Seizure-Related Homolog Protein 6 (SEZ6): Biology and Therapeutic Target in Neuroendocrine Carcinomas.

Seizure-related homolog protein 6 (SEZ6) is a cell surface type 1 transmembrane protein involved in neuronal development, expression of which in adult tissues is almost exclusively limited to the central nervous system. Aberrant expression of SEZ6 has been associated with neurodevelopmental and psychiatric disorders including epilepsy, schizophrenia, and Alzheimer's disease. More recently, SEZ6 overexpression has been detected in small cell lung cancer (SCLC) and other high-grade neuroendocrine malignancies, although our understanding of the function of SEZ6 as a driver of cancer is limited.

L1CAM signaling through planar cell polarity generates SOX2 metastatic progenitors in lung adenocarcinoma.

Plasticity transitions during carcinoma progression generate fetal-like progenitor states with metastatic capacity. How these progenitors emerge and persist during tumor progression remains unknown. Here, we elucidate a process that drives the emergence of SOX2 metastatic progenitors in lung adenocarcinomas (LUAD).

Phase I Dose Escalation Trial Combining Olaparib and Thoracic Radiation Therapy in Extensive-Stage Small Cell Lung Cancer.

Purpose: Patients with extensive-stage small cell lung cancer (ES-SCLC) are commonly treated with induction systemic therapy and consolidative thoracic radiation therapy (TRT). PARP inhibitors have demonstrated radiosensitization in preclinical lung cancer models. We performed an investigator-initiated, multi-institutional, single-arm, open label phase I study of concurrent olaparib with TRT.

Delta-like ligand 3 expression and functional imaging in gastroenteropancreatic neuroendocrine neoplasms.

Purpose: Delta-like ligand 3 (DLL3) is an emerging target across neuroendocrine cancers, but remains underexplored in gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) including poorly differentiated neuroendocrine carcinomas (GEP NECs) and well differentiated neuroendocrine tumors (NETs). We aimed to define the landscape of DLL3 expression and feasibility of DLL3-targeted imaging in this population.

Patients And Methods: We completed DLL3 immunohistochemistry (IHC) on 360 tumor samples from patients with GEP NENs, analyzing associations between DLL3 IHC positivity and clinicopathologic features and outcomes.

Complementary modes of resistance to TKI in lung adenocarcinoma through MAPK activation and cellular plasticity.

-mutant lung adenocarcinoma (LUAD) represents 20% of all non-small cell lung carcinomas, with most patients presenting with incurable metastatic disease. Treatment with mutant-selective tyrosine kinase inhibitors (TKIs) results in initial tumor reduction, yet nearly all patients eventually relapse. The mechanisms driving drug resistance are incompletely understood, creating significant barriers to curing metastatic disease.

Integration of Next Generation Sequencing Data to Inform Survival Prediction of Patients with Spine Metastasis.

: Spinal metastatic disease is a life-altering problem for individuals with cancer. Prognostication is key for tailored treatment of spinal metastases. This manuscript provides a comprehensive overview of the genomic profiles of metastatic spine tumors and investigates the potential of mutational data to stratify overall survival (OS) across various histologies.

RIT1 Drives Oncogenic Transformation and Is an Actionable Target in Lung Adenocarcinoma.

Unlabelled: RIT1 is a small GTPase of the RAS family, and RIT1 mutations have been identified in lung cancer, leukemia, and the developmental disorder Noonan syndrome. Mutations in RIT1 lead to increased protein levels due to impaired proteolysis, resulting in dysregulation of RAS/MAPK signaling and other pathways. In this study, we documented the diversity of RIT1 mutations in human lung cancer and showed that physiologic expression of RIT1 M90I is sufficient to drive autochthonous lung tumor development in vivo in mouse models.

Multidimensional Analysis of B7 Homolog 3 RNA Expression in Small Cell Lung Cancer Molecular Subtypes.

Purpose: B7 homolog 3 (B7-H3) is a promising target for antibody-drug conjugates, with ifinatamab deruxtecan demonstrating an objective response rate of 54.8% in previously treated extensive-stage small cell lung cancer (SCLC). This analysis aimed to characterize B7-H3 RNA expression with reference to SCLC molecular subtypes (SCLC-A, SCLC-N, SCLC-P, and SCLC-I) and immune-related parameters.

Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy.

Background: Tarlatamab, a bispecific delta-like ligand 3-directed T-cell engager immunotherapy, received accelerated approval for the treatment of patients with previously treated small-cell lung cancer. Whether tarlatamab is more effective than chemotherapy in the treatment of patients whose small-cell lung cancer has progressed during or after initial platinum-based chemotherapy is not known.

Methods: We conducted a multinational, phase 3, open-label trial to compare tarlatamab with chemotherapy as second-line treatment in patients with small-cell lung cancer whose disease had progressed during or after platinum-based chemotherapy.

FOXA2 promotes metastatic competence in small cell lung cancer.

