to start to understand how neuroendocrine differentiation occurs in prostate cancer. In recent years, we have increasingly observed the rise of the AR-negative neuroendocrine prostate cancer, particularly after AR-targeted therapies. We found that Notch signaling is significantly downregulated in neuroendocrine prostate cancer compared to AR-positive adenocarcinomas, such as downregulations of the Notch-2, ASCL1, and elevation of DLL3.

To investigate the role of Notch signaling in neuroendocrine prostate cancer, we introduced Notch-2 in neuroendocrine prostate cancer organoids, and then implanted in mice to generate an in vivo mouse model. Our studies demonstrate that Notch-2 expression significantly restrained the tumor growth. More importantly, Notch-2 expression suppressed neuroendocrine differentiation by downregulating neuroendocrine genes, including DLL3 and ASCL1, and induced a prostate luminal differentiation.

In addition, we observed that Notch signaling-expressing tumors display multi-tumor lineages, including synaptophysin-positive neuroendocrine lineage, KRT8-positive luminal lineages, and transition lineages that contain both neuroendocrine and luminal lineage, suggesting the plasticity of Notch signaling in prostate cancer lineage differentiation.

Moreover, we observed that Notch signaling also upregulated MHC class I and class II expression. In our transgenic mouse models, we observed that Notch signaling enriched the dendritic cells, macrophage, NK cells, and neutrophils infiltration in tumor microenvironments, suggesting that Notch signals not only change the tumor lineages but also influence the immune microenvironment in neuroendocrine prostate cancer.

In summary, our studies suggested that the Notch signaling is a tumor suppressor in neuroendocrine prostate cancer, where it suppresses neuroendocrine differentiation, induces prostate luminal lineage, and also alters the immune microenvironment. This study may help us understand how neuroendocrine is regulated during the prostate cancer progression.

Lastly, I would like to thank the Prostate Cancer Foundation, National Cancer Institute, and the Department of Defense for funding our work. Thank you.

Andrea Miyahara: Thank you so much for sharing that. So, based on the possible differential role for Notch in prostate adenocarcinoma versus NEPC, do you think Notch is a viable therapeutic target versus targeting something else like ASCL1, and how or when would you envision targeting Notch?

Sheng-Yu Ku: Yes, thanks for this very important question. Notch targeting, Notch signaling, possibly might be a therapeutic strategy for neuroendocrine prostate cancer. However, Notch signaling is also oncogenic in prostate adenocarcinoma. Therefore, when we talk and... sometimes the prostate cancer may contain both the neuroendocrine cells and the adenocarcinoma cells. Therefore, when we target the Notch signaling pathway, we have to be very cautious because we limit one type of cells, but at the same time we enrich another population.

Currently, we are investigating a T-cell engager therapy by targeting DLL3. The phase I-II clinical trial is still ongoing, and we do see some preliminary responses. So this could be a therapeutic option for patients with neuroendocrine prostate cancer in the future.

Andrea Miyahara: Okay, thank you. So how do you think Notch may be regulating interactions with immune cells in the tumor microenvironment? Does it regulate any immune genes such as MHC?

Sheng-Yu Ku: Yes. So the Notch signaling pathway is regulated through the cell-cell contact, and this cell-cell contact can also occur between tumor cells and immune cells in microenvironments. There are several studies suggesting that Notch signaling pathway could influence the immune cell differentiations and maturations such as macrophage, T cells, and B cells. Therefore, by changing the tumor lineages, we believe that the immune system could also be impacted elsewhere by manipulating Notch signaling activity.

Andrea Miyahara: Okay, thank you. And what are your next steps in the study and are there any translational plans?

Sheng-Yu Ku: Yeah, so far we know that the Notch signaling is a tumor suppressor in neuroendocrine cancer and significantly downregulated in neuroendocrine cancer. However, loss-of-function mutations are not very common in prostate cancer. Therefore, we're exploring to understand how Notch signaling is suppressed in neuroendocrine prostate cancer. If these puzzles were unlocked, then we may have more understanding to know how Notch signaling is regulated and suppressed to induce neuroendocrine differentiation in prostate cancer.

Andrea Miyahara: Okay. Thank you so much, Dr. Ku, for sharing this with us, and we look forward to your next study.

Sheng-Yu Ku: Thank you so much for having me.