bims-necame 2025-10-05 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2025–10–05
seven papers selected by
Grigor Varuzhanyan, UCLA

Metabolic and imaging phenotypes associated with RB1 and TP53 loss in prostate cancer.
Preclinical activity of the DLL3-targeted T cell engager MK-6070 in neuroendocrine prostate cancer.
SMARCA4 is essential for early-stage tumor development but its loss promotes late-stage cancer progression in small-cell lung cancer.
Mechanisms of neuroendocrine differentiation in castration-resistant prostate cancer and advances in the treatment of neuroendocrine prostate cancer.
Novel therapeutic strategy targeting STMN1 using chlorambucil-conjugated pyrrole-imidazole polyamide in small cell lung cancer.
CLDN4 regulates cell proliferation in small cell lung cancer cells via SAA1 inhibition.
Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with small cell lung cancer: A dramatic recovery after chemotherapy.

bioRxiv. 2025 Apr 30. pii: 2023.11.15.567250. [Epub ahead of print]

Metabolic and imaging phenotypes associated with RB1 and TP53 loss in prostate cancer.

Fahim Ahmad, Margaret White, Kazutoshi Yamamoto, Daniel R Crooks, Supreet Agarwal, Ye Yang, Brian Capaldo, Sonam Raj, Aian Neil Alilin, Anita Ton, Stephen Adler, Jurgen Seidel, Colleen Olkowski, Murali Krishna Cherukuri, Peter L Choyke, Kathleen Kelly, Jeffrey R Brender.

Advanced prostate cancer is treated with androgen receptor (AR) signaling inhibitors, which are initially effective, but most patients eventually develop resistance and progress to castrate-resistant prostate cancer (CRPC). Loss of RB1 in CRPC tumors is correlated with rapid progression and poor patient survival and, in combination with TP53 loss, predisposes patients to the development of transitional neuroendocrine prostate cancer (NEPC). Although progressive CRPC is clinically associated with higher 18FDG-PET SUVmax values, it is unknown whether inactivation of RB1 and/or TP53 is a driver of increased glucose import. Using a cohort of patient-derived xenograft (PDX)-derived CRPC organoids, we found that NEPC could not be conclusively distinguished from adenocarcinoma by 18FDG uptake alone, and PSMA protein levels did not correlate with cancer phenotype or 18FDG uptake. Castration-resistant models showed higher 18FDG uptake, but lower pyruvate-to-lactate conversion compared to their castration-sensitive counterparts. In parallel studies using castration-sensitive prostate cancer models, RB1/TP53 knockdown did not affect 18FDG uptake, but increased basal respiration and glycolytic activity, with combined depletion leading to glucose diversion into glycogenesis. These metabolic changes were reflected in increased lactate dehydrogenase flux detected by 13C-hyperpolarized magnetic resonance spectroscopy upon RB1 loss, but not in 18FDG uptake. The metabolic heterogeneity revealed here suggests that a multimodal molecular imaging approach can improve tumor characterization, potentially leading to a better prognosis in cancer treatment.

DOI: https://doi.org/10.1101/2023.11.15.567250
Mol Cancer Ther. 2025 Oct 03.

Preclinical activity of the DLL3-targeted T cell engager MK-6070 in neuroendocrine prostate cancer.

Sheng-Yu Ku, Nishat Manzar, Maria Mica Garcia, Min Jin Kim, David J Einstein, Steven P Balk, Yasutaka Yamada, Himisha Beltran.

Neuroendocrine prostate cancer is an aggressive variant of prostate cancer with limited therapeutic options. Delta-like ligand 3 (DLL3) is a cell surface protein and therapeutic target expressed in the vast majority of NEPC tumors. The DLL3-targeted T cell activating construct MK-6070 (formerly called HPN328) binds to both DLL3 on tumor cells and CD3 on T cells, as well as serum albumin to extend half-life. A phase 1/2 trial of MK-6070 is currently underway which includes an NEPC cohort (NCT04471727). Here we report the preclinical activity of MK-6070 in prostate cancer models, showing high specificity and anti-tumor activity in DLL3-expressing NEPC models both in vitro and in vivo, with T cell activation and tumor infiltration of T cells after treatment. MK-6070 also demonstrates anti-tumor activity in mixed tumors, impacting DLL3-negative prostate cancer cells after engagement with surrounding DLL3-expressing tumor cells, supporting a potential bystander effect. Overall, these data demonstrate promising activity of MK-6070 in NEPC preclinical models including heterogeneous tumors, supporting the clinical development of MK-6070.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0453
bioRxiv. 2025 May 24. pii: 2025.05.21.655382. [Epub ahead of print]

SMARCA4 is essential for early-stage tumor development but its loss promotes late-stage cancer progression in small-cell lung cancer.

