BACKGROUND: Therapy-induced senescent cancer and stromal cells secrete cytokines and growth factors to promote tumor progression. Therefore, senescent cells may be novel targets for tumor treatment. Near-infrared photoimmunotherapy (NIR-PIT) is a highly tumor-selective therapy that employs conjugates of a molecular-targeting antibody and photoabsorber. Thus, NIR-PIT has the potential to be applied as a novel senolytic therapy. This study aims to investigate the efficacy of NIR-PIT treatment on senescent cancer and stromal cells.
METHODS: Two cancer cell lines (human lung adenocarcinoma A549 cells and human pancreatic cancer MIA PaCa-2 cells) and two normal cell lines (mouse fibroblast transfected with human epidermal growth factor receptor 2 [HER2] cells and human fibroblast WI38 cells) were used. The cytotoxicity of NIR-PIT was evaluated using anti-epidermal growth factor receptor (EGFR) antibody panitumumab and anti-HER2 antibody transtuzumab.
RESULTS: Cellular senescence was induced in A549 and MIA PaCa-2 cells by 10 Gy γ-irradiation. The up-regulation of cellular senescence markers and characteristic morphological changes in senescent cells, including enlargement, flattening, and multinucleation, were observed in cancer cells after 5 days of γ-irradiation. Then, NIR-PIT targeting EGFR was performed on these senescent cancer cells. The NIR-PIT induced morphological changes, including bleb formation, swelling, and the inflow of extracellular fluid, and induced a significant decrease in cellular viability. These results suggested that NIR-PIT may induce cytotoxicity using the same mechanism in senescent cancer cells. In addition, similar morphological changes were also induced in radiation-induced senescent 3T3-HER2 fibroblasts by NIR-PIT targeting human epidermal growth factor receptor 2.
CONCLUSIONS: NIR-PIT eliminates both senescent cancer and stromal cells in vitro suggesting it may be a novel strategy for tumor treatment.

暂无摘要。

Uveal melanoma (UM) is the most prevalent primary intraocular cancer in adult population. Primary methods for treatment of UM involves surgery Proton Beam Therapy (PBT), Plaque Brachytherapy, phototherapy, and Charged Particle Radiation Therapy (CPT). It has been found that approximately 50 % of patients diagnosed with UM ultimately experience development of metastatic disease. Furthermore, it has been identified that majority of the patient experience metastasis in liver with a prevalence of 95 %. Management of metastatic UM (MUM) involves various therapeutic modalities, including systemic chemotherapy, molecular targeted therapy, immunotherapy and liver directed interventions. We outline gene mutation in UM and addresses various treatment modalities, including molecular targeted therapy, miRNA-based therapy, and immunotherapy. Additionally, inclusion of ongoing clinical trials aimed at developing novel therapeutic options for management of UM are also mentioned.

To investigate the efficacy of pharmacotherapy for metastatic non-clear cell renal cell carcinoma (nccRCC) in Japanese population.
In this retrospective analysis, we compared the time to treatment failure (TTF) for molecular-targeted agents as first-line therapy, or nivolumab therapy as sequential therapy between ccRCC and nccRCC using the data of Japanese metastatic RCC patients registered in the Michinoku Japan Urological Cancer Study Group database.
In total, 511 cases of ccRCC and 77 cases of nccRCC were treated with pharmacotherapy. After excluding the patients who received cytokine therapy, chemotherapy, or others, there were 391 ccRCC patients and 60 nccRCC patients who were treated with tyrosine kinase inhibitors (TKIs), and 7 ccRCC patients and 7 nccRCC patients who were treated with mammalian-target of rapamycin inhibitors (mTORIs). In addition, 132 ccRCC patients and 16 nccRCC patients received nivolumab. There was no significant difference in IMDC risk classification before first-line therapy between ccRCC and nccRCC groups, or in each subgroup within the nccRCC group. TTF for TKIs (161 days, 95% CI: 75-212 days) and mTORIs (21 days, 95% CI: 9-31 days) didn\'t differ significantly between nccRCC and ccRCC groups (205 days, 95% CI: 174-243 days and 33 days, 95% CI: 8-113 days, respectively). TTF for TKIs was significantly longer than that for mTORIs in nccRCC group (p<0.01). There was no significant difference in TTF between the different TKIs in nccRCC group. In addition, no significant difference in TTF for nivolumab was seen between ccRCC and nccRCC groups.
The results showed that the efficacy of molecular-targeted agents as first-line therapy was similar oncological outcomes between metastatic nccRCC and ccRCC in Japanese patients. TKIs may be more effective than mTORIs in metastatic nccRCC patients. Nivolumab administration might also be as effective in nccRCC patients as in ccRCC patients in Japanese population.

