The perspective for next-generation lung replacement therapies: functional whole lung generation by blastocyst complementation.

PURPOSE OF REVIEW: Blastocyst complementation represents a promising frontier in next-generation lung replacement therapies. This review aims to elucidate the future prospects of lung blastocyst complementation within clinical settings, summarizing the latest studies on generating functional lungs through this technique. It also explores and discusses host animal selection relevant to interspecific chimera formation, a challenge integral to creating functional human lungs via blastocyst complementation. RECENT FINDINGS: Various gene mutations have been utilized to create vacant lung niches, enhancing the efficacy of donor cell contribution to the complemented lungs in rodent models. By controlling the lineage to induce gene mutations, chimerism in both the lung epithelium and mesenchyme has been improved. Interspecific blastocyst complementation underscores the complexity of developmental programs across species, with several genes identified that enhance chimera formation between humans and other mammals. SUMMARY: While functional lungs have been generated via intraspecies blastocyst complementation, the generation of functional interspecific lungs remains unrealized. Addressing the challenges of controlling the host lung niche and selecting host animals relevant to interspecific barriers between donor human and host cells is critical to enabling the generation of functional humanized or entire human lungs in large animals.

TAS2940, a novel brain-penetrable pan-ERBB inhibitor, for tumors with HER2 and EGFR aberrations.

Genetic alterations in human epidermal growth factor receptor type 2 (HER2)/epidermal growth factor receptor (EGFR) are commonly associated with breast and lung cancers and glioblastomas. Cancers with avian erythroblastosis oncogene B (ERBB) deregulation are highly metastatic and can cause primary brain tumors. Currently, no pan-ERBB inhibitor with remarkable brain penetration is available. Here, TAS2940, a novel irreversible pan-ERBB inhibitor with improved brain penetrability, was evaluated for its efficacy against several ERBB aberrant cancer models. The selectivity of TAS2940 was evaluated by enzymatic kinase assays. The inhibitory effects of TAS2940 against ERBB genetic alterations were examined using MCF10A cells expressing various HER2 or EGFR mutations and other generic cell lines harboring deregulated ERBB expression. In vivo efficacy of TAS2940 was examined following oral treatment in subcutaneous or intracranial xenograft cancer models. TAS2940 was highly potent against cells harboring HER2/EGFR alterations. TAS2940 could selectively inhibit phosphorylation of targets and the growth of cancer cells with ERBB aberrations in vitro. TAS2940 also inhibited tumor growth in xenograft mouse models with ERBB aberrations: HER2 amplification, HER2/EGFR exon 20 insertions, and EGFR vIII mutation. TAS2940 was effective in the intracranial xenograft models of HER2/EGFR cancers and improved the survival of these mice. TAS2940 has promising therapeutic effects in preclinical study against cancers harboring HER2/EGFR mutations, especially metastatic and primary brain tumors. Our results highlight potential novel strategies against lung cancers with brain metastases harboring HER2/EGFR exon 20 insertions and glioblastomas with EGFR aberrations.

Nucleic acid-triggered tumoral immunity propagates pH-selective therapeutic antibodies through tumor-driven epitope spreading.

Important roles of humoral tumor immunity are often pointed out; however, precise profiles of dominant antigens and developmental mechanisms remain elusive. We systematically investigated the humoral antigens of dominant intratumor immunoglobulin clones found in human cancers. We found that approximately half of the corresponding antigens were restricted to strongly and densely negatively charged polymers, resulting in simultaneous reactivities of the antibodies to both densely sulfated glycosaminoglycans (dsGAGs) and nucleic acids (NAs). These anti-dsGAG/NA antibodies matured and expanded via intratumoral immunological driving force of innate immunity via NAs. These human cancer-derived antibodies exhibited acidic pH-selective affinity across both antigens and showed specific reactivity to diverse spectrums of human tumor cells. The antibody-drug conjugate exerted therapeutic effects against multiple cancers in vivo by targeting cell surface dsGAG antigens. This study reveals that intratumoral immunological reactions propagate tumor-oriented immunoglobulin clones and demonstrates a new therapeutic modality for the universal treatment of human malignancies.

Oncogenic potential of human pluripotent stem cell-derived lung organoids with HER2 overexpression.

Lung adenocarcinoma (LUAD) is the most common types among lung cancers generally arising from terminal airway and understanding of multistep carcinogenesis is crucial to develop novel therapeutic strategy for LUAD. Here we used human induced pluripotent stem cells (hiPSCs) to establish iHER2-hiPSCs in which doxycycline induced the expression of the oncoprotein human epidermal growth factor receptor 2 (HER2)/ERBB2. Lung progenitors that differentiated from iHER2-hiPSCs, which expressed NKX2-1/TTF-1 known as a lung lineage maker, were cocultured with human fetal fibroblast and formed human lung organoids (HLOs) comprising alveolar type 2-like cells. HLOs that overexpressed HER2 transformed to tumor-like structures similar to atypical adenomatous hyperplasia, which is known for lung precancerous lesion and upregulated the activities of oncogenic signaling cascades such as RAS/RAF/MAPK and PI3K/AKT/mTOR. The degree of morphological irregularity and proliferation capacity were significantly higher in HLOs from iHER2-hiPSCs. Moreover, the transcriptome profile of the HLOs shifted from a normal lung tissue-like state to one characteristic of clinical LUAD with HER2 amplification. Our results suggest that hiPSC-derived HLOs may serve as a model to recapitulate the early tumorigenesis of LUAD and would provide new insights into the molecular basis of tumor initiation and progression.