Nicole A Kirk, Jin Ng, Kate-Lin Ly, Young Ho Ban, Godfrey Dzhivhuho, Jinho Jang, Kyung-Pil Ko, Michael S Kareta, Jae-Il Park, Anthony N Karnezis, Anish Thomas, Kate D Sutherland, Kwon-Sik Park.

SMARCA4 and other components of the SWI/SNF chromatin remodeling complex have been implicated in various cancers. Yet, its role in small cell lung cancer (SCLC) tumorigenesis remains poorly understood. Genetically engineered mouse models (GEMMs) of SCLC revealed that deletion of Smarca4 significantly decreased tumor development in this model. Pharmacological inhibition of SMARCA4 decreased the proliferation of preneoplastic neuroendocrine (NE) cells. These effects coincided with reduced expression of the lineage-specific transcription factor, ASCL1, suggesting that disruption of the SMARCA4-ASCL1 axis impairs tumor development. However, Smarca4 -deficient tumors, albeit smaller than controls, displayed features associated with malignant progression, including variant histology and the loss of NE differentiation. This prompted us to test the functional role of SMARCA4 in established tumor cells that recapitulate late-stage disease. Intriguingly, whilst Smarca4 knockdown in tumor cells failed to affect their proliferative capacity in vitro, Smarca4 knockdown tumors exhibited enhanced growth following subcutaneous transplantation in athymic nude mice. Interestingly, SMARCA4 knockdown significantly reduced expression and cell-surface display of PVR, a ligand for activating natural killer (NK) cells. These results led to an idea that the enhanced tumor formation was partly owing to altered tumor-NK cell interactions mediated by the SMARCA4-PVR axis in tumor cells. These findings suggest that SMARCA4 plays a temporally distinct role in SCLC, supporting early tumorigenesis but potentially functioning as a tumor suppressor in the later stages. The dramatic differences observed when targeting SMARCA4 in distinct disease states emphasize a need to acknowledge how differences in the timing of alterations can drastically alter tumor evolution.

DOI: https://doi.org/10.1101/2025.05.21.655382
Ann Med. 2025 Dec;57(1): 2548975

Mechanisms of neuroendocrine differentiation in castration-resistant prostate cancer and advances in the treatment of neuroendocrine prostate cancer.

Bo Shao, Yu Zeng.

   AIMS: Prostate cancer (PC) is a common male malignancy. Although androgen deprivation therapy (ADT) is standard for advanced PC, many patients develop castration-resistant PC (CRPC), and some progress to neuroendocrine PC (NEPC). This study aims to clarify mechanisms of this transition, especially the role of cancer stem cells (CSCs), and explore therapeutic targets.
METHODS: A literature review was conducted on genetic alterations, signaling pathways, tumor microenvironment, and CSC biology related to CRPC and NEPC progression.
FINDINGS: Evidence shows that lineage plasticity, alternative signaling activation, and CSC expansion drive CRPC and NEPC development. CSCs promote heterogeneity, resistance, and metastasis, while current treatments remain largely ineffective for NEPC.
CONCLUSIONS: Understanding mechanisms of PC progression is crucial for new interventions. Targeting CSC-related pathways may help prevent resistance and improve outcomes in advanced prostate cancer.

Keywords:  Neuroendocrine prostate cancer; cancer stem cells; cellular heterogeneity; neuroendocrine differentiation; review

DOI:  https://doi.org/10.1080/07853890.2025.2548975
Int J Cancer. 2025 Sep 30.

Novel therapeutic strategy targeting STMN1 using chlorambucil-conjugated pyrrole-imidazole polyamide in small cell lung cancer.

Ryohei Yoshikawa, Takayoshi Watanabe, Yoichi Ohtaki, Toshikazu Bando, Hiroshi Sugiyama, Takuya Araki, Hideaki Yashima, Bilguun Erkhem-Ochir, Haruka Okami, Gendensuren Dorjkhorloo, Ikuma Shioi, Toshiteru Nagashima, Natsuko Kawatani, Tomohiro Yazawa, Eiji Narusawa, Takayuki Kosaka, Osamu Kawashima, Mitsuhiro Kamiyoshihara, John D Minna, Luc Girard, Ken Shirabe, Hiroki Nagase, Kimihiro Shimizu, Takehiko Yokobori.