Pancreatic neuroendocrine neoplasms (panNENs) are rare pancreatic neoplasms, and descriptions of treatment remain limited. Autotaxin (ATX) is a secreted autocrine motility factor involved in the production of lysophosphatidic acid (LPA), a lipid mediator that promotes the progression of various cancers. The aim of this study was to clarify the importance of the ATX-LPA axis in panNENs and to confirm its contribution to panNEN progression using clinical data, cell lines, and a mouse model. Serum ATX level was higher in patients with panNEN than in patients with other pancreatic diseases (chronic pancreatitis, pancreatic ductal adenocarcinoma [PDAC], intraductal papillary mucinous neoplasm, autoimmune pancreatitis) and healthy controls, and 61% of clinical specimens stained strongly for ATX. In a case we encountered, serum ATX level fluctuated with disease progression. An in vitro study showed higher ATX mRNA expression in panNEN cell lines than in PDAC cell lines. Cell proliferation and migration in panNEN cell lines were stimulated via the ATX-LPA axis and suppressed by RNA interference or inhibitors. An in vivo study showed that intraperitoneal injection of GLPG1690, an ATX inhibitor, suppressed tumor progression in a xenograft model. These findings revealed that ATX expression is significantly elevated in panNEN and is related to the progression of panNEN. We showed the potential of ATX as a novel biomarker and therapeutic target.

Neuroblastoma, a childhood cancer affecting the sympathetic nervous system, continues to challenge the development of potent treatments due to the limited availability of druggable targets for this aggressive illness. Recent investigations have uncovered that phosphoglycerate dehydrogenase (PHGDH), an essential enzyme for de novo serine synthesis, serves as a non-oncogene dependency in high-risk neuroblastoma. In this study, we show that homoharringtonine (HHT) acts as a PHGDH inhibitor, inducing intricate alterations in cellular metabolism, and thus providing an efficient treatment for neuroblastoma. We have experimentally verified the reliance of neuroblastoma on PHGDH and employed molecular docking, thermodynamic evaluations, and X-ray crystallography techniques to determine the bond interactions between HHT and PHGDH. Administering HHT to treat neuroblastoma resulted in effective cell elimination in vitro and tumor reduction in vivo. Metabolite and functional assessments additionally disclosed that HHT treatment suppressed de novo serine synthesis, initiating intricate metabolic reconfiguration and oxidative stress in neuroblastoma. Collectively, these discoveries highlight the potential of targeting PHGDH using HHT as a potent approach for managing high-risk neuroblastoma.

BACKGROUND: Although targeted treatments against human epidermal growth factor receptor 2 (HER2) have improved survival in patients with metastatic HER2-positive breast cancer, long and repeated treatment is time-consuming and costly for patients. To reduce these burdens, we developed ex vivo gene-transduced adipocytes that secrete anti-HER2 antibodies and evaluated their anti-tumor effects.
METHODS: Ceiling culture-derived proliferative adipocytes (ccdPA) secreting anti-HER2 antibody against domain IV receptors: TRA-ccdPA, and domain II receptors: PER-ccdPA, were constructed using a plasmid lentivirus. Delivery of secreted antibody and its specific binding to HER2 breast cancer were evaluated in vitro and in vivo. To optimize antibody production from ccdPA, different conditions of ccdPA implantation were examined. Anti-tumor efficacy was evaluated in HER2-positive-cancer-inoculated nude mice.
RESULTS: Anti-HER2 antibody against domain II was identified in supernatants from PER-ccdPAs. The optimal method to achieve the highest concentration of antibody in mouse sera was injecting differentiated ccdPA cells into the mammary fat pad. Antibody in supernatants from PER-ccdPAs bound to the surface of HER2-positive breast cancer cells similar to pertuzumab. Antibodies in mouse sera were delivered to HER2-positive breast cancer tumors and tumor necrosis was observed microscopically. One-time administration of combined TRA-ccdPAs and PER-ccdPAs produced antibody continuously in mouse sera, and anti-tumor effects were maintained for the duration of this study in xenograft models. Furthermore, combination therapy significantly suppressed tumor growth compared with a single administration.
CONCLUSIONS: Ex vivo gene-transduced adipocytes might be useful for cell-based gene therapy. This system may be a platform for various antibody therapies.

