Biomedical subjects

John V Heymach

Publications and source records attributed to John V Heymach.

5 recordsLinked to original sources

PubMed2026

Accelerating Lung Cancer Management Through Previsit Liquid Biopsy: Results From the LUNG-FAST Pilot Study.

BACKGROUND: Timely molecular profiling is essential for treatment selection in non-small cell lung cancer (NSCLC), yet delays in biomarker testing remain common. We evaluated the feasibility and early clinical impact of a nurse navigator-driven workflow to initiate liquid biopsy before the initial oncology visit. METHODS: LUNG-FAST (Liquid Biopsy for Urgent Neoplastic Genomic Profiling Focused Accelerated Stratification and Testing) was a 4-month prospective pilot at a tertiary cancer center. Intake nurse navigators identified eligible patients with suspected or newly diagnosed lung cancer and facilitated previsit liquid biopsy ordering. Feasibility, turnaround times, genomic findings, and early clinical outcomes were assessed. RESULTS: Among 64 patients, intake nurse navigators identified 94% (60/64) of eligible cases. Liquid biopsy was ordered in 58 patients, with 62% (36/58) placed before the initial oncology visit. Median turnaround time from blood draw to results was 8.5 days for commercial testing and 12.5 days for institutional testing. FDA-actionable genomic alterations were identified in 34% (22/64) of patients, while an additional 11% (7/64) harbored clinically relevant, non-FDA-actionable alterations. Overall, FDA-actionable or clinically relevant alterations were identified in 45% (29/64), with 22% detected by liquid biopsy and an additional 23% by tissue-only profiling. Median time from new patient visit to systemic therapy was 26 days. CONCLUSIONS: A nurse navigator-driven workflow enabling previsit liquid biopsy is feasible and identifies actionable genomic alterations in a substantial proportion of patients with lung cancer. Plasma and tissue profiling are complementary, and earlier plasma-based testing may expedite treatment decision-making while highlighting opportunities to optimize biomarker testing workflows.

Humans↗

PubMed2026

FOXM1-Specific TCR-Engineered T Cells Target Non-Small Cell Lung Cancer.

FOXM1 is highly expressed in various cancer types and considered a key driver of cancer progression. Accordingly, we evaluated the immunogenicity of FOXM1 and investigated the feasibility of targeting this transcription factor using T-cell receptor (TCR) engineering. We identified epitopes derived from FOXM1 which were immunogenic on HLA-A*02:01, HLA-A*24:02, and HLA-A*23:01, endogenously processed and presented, and resulted in T-cell activation and cytotoxic T-cell responses. Following the generation of TCR-T cells, sensitivity and specificity were confirmed by peptide dose-response and X-scan, respectively. Most importantly, adoptive transfer of TCR-engineered T cells led to a significant reduction in tumor growth, as well as significantly prolonged survival in a tumor-bearing immunocompromised murine model. Our studies confirm the immunogenicity of FOXM1 and feasibility of targeting this antigen using TCR engineering.

Forkhead Box Protein M1↗

PubMed2026

NOTCH1 acts as a tumor suppressor that induces early differentiation in head and neck cancer.

Inactivating NOTCH1 mutations in head and neck squamous cell carcinoma (HNSCC) were described over a decade ago, suggesting a tumor suppressor function - unlike its oncogenic role in other tumors. Today, much debate persists regarding a putative oncogenic role in HNSCC as well, with reports that NOTCH1 signaling drives tumor growth and a cancer stem cell (CSC) phenotype. In this work, comprehensive experiments unequivocally demonstrate that NOTCH1 is a tumor suppressor in HNSCC regardless of mutation or activation status and that it reduces CSC frequency. We developed a signature of NOTCH1 activation showing the pathway is associated with very early differentiation, an altered tumor microenvironment, and better prognosis. Clarifying whether NOTCH1 occasionally functions as an oncogenic driver in HNSCC is crucial to prognosis and personalized therapy. The results presented unify the field, reconcile conflicting data, and provide critical insights into the biological and clinical significance of NOTCH1, with broader implications in other squamous carcinomas with NOTCH1 mutations.

Receptor, Notch1↗

PubMed2025

Distinct Clinicogenomic Features and Immunotherapy Associations in Pulmonary Sarcomatoid Carcinoma: A Multicenter Retrospective Study.

INTRODUCTION: Pulmonary sarcomatoid carcinoma (PSC) is a rare NSCLC subtype with poor prognosis. Outcomes to immune checkpoint inhibitors (ICIs) and genomic features in PSC remain underexplored compared with other NSCLC subtypes. METHODS: Patients from three institutions and the National Cancer Database (NCDB) with metastatic NSCLC treated with ICI alone or with chemotherapy were identified. Clinicogenomics and treatment outcomes were compared across PSC, lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). RESULTS: We analyzed 4841 patients including 165 PSC cases treated with ICI-based therapy from three institutions and 201 PSC from NCDB. In MDACC, 65 (4.3%) were PSC, 1138 (75.1%) LUAD, and 312 (20.6%) LUSC. Patients with PSC were older and more likely to present with metastatic disease. In both the MDACC and NCDB cohorts, ICIs resulted in better outcomes for patients with PSC compared with chemotherapy. In these patients, there was no difference in outcome between ICI-monotherapy and ICI-chemotherapy. Across the three institutional cohorts, 37% to 43% of patients with PSC who received ICIs were responders, compared with 26% to 29% in LUAD and 22% to 46% in LUSC (p < 0.05). Improved ICI outcomes in PSC appeared driven by high PD-L1 (≥50% in 73%-77% cases). Among patients with high PD-L1, response rates were similar across histologic subtypes. Conversely, TMB was similar in PSC compared with LUAD or LUSC and was not associated with ICI outcomes. Across cohorts, PSC tumors were enriched for TP53, NF1, NF2, and NRAS, with relative depletion of STK11 and KEAP1 compared with LUAD. Case observation revealed relatively better outcomes to ICI than targeted therapies in patients with PSC with MET exon 14 skipping or KRAS G12C. CONCLUSION: PSC exhibits improved outcomes to ICI relative to other therapies, potentially driven by high PD-L1 expression. Genomic analysis highlights a distinct genomic landscape of PSC when compared with LUAD.

Humans↗

PubMed2023

MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma.

Inactivating STK11/LKB1 mutations are genomic drivers of primary resistance to immunotherapy in KRAS-mutated lung adenocarcinoma (LUAD), although the underlying mechanisms remain unelucidated. We find that LKB1 loss results in enhanced lactate production and secretion via the MCT4 transporter. Single-cell RNA profiling of murine models indicates that LKB1-deficient tumors have increased M2 macrophage polarization and hypofunctional T cells, effects that could be recapitulated by the addition of exogenous lactate and abrogated by MCT4 knockdown or therapeutic blockade of the lactate receptor GPR81 expressed on immune cells. Furthermore, MCT4 knockout reverses the resistance to PD-1 blockade induced by LKB1 loss in syngeneic murine models. Finally, tumors from STK11/LKB1 mutant LUAD patients demonstrate a similar phenotype of enhanced M2-macrophages polarization and hypofunctional T cells. These data provide evidence that lactate suppresses antitumor immunity and therapeutic targeting of this pathway is a promising strategy to reversing immunotherapy resistance in STK11/LKB1 mutant LUAD.

Animals↗