  Small cell lung cancer (SCLC) is aggressive, with limited treatment progress for decades. Stathmin 1 (STMN1) is a cytoplasmic phosphorylated protein that is specific to cancerous tissues including SCLC and is associated with malignancy. Pyrrole-imidazole polyamide (PIP) compounds decrease gene expression by binding to specific DNA sites and disturbing RNA transcription. In this study, we synthesized a novel chlorambucil-conjugated PIP compound targeting both the STMN1 promoter and STMN1 DNA sequences (Chb-STMN1 PIP) to evaluate its therapeutic efficacy against SCLC. We examined the expression of STMN1 in surgically resected tissues and cell line database. Suppression of STMN1 by Chb-STMN1 PIP was analyzed using RT-PCR, WB, and CAGE-seq in vitro. The anti-tumor effects of Chb-STMN1 PIP were evaluated in vitro and in vivo. STMN1 mRNA expression was higher in cell lines with more STMN1 copy number alterations. In vitro studies showed that Chb-STMN1 PIP treatment resulted in significant STMN1 suppression and cell viability reduction compared to the control groups. Administration of Chb-STMN1 PIP to an SCLC xenograft mouse model also showed a tumor reduction effect and significantly suppressed angiogenesis, proliferation potency, and cell viability of SCLC. CAGE analysis indicated that the expression of STMN1 was suppressed in Chb-STMN1 PIP-treated cells compared to that in control cells. A novel compound, Chb-STMN1 PIP, induced significant anti-tumor effects and suppressed STMN1 expression in SCLC cell lines. Furthermore, SCLC xenograft mouse models showed tumor shrinkage and reduced malignant properties. Targeting STMN1 with our developed PIP compound appears to be a novel strategy and promising in SCLC.

Keywords:  pyrrole–imidazole polyamide; small cell lung cancer; stathmin 1

DOI:  https://doi.org/10.1002/ijc.70179
Biochem Biophys Res Commun. 2025 Sep 25. pii: S0006-291X(25)01426-3. [Epub ahead of print]785 152710

CLDN4 regulates cell proliferation in small cell lung cancer cells via SAA1 inhibition.

Korehito Kashiwagi, Hanako Sato-Yazawa, Jun Ishii, Masami Iwamoto, Kakeru Kohno, Tadasuke Miyazawa, Tamotsu Kamimura, Shunsuke Miyata, Ruri Sugiyama, Hideki Chiba, Takuya Yazawa.

  Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid progression and high recurrence rates, making it a refractory cancer. However, its treatment still relies on a combination of platinum-based chemotherapy and etoposide, and a new effective therapeutic strategy is urgently needed. Claudin-4 (CLDN4) is a tight junction protein that has been reported to regulate malignant phenotypes in various types of cancer. However, its role in SCLC remains unclear. Therefore, we established CLDN4 knockout H1688 SCLC cells to evaluate its effect on malignant phenotypes, including proliferation, migration, and invasion. The results showed that CLDN4 knockout significantly promoted cell proliferation by accelerating cell cycle progression; however, it did not affect cell migration or invasion under in vitro conditions. Additionally, RNA-seq analysis identified serum amyloid A1 (SAA1) as a key downstream effector upregulated by CLDN4 knockout. SAA1 partly mediated the proliferation-promoting effect. The regulatory mechanism of CLDN4 in SCLC was also investigated. CLDN4 expression was directly regulated by SP1, with DNA methylation also contributing to its transcriptional regulation. These findings indicate that CLDN4, which is transcriptionally regulated by SP1 and DNA methylation, suppresses SCLC cell proliferation by inhibiting SAA1 expression and may serve as a potential therapeutic target.

Keywords:  Claudin; Serum amyloid A1; Small cell lung cancer

DOI:  https://doi.org/10.1016/j.bbrc.2025.152710
Intern Med. 2025 Oct 02.

Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with small cell lung cancer: A dramatic recovery after chemotherapy.

Koichi Yano, Takuto Ishida, Kyoko Yokosuka, Kentaro Sakashita, Masafumi Mizuno.

  Tumor management is the cornerstone of treatment for anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis that is refractory to immunosuppressive therapy. However, little is known about the effectiveness of chemotherapy for malignant tumors in patients with severe neurological conditions. We herein report a 66-year-old male who fell into a coma caused by anti-NMDAR encephalitis associated with small cell lung cancer (SCLC). Corticosteroid pulse therapy failed to improve his neurological condition, but a chemotherapy regimen containing atezolizumab led to rapid improvement in his condition. This case suggests that chemotherapy, including atezolizumab, may provide a rapid therapeutic benefit for anti-NMDAR encephalitis associated with SCLC.

Keywords:  anti-NMDAR encephalitis; atezolizumab; chemotherapy; coma; paraneoplastic; small-cell lung cancer

DOI:  https://doi.org/10.2169/internalmedicine.5586-25