bims-necame 2026-02-22 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2026–02–22
six papers selected by
Grigor Varuzhanyan, UCLA

Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity.
Altered bacteriome and mycobiome in small cell lung cancer: insights from microbial profiling.
Hypoxia‑induced miR‑135b‑5p promotes neuroendocrine differentiation of prostate cancer cells through HIF1AN‑HIF1α axis.
Comparison of Lanreotide and Octreotide LAR Use and Outcomes for Gastrointestinal Neuroendocrine Tumors in British Columbia, Canada.
Axitinib and Long-Acting Octreotide in Advanced Extrapancreatic Neuroendocrine Tumors: A Randomized, Double-Blind, Placebo-Controlled, Phase III Clinical Trial (AXINET, GETNE 1107).
Orally Bioavailable Cyclin A/B RxL Inhibitors: Optimization of a Novel Class of Macrocyclic Peptides That Target E2F-High and G1-S-Checkpoint-Compromised Cancers.

Nat Commun. 2026 Feb 21.

Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity.

Richa Singh, Varadha Balaji Venkadakrishnan, Eddie Imada, Yasutaka Yamada, Nicholas J Brady, Kate E Dunmore, Richard Garner, Matthew A Booker, Brian Hanratty, Michael C Haffner, Michael Y Tolstorukov, Luigi Marchionni, Brian D Robinson, David S Rickman, Himisha Beltran.

Prostate cancer lineage plasticity is associated with changes in DNA methylation and enhancer of zeste homolog 2 (EZH2) activity. How these epigenetic programs functionally interact to modulate transcriptional reprogramming in neuroendocrine prostate cancer (NEPC) is not well understood. In this study, we demonstrate that hypomethylated regions of DNA preferentially accumulate the repressive mark, H3K27me3. We established an NEPC mouse model with deletion of Ezh2 in the background of Pten and Rb1 loss plus human MYCN overexpression. Deletion or pharmacological inhibition of EZH2 in NEPC murine or patient-derived models leads to a genome-wide rewiring of DNA methylation, characterized by hypomethylation and upregulation of neuroendocrine-lineage genes along with hypermethylation and repression of polycomb repressive complex 2 (PRC2) targets. On the other hand, deletion of DNA methyltransferase 1 (DNMT1) results in significant changes in H3K27me3 distribution, particularly affecting bivalent promoters bearing both H3K27me3 and active H3K4me3 marks. In NEPC models, neuroendocrine-lineage genes are repressed upon DNMT1 deletion associated with increased H3K27me3. Conversely, in prostate adenocarcinoma models, DNMT1 deletion leads to de-repression of neuroendocrine lineage genes with a loss of H3K27me3 marks. Our findings reveal a functional interplay between two repressive epigenetic machineries that mediates lineage plasticity in prostate cancer.

DOI: https://doi.org/10.1038/s41467-026-69308-0
Lung Cancer. 2026 Feb 11. pii: S0169-5002(26)00059-0. [Epub ahead of print]214 109315

Altered bacteriome and mycobiome in small cell lung cancer: insights from microbial profiling.

Ines Rolim, Antonio Lopez-Beltran, Marcos Pantarotto, Eric de Sousa, Joao Sobral, Nuno Gil, Carlos Penha-Gonçalves, Carol Farver.

   BACKGROUND: The tumor-associated microbiome influences cancer development and progression, yet the microbial landscape of small cell lung cancer (SCLC) remains unexplored. Given the absence of SCLC-specific microbiome studies, we conducted an exploratory analysis to describe the bacterial and fungal communities present in SCLC tissue.
RESULTS: Using 16S rRNA sequencing, we profiled the bacteriome of lung specimens from SCLC and control cases and observed increased bacterial signal and reduced bacterial diversity in SCLC, accompanied by relative enrichment of Firmicutes and Bacteroidota. Actinobacteria were comparatively underrepresented, resulting in a higher Proteobacteria-to-Actinobacteria ratio, although this difference did not reach statistical significance. At the genus level, SCLC samples were dominated by Pseudomonas, Streptococcus, Haemophilus, and Granulicatella, which together accounted for approximately half of the bacterial community. As a secondary, hypothesis-generating analysis, we examined the mycobiome using ITS sequencing and detected the unexpected presence of the biotrophic plant-pathogenic genus Taphrina in a subset (25%) of SCLC samples. Given the methodological constraints and contamination risks inherent to low-biomass FFPE tissues, this fungal signal is interpreted cautiously and framed strictly as preliminary.
CONCLUSIONS: This study provides the first descriptive characterization of the lung bacteriome and mycobiome in SCLC using FFPE tissue. The observed alterations in microbial composition, including an unexpected fungal signal, offer hypothesis-generating insights that require validation in larger, prospectively collected cohorts incorporating more comprehensive contamination-control strategies.