BACKGROUND: At the meetings of the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) in 2022, studies were presented which suggest changes in the clinical routine of nasopharyngeal, salivary gland, and thyroid cancer.
OBJECTIVE: Therapeutic innovations for special otorhinolaryngological tumor entities with potential clinical relevance were assessed after reviewing the studies presented at the ASCO 2022/ESMO 2022 meetings.
METHODS: The presented clinical phase II and phase III studies were analyzed. Results were classified according to their potential clinical importance, taking into account current treatment standards.
RESULTS: Three studies were presented that dealt with the topic of risk-adapted treatment stratification in advanced nasopharyngeal cancer. Dose-reduced radiotherapy (60 Gy) in low-risk patients resulted in a favorable toxicity profile with promising oncological results in a single-arm phase II study. In a phase III study, intensity-modulated radiotherapy alone showed comparable survival to combined radiochemotherapy with cisplatin in selected low-risk patients. In high-risk patients, addition of the EGFR antibody nimotuzumab to definitive radiochemotherapy showed an increased 5‑year survival rate compared to placebo (phase III study). Although an immediate change in clinical practice in Europe based on these studies is questionable, the concept of risk-adapted therapy taking into account biological characteristics (Epstein-Barr virus [EBV] DNA level) is future orientated. Similar to previous years, the contributions on recurrent/metastatic salivary gland and thyroid cancer emphasized the importance of targeted therapies based on vulnerable molecular target lesions.
UNASSIGNED: HINTERGRUND: Bei den Tagungen der American Society of Clinical Oncology (ASCO) und European Society for Medical Oncology (ESMO) 2022 wurden u. a. Studien zur Therapie von speziellen HNO-Tumoren vorgestellt, den Nasopharynx‑, Speicheldrüsen-, und Schilddrüsenkarzinomen.
UNASSIGNED: Es werden potenziell klinisch relevante Studien der Kongresse ASCO/ESMO 2022 zu speziellen HNO-Tumoren präsentiert.
METHODS: Dazu erfolgte die Analyse der präsentierten klinischen Phase-II- und -III-Studie sowie eine Abschätzung ihrer klinischen Bedeutung unter Berücksichtigung der aktuellen Therapiestandards.
UNASSIGNED: Es wurden 3 Studien vorgestellt, welche sich mit dem Thema der risikoadaptierten Therapiestratifizierung bei fortgeschrittenen Nasopharynxkarzinomen befassten. Eine dosisreduzierte Strahlentherapie (60 Gy) bei Niedrigrisikopatienten führte in einer einarmigen Phase-II-Studie zu einem günstigen Toxizitätsprofil bei vielversprechenden onkologischen Ergebnissen. In einer Phase-III-Studie zeigte eine alleinige intensitätsmodulierte Strahlentherapie ein vergleichbares Überleben wie eine kombinierte Radiochemotherapie mit Cisplatin bei ausgewählten Patienten mit niedrigem Risikoprofil. Bei Hochrisikopatienten zeigte sich eine erhöhte 5‑Jahres-Überlebensrate bei Addition des EGFR-Antikörpers Nimotuzumab zur definitiven Radiochemotherapie im Vergleich zur Placebogabe (Phase-III-Studie). Wenngleich eine unmittelbare Änderung der klinischen Praxis in Europa auf Grundlage dieser Studien fraglich ist, ist das Konzept der risikoadaptierten Therapie unter Berücksichtigung biologischer Merkmale (Level für Epstein-Barr-Virus[EBV]-DNA) zukunftsweisend. Bei den Beiträgen zu rezidivierten/metastasierten Speicheldrüsen- und Schilddrüsenkarzinomen wurde ähnlich wie in den Vorjahren die Wichtigkeit zielgerichteter Therapien auf Grundlage molekularer angreifbarer Zielläsionen in den Vordergrund gestellt.

Heat shock protein 90 (HSP90) facilitates diverse cellular processes by interacting process with more than 200 client proteins. Overexpression of HSP90 contributes to the pathogenesis of various malignant tumors, and HSP90 inhibitors attenuate the progression of malignant tumors in vitro/vivo. Numerous clinical trials have used HSP90 inhibitors to treat several cancers, and pimitespib (an HSP90 inhibitor) is covered by insurance for advanced gastrointestinal stromal tumor in Japan. In this study, we investigated the expression pattern of HSP90 and analyzed its clinical significance in extramammary Paget\'s disease (EMPD). All 77 EMPD tissues investigated were positive for HSP90 expression. The immunoreactivity of HSP90 in fetal cases due to EMPD tended to be highly stained. Although there was no significant difference in HSP90 mRNA levels between 24 paired lesional and nonlesional tissues, microRNA-inhibiting HSP90 levels in tumor tissues were significantly decreased compared with those in normal tissues. Thus, HSP90 may play an important role in the pathogenesis of EMPD and may be a novel therapeutic target for EMPD.

Molecular target inhibitors have been regularly approved by Food and Drug Administration (FDA) for tumor treatment, and most of them intervene in tumor cell proliferation and metabolism. The RAS-RAF-MEK-ERK pathway is a conserved signaling pathway that plays vital roles in cell proliferation, survival, and differentiation. The aberrant activation of the RAS-RAF-MEK-ERK signaling pathway induces tumors. About 33% of tumors harbor RAS mutations, while 8% of tumors are driven by RAF mutations. Great efforts have been dedicated to targeting the signaling pathway for cancer treatment in the past decades. In this review, we summarized the development of inhibitors targeting the RAS-RAF-MEK-ERK pathway with an emphasis on those used in clinical treatment. Moreover, we discussed the potential combinations of inhibitors that target the RAS-RAF-MEK-ERK signaling pathway and other signaling pathways. The inhibitors targeting the RAS-RAF-MEK-ERK pathway have essentially modified the therapeutic strategy against various cancers and deserve more attention in the current cancer research and treatment.