Small cell lung cancer (SCLC) is known for its high metastatic potential, with most patients demonstrating clinically evident metastases in multiple organs at diagnosis. The factors contributing to this exceptional metastatic capacity have not been defined. To bridge this gap, we compare gene expression in SCLC patient samples who never experienced metastasis or relapse throughout their clinical course, versus primary SCLC patient samples from more typical patients who had metastatic disease at diagnosis.

Sarcoid-like reactions in patients treated with checkpoint inhibitors for advanced solid tumors.

Importance: While new intrathoracic adenopathy in a patient with cancer can represent progression of disease, the differential diagnosis is broad. Sarcoid-like reactions (SLR) remain an underreported source of lymphadenopathy in patients treated with immune checkpoint inhibitors (ICI), with limited reports in patients with cancers other than melanoma.

Objective: To characterize SLRs among patients treated with ICI for advanced solid tumors.

Dopamine D receptor agonists abrogate neuroendocrine tumour angiogenesis to inhibit chemotherapy-refractory small cell lung cancer progression.

Small cell lung cancer (SCLC) is difficult to treat due to its aggressiveness, early metastasis, and rapid development of resistance to chemotherapeutic agents. Here, we show that treatment with a dopamine D receptor (DR) agonist reduces tumour angiogenesis in multiple in vivo xenograft models of human SCLC, thereby reducing SCLC progression. An FDA-approved DR agonist, cabergoline, also sensitized chemotherapy-resistant SCLC tumours to cisplatin and etoposide in patient-derived xenograft models of acquired chemoresistance in mice.

Functional characterization of the ATOH1 molecular subtype indicates a pro-metastatic role in small cell lung cancer.

Molecular subtypes of small cell lung cancer (SCLC) have been described based on differential expression of the transcription factors (TFs) ASCL1, NEUROD1, and POU2F3 and immune-related genes. We previously reported an additional subtype based on expression of the neurogenic TF ATOH1 within our SCLC circulating tumor cell-derived explant (CDX) model biobank. Here, we show that ATOH1 protein is detected in 7 of 81 preclinical models and 16 of 102 clinical samples of SCLC.

The Lung Cancer Autochthonous Model Gene Expression Database Enables Cross-Study Comparisons of the Transcriptomic Landscapes Across Mouse Models.

Lung cancer, the leading cause of cancer mortality, exhibits diverse histologic subtypes and genetic complexities. Numerous preclinical mouse models have been developed to study lung cancer, but data from these models are disparate, siloed, and difficult to compare in a centralized fashion. In this study, we established the Lung Cancer Autochthonous Model Gene Expression Database (LCAMGDB), an extensive repository of 1,354 samples from 77 transcriptomic datasets covering 974 samples from genetically engineered mouse models (GEMM), 368 samples from carcinogen-induced models, and 12 samples from a spontaneous model.

Tumor-Infiltrating Clonal Hematopoiesis.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear.

A phase 1 study of the combination of BH3-mimetic, navitoclax, and mTORC1/2 inhibitor, vistusertib, in patients with advanced solid tumors.

Purpose: To determine the, safety, tolerability and recommended phase 2 dosing of the combination of navitoclax, a dual Bcl-2/xL inhibitor, and vistusertib, a TORC1/2 inhibitor.

Methods: Patients with advanced solid tumors received navitoclax plus vistusertib following a 3 + 3 dose escalation design. To mitigate thrombocytopenia, a known toxicity of navitoclax, all patients received lead-in dosing of navitoclax alone at 150 mg orally daily for a minimum of 7 days.

Brief Report: Clinical Characteristics and Outcomes of Patients With Thoracic SMARCA4-Deficient Undifferentiated Tumors.

Introduction: Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs) are a recently defined group of aggressive cancers in which the effectiveness of standard treatments for lung cancer is unknown.

Methods: We collected clinical, pathologic, and demographic variables from five institutions for patients whose tumors met criteria for SMARCA4-UTs (undifferentiated phenotype and loss of SMARCA4 (BRG1) by immunohistochemistry).

Results: We identified 92 patients with SMARCA4-UTs; 58 (63%) had stage IV disease at diagnosis and 16 (17%) developed recurrent or metastatic disease after initial diagnosis.

Basal cell of origin resolves neuroendocrine-tuft lineage plasticity in cancer.

Neuroendocrine and tuft cells are rare, chemosensory epithelial lineages defined by expression of ASCL1 and POU2F3 transcription factors, respectively. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes. The mechanisms driving neuroendocrine-tuft tumour heterogeneity, and the origins of tuft-like cancers are unknown.

Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.

Mitochondria serve a crucial role in cell growth and proliferation by supporting both ATP synthesis and the production of macromolecular precursors. Whereas oxidative phosphorylation (OXPHOS) depends mainly on the oxidation of intermediates from the tricarboxylic acid cycle, the mitochondrial production of proline and ornithine relies on reductive synthesis. How these competing metabolic pathways take place in the same organelle is not clear.