Keywords:  Lung microbiome; Mycobiome; Proteobacteria-to-Actinobacteria ratio; Small cell lung cancer; Taphrina

DOI:  https://doi.org/10.1016/j.lungcan.2026.109315
Oncol Rep. 2026 Apr;pii: 74. [Epub ahead of print]55(4):

Hypoxia‑induced miR‑135b‑5p promotes neuroendocrine differentiation of prostate cancer cells through HIF1AN‑HIF1α axis.

Pampana Sandhya Venkata Lakshmi, Jagrati Parashar, Biswajit Biswas, Ramesh Ummanni.

  Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PCa), associated with poor prognosis and resistance to androgen receptor (AR)‑targeted therapies. Hypoxia is a well‑established driver of lineage plasticity and has been implicated in promoting NE differentiation (NED) of tumors. However, the underlying molecular mechanisms linking hypoxia to NED remain unclear. In the present study, miR‑135b‑5p was identified as a critical regulator of hypoxia‑induced NED through modulation of the hypoxia‑inducible factor alpha‑1 subunit alpha inhibitor (HIF1AN)‑HIF1α axis. Exposure of androgen‑dependent PCa cell lines (LNCaP and VCaP) to hypoxia induced neurite outgrowth and increased expression of NE markers, concurrent with upregulation of miR‑135b‑5p. Target prediction followed by experimental validation in luciferase reporter assays confirmed that HIF1AN is a direct target of miR‑135b‑5p. Suppression of HIF1AN results in the stabilization of HIF1α, which in turn activates the AKT/mTOR signaling pathway, facilitating NE trans differentiation. Functional studies demonstrated that overexpression of miR‑135b‑5p by mimics promotes NED in LNCaP cells, while inhibition of miR‑135b‑5p reverses the NE features in NE‑LNCaP and NCI‑H660, NE cells. Furthermore, pharmacological inhibition of HIF1α using PX‑478 abrogated hypoxia‑induced NED and attenuated activation of AKT/mTOR signaling, further underscoring the significance of the miR‑135b‑5p‑HIF1AN‑HIF1α axis in NED of PCa cells. Collectively, the findings of the present study reveal a novel miR‑135b‑5p‑HIF1AN‑HIF1α signaling axis that is involved in hypoxia‑induced NED via AKT/mTOR activation and identify miR‑135b‑5p and HIF1α as potential therapeutic targets for NEPC.

Keywords:  NCI‑H660; NE‑LNCaP; anti‑miR‑135b‑5p; hypoxia; miRNA; miR‑135b‑5pmimic

DOI:  https://doi.org/10.3892/or.2026.9079
Cancer Control. 2026 Jan-Dec;33:33 10732748261417423

Comparison of Lanreotide and Octreotide LAR Use and Outcomes for Gastrointestinal Neuroendocrine Tumors in British Columbia, Canada.

Ashley Paul, Shehara Mendis, Michael Diaz-Stewart, Justin Jao, Melina Boutin, Maria Safro, Marie-Hélène Denault, Caroline Speers, Heather Stuart, Sharlene Gill, Daniel J Renouf, David F Schaeffer, David Farnell, Jonathan M Loree.

  IntroductionThe long-acting somatostatin analogues (LA-SSAs) octreotide LAR (OCT) and lanreotide (LAN) improve progression-free survival (PFS) in gastrointestinal neuroendocrine tumors (NETs), however, no head-to-head comparison exists. We compared treatment patterns and efficacy in a small bowel and pancreatic NET population-based cohort from British Columbia, Canada.MethodsWe identified 321 patients receiving either LAN or OCT for retrospective chart review. These somatostatin analogs were evaluated for impact on progression-free and overall survival.ResultsAge, sex, ECOG, and primary site did not differ by treatment, however, LAN was more commonly used in higher grade tumors (P = 0.019). PFS was longer for patients receiving LAN than OCT (Hazard Ratio (HR) 0.60, 95% CI 0.40-0.89, P = 0.011). Similarly, overall survival (OS) was longer for patients receiving LAN than OCT (HR 0.45, 95% CI 0.28-0.73, P = 0.016). Sensitivity analysis among patients diagnosed after both agents were reimbursed showed similar results for PFS (HR 0.50, 95% CI 0.28-0.90, P = 0.018). There was similar dose escalation with LAN vs OCT (OR: 0.80, CI 0.38-1.77, P = 0.70), with 29.4% of patients in the LAN group requiring LA-SSA dose escalation compared to 34.3% in the OCT group. There was numerically less short acting octreotide use in the LAN group (P = 0.087), with none of these patients requiring short acting octreotide, compared to 8.7% of the OCT group.ConclusionLAN was associated with longer time to cancer progression, as well as less use of short acting rescue octreotide in our population-based cohort. However, given the retrospective design and reimbursement-era differences, these findings should be interpreted cautiously and warrant confirmation in prospective or head-to-head studies.

Keywords:  NET; cancer; lanreotide; octreotide; somatostatin

DOI:  https://doi.org/10.1177/10732748261417423
J Clin Oncol. 2026 Feb 20. JCO2501808

Axitinib and Long-Acting Octreotide in Advanced Extrapancreatic Neuroendocrine Tumors: A Randomized, Double-Blind, Placebo-Controlled, Phase III Clinical Trial (AXINET, GETNE 1107).