TAS-119, a novel selective Aurora A and TRK inhibitor, exhibits antitumor efficacy in preclinical models with deregulated activation of the Myc, ß-Catenin, and TRK pathways.

Aurora kinase A, a mitotic kinase that is overexpressed in various cancers, is a promising cancer drug target. Here, we performed preclinical characterization of TAS-119, a novel, orally active, and highly selective inhibitor of Aurora A. TAS-119 showed strong inhibitory effect against Aurora A, with an IC50 value of 1.04 nmol/L. The compound was highly selective for Aurora A compared with 301 other protein kinases, including Aurora kinase B. TAS-119 induced the inhibition of Aurora A and accumulation of mitotic cells in vitro and in vivo. It suppressed the growth of various cancer cell lines harboring MYC family amplification and CTNNB1 mutation in vitro. In a xenograft model of human lung cancer cells harboring MYC amplification and CTNNB1 mutation, TAS-119 showed a strong antitumor activity at well-tolerated doses. TAS-119 induced N-Myc degradation and inhibited downstream transcriptional targets in MYCN-amplified neuroblastoma cell lines. It also demonstrated inhibitory effect against tropomyosin receptor kinase (TRK)A, TRKB, and TRKC, with an IC50 value of 1.46, 1.53, and 1.47 nmol/L, respectively. TAS-119 inhibited TRK-fusion protein activity and exhibited robust growth inhibition of tumor cells via a deregulated TRK pathway in vitro and in vivo. Our study indicates the potential of TAS-119 as an anticancer drug, especially for patients harboring MYC amplification, CTNNB1 mutation, and NTRK fusion.

The prognostic impact of sarcopenia on elderly patients undergoing pulmonary resection for non-small cell lung cancer.

PURPOSE: The number of elderly patients who undergo surgery is increasing, even though they are at a high risk due to a decreased physical strength. Furthermore, sarcopenia is generally associated with a poor prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: This study included NSCLC patients ≥ 65 years old who underwent pulmonary resection in our hospital between 2012 and 2015. Sarcopenia was assessed using the psoas muscle mass index based on computed tomography at the level of the third lumbar vertebra. We elucidated the impact of sarcopenia on short- and long-term outcomes after surgery. RESULTS: We enrolled 259 patients, including 179 with sarcopenia. Patients with sarcopenia before surgery tended to have postoperative complications (p = 0.0521), although they did not show a poor prognosis. In patients with sarcopenia, a multivariate analysis revealed that postoperative complications and the progression of sarcopenia 1 year after surgery were significant risk factors for a poor prognosis (p = 0.0169 and 0.00370, respectively). CONCLUSIONS: The progression of sarcopenia after surgery is associated with a poor prognosis in elderly NSCLC patients with sarcopenia. A strategy to prevent postoperative progressive sarcopenia may be necessary for improving the clinical outcome of this population.

YES1 activation induces acquired resistance to neratinib in HER2-amplified breast and lung cancers.

Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.

Overcoming epithelial-mesenchymal transition-mediated drug resistance with monensin-based combined therapy in non-small cell lung cancer.

BACKGROUND: The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors. MATERIALS AND METHODS: A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-ß-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed. RESULTS: TGF-ß treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-ß-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-ß-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor. CONCLUSION: Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance.

A Giant Thymic Cyst Accompanied by Acute Mediastinitis.

We encountered a rare case of thymic cyst accompanied by mediastinitis. A 39-year-old Japanese male presented with fever and chest pain. The chest CT revealed a mass composed of a lobular cystic lesion with inflammation, suggesting the onset of mediastinitis. A definitive histological diagnosis was not obtained, and we performed a thymectomy. Pathologically, the thymic cyst was accompanied by multiple cavities, mimicking thymic cysts, caused by the inflammatory abscess. The surrounding adipose tissue showed inflammatory cell infiltrations with chronic fibrosis. These findings indicate that clinicians should be aware that thymic cysts may cause severe mediastinitis.

[Induction Chemoradiotherapy for Locally Advanced Non-small Cell Lung Cancer].

The management of locally advanced non-small cell lung cancer (LA-NSCLC) is still controversial, because of complicated patient status and poor prognosis. The purpose of this study was to evaluate the treatment results for induction chemoradiotherapy (iCRT) followed by surgery for LA-NSCLC. From 1999 to 2016, 157 patients were surgically treated after iCRT in our hospital, and their median follow-up was 43 months. Overall survival( OS) was 66.8%, and relapse-free survival( RFS) was 52.0%. The poor prognostic factor in OS by multivariate analysis was lower-lobe origin, incomplete radiotherapy, reoperation, and RFS was lower-lobe origin. The result of our hospital was feasible compared with definitive CRT. The definitive CRT is mainstream for treatment of LA-NSCLC and adjuvant anti-programmed death ligand 1 antibody will influence the treatment strategy, however there are some patients who can get benefit only by iCRT followed by surgery. iCRT followed by surgery is one of the feasible treatment for LA-NSCLC.