Targeted therapies lung cancer

Non-small cell lung cancer (NSCLC), accounting for more than 80% of all cases, is the predominant form of lung cancer and the leading cause of cancer-related deaths worldwide. Significant progress has been made in diagnostic techniques, surgical interventions, chemotherapy protocols, and targeted therapies at the molecular level, leading to enhanced treatment outcomes in patients with NSCLC. Extensive evidence supports the use of circular RNAs (circRNAs), a specific category of naturally occurring non-coding small RNAs (ncRNAs), for the diagnosis, monitoring of treatment efficacy, and assessment of survival in NSCLC...

PURPOSE: Small cell lung cancer (SCLC) often metastasizes to the brain and has poor prognosis. SCLC subtypes distinguished by expressing transcriptional factors ASCL1 or NEUROD1 have been identified. This study investigates the impact of transcription factor-defined SCLC subtype on incidence and outcomes of brain metastases (BMs). METHODS: Patients with SCLC with ASCL1 (A) and NEUROD1 (N) immunohistochemical expression status were identified and classified: (1) A+/N-, (2) A+/N+, (3) A-/N+, and (4) A-/N-...

PURPOSE: Previous studies document underuse of next-generation sequencing (NGS). We examined the impact to oncology care for veterans of incorporating NGS ordering into the Veterans Affairs (VA) electronic medical record (EMR) at two New York City VA Medical Centers. METHODS: We identified patients with non-small cell lung cancer and prostate cancer with oncology clinic visits and NGS testing indications between January and December 2021. Patients were divided into external ordering (EO) with visits before we implemented an EMR ordering system for NGS in July 2021, and internal ordering (IO) with visits after this date...

Targeting tumor-associated macrophages (TAMs) is an emerging approach being tested in multiple clinical trials. TAMs, depending on their differentiation state, can exhibit pro- or antitumorigenic functions. For example, the M2-like phenotype represents a protumoral state that can stimulate tumor growth, angiogenesis, metastasis, therapy resistance, and immune evasion by expressing immune checkpoint proteins. In this issue of the JCI, Vaccaro and colleagues utilized an innovative drug screen approach to demonstrate that targeting driver oncogenic signaling pathways concurrently with anti-CD47 sensitizes tumor cells, causing them to undergo macrophage-induced phagocytosis...

INTRODUCTION: Mitochondrial fission process 1 ( MTFP1 ) is an inner mitochondrial membrane (IMM) protein implicated in the development and progression of various tumors, particularly lung squamous cell carcinoma (LUSC). This study aims to provide a more theoretical basis for the treatment of LUSC. METHODS: Through bioinformatics analysis, MTFP1 was identified as a novel target gene of HIF1A . MTFP1 expression in LUSC was examined using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Proteomics Data Commons (PDC) databases...

BACKGROUND: Treatment for osteosarcoma, a paediatric bone cancer with no therapeutic advances in over three decades, is limited by a lack of targeted therapies. Osteosarcoma frequently metastasises to the lungs, and only 20% of patients survive 5 years after the diagnosis of metastatic disease. We found that WNT5B is the most abundant WNT expressed in osteosarcoma tumours and its expression correlates with metastasis, histologic subtype and reduced survival. METHODS: Using tumor-spheroids to model cancer stem-like cells, we performed qPCR, immunoblotting, and immunofluorescence to monitor changes in gene and protein expression...

Osimertinib, a selective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), effectively targets the EGFR T790M mutant in non-small cell lung cancer (NSCLC). However, the newly identified EGFR C797S mutation confers resistance to osimertinib. In this study, we explored the role of pyruvate dehydrogenase kinase 1 (PDK1) in osimertinib resistance. Patients exhibiting osimertinib resistance initially displayed elevated PDK1 expression. Osimertinib-resistant cell lines with the EGFR C797S mutation were established using A549, NCI-H292, PC-9, and NCI-H1975 NSCLC cells for both in vitro and in vivo investigations...

Recent clinical evidence shows that the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) can successfully treat patients with advanced HER2-mutant non-small cell lung cancer (NSCLC). We aimed to characterize HER2 mutations in cervical neuroendocrine carcinoma (NEC) among Taiwanese women to provide the rationale for exploring T-DXd as a tumor-agnostic targeted therapy option. We analyzed 12 archived primary cervical NEC samples from Taiwanese patients. Tumor-rich areas were marked for microdissection on 10 μm unstained sections...

Antibodies targeting the immune checkpoint molecules PD-1, PD-L1 and CTLA-4, administered alone or in combination with chemotherapy, are the standard of care in most patients with metastatic non-small-cell lung cancers. When given before curative surgery, tumor responses and improved event-free survival are achieved. New antibody combinations may be more efficacious and tolerable. In an ongoing, open-label phase 2 study, 60 biomarker-unselected, treatment-naive patients with resectable non-small-cell lung cancer were randomized to receive two preoperative doses of nivolumab (anti-PD-1) with or without relatlimab (anti-LAG-3) antibody therapy...

Alterations of bases in DNA constitute a major source of genomic instability. It is believed that base alterations trigger base excision repair (BER), generating DNA repair intermediates interfering with DNA replication. Here, we show that genomic uracil, a common type of base alteration, induces DNA replication stress (RS) without being processed by BER. In the absence of uracil DNA glycosylase (UNG), genomic uracil accumulates to high levels, DNA replication forks slow down, and PrimPol-mediated repriming is enhanced, generating single-stranded gaps in nascent DNA...

Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies. The Kirsten rat sarcoma virus (KRAS) oncogene is mutated in up to 90% of all pancreatic ductal adenocarcinomas (PDACs) and constitutes an attractive target for therapy. However, the most common KRAS mutations in PDAC are G12D (44%), G12V (34%) and G12R (20%) that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer...

Epidermal growth factor receptor (EGFR) exon 20 insertions are a rare subtype of EGFR mutations that do not respond to EGFR tyrosine kinase inhibitors developed for sensitizing mutations. In 2021, two drugs, amivantamab and mobocertinib each received FDA accelerated approval for second line use after platinum based therapy. These drugs were then brought to first line setting clinical trials; PAPILLON and EXCLAIM2. PAPILLON, which compared amivantamab plus chemotherapy to chemotherapy was positive, whereas EXCLAIM2, which compared mobocertinib to chemotherapy was negative...

There remains an unmet need for targeted therapies against advanced non-small-cell lung cancer (NSCLC) with HER2 mutations. To improve the antitumor activity of single anti-HER2 agent, this prospective, single-arm clinical trial (NCT05016544) examined the safety profile and efficacy of anti-HER2 antibody inetetamab and pan-HER TKI pyrotinib in HER2-posivite advanced NSCLC patients. Enrolled patients received inetetamab every 3 weeks and pyrotinib once per day (pyrotinib, dose-escalation part, 240 mg, 320 mg; dose-expansion part, 320 mg)...

BACKGROUND: Recent studies have unveiled disulfidptosis as a phenomenon intimately associated with cellular damage, heralding new avenues for exploring tumor cell dynamics. We aimed to explore the impact of disulfide cell death on the tumor immune microenvironment and immunotherapy in lung adenocarcinoma (LUAD). METHODS: We initially utilized pan-cancer transcriptomics to explore the expression, prognosis, and mutation status of genes related to disulfidptosis. Using the LUAD multi- -omics cohorts in the TCGA database, we explore the molecular characteristics of subtypes related to disulfidptosis...

BACKGROUND: Brain metastasis is one of the main causes of recurrence and death in non-small cell lung cancer (NSCLC). Although radiotherapy is the main local therapy for brain metastasis, it is inevitable that some cancer cells become resistant to radiation. Microglia, as macrophages colonized in the brain, play an important role in the tumor microenvironment. Radiotherapy could activate microglia to polarize into both the M1 and M2 phenotypes. Therefore, searching for crosstalk molecules within the microenvironment that can specifically regulate the polarization of microglia is a potential strategy for improving radiation resistance...

Advances in linker payload technology and target selection have been at the forefront of recent improvements in antibody-drug conjugate (ADC) design, leading to several approvals over the last decade. In contrast, the potential of novel ADC technologies to enhance payload delivery to tumors is relatively underexplored. We demonstrate that incorporation of pH-dependent binding in the antibody component of a cMET targeting ADC (MYTX-011) can overcome the requirement for high cMET expression on tumors, an innovation that has the potential to benefit a broader population of patients with lower cMET levels...

BACKGROUND: Pencil beam scanning (PBS) proton therapy for moving targets is known to be impacted by interplay effects between the scanning beam and organ motion. While respiratory motion in the thoracic region is the major cause for organ motion, interplay effects depend on the delivery characteristics of proton accelerators. PURPOSE: To evaluate the impact of different types of PBS proton accelerators and spot sizes on interplay effects, mitigations, and plan quality for Stereotactic Body Radiation Therapy (SBRT) treatment of non-small cell lung cancer (NSCLC)...

Metastases of malignant diseases are the most frequent tumors diagnosed in the human eye. They occur in approximately 5-10% of patients with solid tumors during the course of the disease. Their frequency is particularly high in patients with breast and lung cancer. Many highly sensitive periorbital tissues can be affected by the localization of the metastatic lesions and pose a number of clinical challenges. The main goal of the therapy of ocular metastases consists of the control of tumor growth (including the control of other possible manifestations throughout the body), the preservation of the affected eye and the minimization of potential iatrogenic damage to adjacent tissues...

PURPOSE: Despite the increasing interest in using continuous positive airway pressure (CPAP) in radiation therapy (RT), direct comparisons with the more widely used deep inspiration breath-hold (DIBH) have been limited. This planning study aimed to offer comprehensive geometric and dosimetric evidence by comparing CPAP and DIBH-based RT plans. MATERIALS AND METHODS: A retrospective data set of 35 patients with left-sided breast cancer with planning computed tomography scans under three breathing conditions (free breathing (FB), CPAP with 10 cmH2 O pressure, and DIBH) was collected...

PURPOSE: To report continuous positive airway pressure (CPAP)-assisted breathing with supine tangential left breast radiation therapy (CPAP-RT) when deep inspiration breath-hold RT (DIBH-RT) was ineffective or unsuitable. METHODS AND MATERIALS: Ten patients with left breast cancer underwent computed tomography simulation scan (CT-sim) under DIBH followed by CPAP-assisted breathing (15 cm H2 O) to create CPAP-RT plans in authors' institute. Reasons for CPAP-RT include inability to reproduce DIBH (n = 5), DIBH-RT plan exceeded dose limits to the heart (n = 2), and unable to proceed with planned DIBH-RT due to mechanical issues (n = 3)...