Rocio Garcia-Carbonero, Marta Benavent, Paula Jimenez-Fonseca, Teresa Alonso-Gordoa, Alex Teulé, Ana Custodio, Salvatore Tafuto, Adelaida La Casta, Francesca Spada, Carlos López, Toni Ibrahim, Vega Iranzo, Pilar García-Alfonso, Encarna González-Flores, María José Villanueva Silva, Enrique Grande, Francesco Panzuto, Guillermo Crespo, Miguel Navarro, Daniel Castellano, Jorge Hernando, Rocío Morales-Herrero, German Iglesias Álvarez, Beatriz Soldevilla, Jaume Capdevila.

PURPOSE: Angiogenesis plays an essential role in neuroendocrine tumors (NETs). This study evaluates efficacy and safety of axitinib in extrapancreatic (ep)-NETs.
PATIENTS AND METHODS: AXINET was an international, randomized, double-blind, placebo-controlled, phase II/III trial including patients age 18 years and older, with unresectable/metastatic G1-2 epNETs and up to two previous treatment lines. Patients were randomly assigned (1:1) to axitinib 5 mg or placebo, both orally twice a day, in combination with intramuscular octreotide long-acting release 30 mg once every 28 days until disease progression or unacceptable toxicity. Randomization was stratified by primary tumor site, Ki-67 index (≤5% or >5%), and time from diagnosis (> or ≤12 months). The primary end point was investigator-assessed progression-free survival (PFS). Efficacy was also assessed by a blinded independent central review (BICR).
RESULTS: From October 2011 to May 2019, 256 patients were assigned to axitinib (n = 126) or placebo (n = 130). Investigator-assessed median PFS was 17.2 months (95% CI, 13.6 to 24.7) versus 13.1 months (95% CI, 10.9 to 18.6) in the axitinib and placebo groups, respectively (hazard ratio [HR], 0.86 [95% CI, 0.65 to 1.15]). The median BICR PFS was 16.6 months (95% CI, 13.5 to 24.2) versus 9.9 months (95% CI, 8.2 to 13.9) in the axitinib and placebo groups, respectively (HR, 0.71 [95% CI, 0.54 to 0.94], P = .017). Objective response rate (ORR) was significantly greater for axitinib per investigator assessment (17.5% v 4.6%; P = .001) and BICR (12.8% v 3.2%; P = .005). Most common grade ≥3 toxicities were hypertension (24.0% v 9.2%) and diarrhea (13.6% v 1.5%).
CONCLUSION: Axitinib significantly increased PFS per BICR assessment and ORR both per investigator and BICR assessment compared with placebo, although the primary study end point was not met. Toxicity profile was manageable with no new safety concerns.

DOI: https://doi.org/10.1200/JCO-25-01808
J Med Chem. 2026 Feb 21.

Orally Bioavailable Cyclin A/B RxL Inhibitors: Optimization of a Novel Class of Macrocyclic Peptides That Target E2F-High and G1-S-Checkpoint-Compromised Cancers.

Justin A Shapiro, Nathan J Dupper, Breena Fraga-Walton, Andrew T Bockus, Siegfried S F Leung, Kai Yang, Chinmay Bhatt, Megan K DeMart, Miguel P Baldomero, Luis Hernandez, Gabriel Fung, Sammy Metobo, Steven Xie, Bryan M Lent, David C Spellmeyer, Joshua Luna, Dalena Hoang, Manesh Chand, Yuliana Gritsenko, Catherine E Gleason, Frances Hamkins-Indik, Jie Zheng, Ranya Odeh, Meisam Nosrati, Daphne He, Ramesh Bambal, Peadar Cremin, Jinshu Fang, Bernard Levin, Evelyn W Wang, Marie Evangelista, David Earp, Constantine Kreatsoulas, Rajinder Singh, Pablo D Garcia, James B Aggen.

Cyclins A and B bind and activate their cognate cyclin-dependent kinase (CDK) to regulate progression through the S and G2/M phases of the cell cycle, respectively. Cyclins recruit substrates and regulators through the binding of an RxL motif with a Hydrophobic Patch (HP) on the cyclin surface. We recently disclosed the first class of passively permeable macrocyclic peptides that bind to the HP of both Cyclin A and Cyclin B and selectively kill cancer cells with high E2F activity. We used a lead example to demonstrate in vivo tumor regression in cell-line-derived xenograft models of small-cell lung cancer (SCLC) via intraperitoneal dosing. Here we describe the optimization of this series for drug-like properties and oral bioavailability, resulting in the discovery of a lead compound, which demonstrates tumor regression in CDX models of SCLC via oral dosing. We are currently evaluating Cyclin A/B inhibition in a Phase 1 clinical trial.

DOI: https://doi.org/10.1021/acs.jmedchem.5c02445