Squamous Cancer Research Articles

Abstract 2360: ADV101, a first-in-class IL-1RAP ADC demonstrates significant anti-tumor activity in solid tumor models

Abstract Chronic inflammation is intricately linked to cancer development, and the IL-1 cytokine family stands out as pivotal regulators of inflammation. All the pro-inflammatory cytokines within the IL-1 family rely on a single co-receptor called IL-1RAP which therefore emerges as a crucial and central node for modulating these pathways. While healthy tissues, except for the placenta, showed minimal plasma membrane IL-1RAP expression, tumor tissues exhibited high IL-1RAP expression, particularly in Acute myeloid leukaemia, Ewing sarcoma, ovarian cancer, head and neck, and squamous gastric and oesophageal cancers. In addition, elevated IL-1RAP expression in haematological and solid malignancies has also been associated with poor overall survival, making it an attractive target for therapeutic intervention. In this study, we present the development and characterization of an antibody-drug-conjugate (ADC) targeting IL-1RAP for potential anti-tumor applications. Following on from this, an anti-IL-1RAP antibody, ADV58, was generated and confirmed to have the anticipated biophysical, specificity, and functional properties, including low nanomolar affinity (SPR and ELISA), selectivity/specificity to human IL-1RAP, and internalization potential into IL-1RAP-positive tumor cells. In addition, ADV58 bind similarly well to human, cynomolgus and rhesus monkey IL-1RAP antigens but not to rat and mouse. Altogether these properties made ADV58 an ideal candidate for an ADC program. Concurrently, solid tumor cell lines from indications of interest with elevated IL-1RAP expression were identified, laying the groundwork for disease relevant pre-clinical tumor models. Using these models, the anti-tumor potential of ADV101 (ADV58-derived ADC) was assessed in vitro and in vivo in successful proof-of-concept studies by conjugating ADV58 with monomethyl auristatin E (MMAE, DAR of 4) or Deruxtecan (DXd, DAR of 8). Humanisation and conjugation did not compromise binding of the naked antibody, the ADV58-MMAE or the ADV58-DXd ADCs to human and non-human primate IL-1RAP. In vitro, the ADCs selectively killed IL-1RAP-positive tumor cells. In vivo efficacy studies in IL-1RAP-positive subcutaneous xenograft tumor models also demonstrated a significant dose-dependent and IL-1RAP antigen-dependent anti-tumor response for both anti-IL-1RAP ADCs. Altogether the robust preclinical data package supports the continued development of ADV101 as a novel targeted ADC therapeutic strategy for a broad spectrum of cancers. Citation Format: Richard C. A. Sainson, Laura Demolis, Edouard De Dreuzy, Olivier Favre-Bulle, Alexis Collette, Lucas Bourhis, Soha Reda El Sayed, Delphine Genin, Clementine Primus, Lucie Bouquet, Ksenija Pavletic, Christophe Ferrand, Marina Deschamps, Stephane Lameynardie, Erik Rutjens, Jens Hasskarl. ADV101, a first-in-class IL-1RAP ADC demonstrates significant anti-tumor activity in solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2360.

Abstract 1980: Validation of a novel Type II HER2 inhibitor through preclinical studies across various cancer models

Abstract HER2 activation through amplification, overexpression or mutation drives many types of human cancers, and has been the target of several therapeutic approaches. The demonstration of clinical benefit of available pan-ERBB and HER2 inhibitors has been hampered by the dose-limiting side effects from their collateral or residual EGFR inhibition. Here we present IAM1363 (also known as ENT-H1), a highly potent and selective irreversible inhibitor of both HER2 wild-type and HER2 oncogenic mutants. IAM1363 binds to HER2 in a type II DFG-out conformation, the only example reported to date for this target. This binding mechanism underlies its strong interactions with HER2, including N-terminally truncated HER2 (p95HER2) and HER2 kinase domain mutants, with cellular IC50s in the low nanomolar range, while sparing WT EGFR. Oral administration of IAM1363 in mice led to tumor regression (TR) in a diverse set of HER2-driven tumor models at levels well below the maximum tolerated dose (MTD). Importantly, strong in vivo efficacy was observed in tumor models that exhibited resistance to the existing HER2-targeting agents. For example, in a p95HER2 xenograft model, IAM1363 caused significant TR, including complete responses, at 100 mg/kg dose, whereas tucatinib achieved at best tumor stasis at MTD and T-DXd showed marginal effect. Besides HER2 truncation, co-occurring EGFR and other receptor tyrosine kinase (RTK) amplification or overexpression can also lead to resistance to HER2-directed treatments. IAM1363 was tested in xenograft models using HER2-amplified/EGFR-high cell lines HCC1954 and SKOV3, and demonstrated robust TRs. Even more strikingly, IAM1363 led to TR in the HCC827 human lung cancer xenograft model with mid-level HER2, and high levels of EGFR and MET expression. The resistance combatting effect of IAM1363 goes beyond co-occurring RTK-mediated mechanism as IAM1363 also showed dose-dependent TR in KYSE410, a human esophageal squamous cancer xenograft model that harbors the KRAS G12C mutation and HER2 amplification. Taken together, IAM1363 represents a promising clinical candidate for the treatment of HER2-driven tumors. Its unique binding mechanism and potent pan-HER2 activity overcome multiple resistance mechanisms, and its strong EGFR avoidance widens the safety margin. Additionally, IAM1363 was found to be consistently enriched in xenograft tumors that had moderate to high HER2 expression levels, and those with HER2 activating mutations. This distinctive pharmacokinetic property facilitates optimal target engagement in tumors, including those occurring in the brain, while minimizing potential systemic side effects. Citation Format: Lana Kulyk, Kelly Chen, Iriny Botrous, Chunmei Zhao, Chang Zhao, Michael Maestre, Shawn Wright, Joseph Dennis, Jeeyoung Park, Abby Adams, Wallace Derricotte, Shane Yost, Mary L. Anderson, Fred Manby, Tom Miller, Chao Zhang, Laurent Gomez, Zhongdong Huang. Validation of a novel Type II HER2 inhibitor through preclinical studies across various cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1980.

Abstract 5555: Lung squamous cancer cell mTORC2 signaling suppresses antitumor immunity by up-regulation of PSGL-1, a ligand of VISTA/PD-1H checkpoint receptor

Abstract Lung squamous cell carcinoma (LUSC) represents 30% of non-small cell lung cancer (NSCLC) cases and has a high mortality rate with limited targeted therapies. Unlike lung adenocarcinoma (LUAD), which has seen advancements in targeted therapies, LUSC has not benefited from similar breakthroughs despite having similar genetic abnormalities. While immune checkpoint inhibitor therapies have shown promise in some LUSC patients, a significant portion does not respond effectively, leaving limited treatment options. In this study, we investigated vulnerabilities in NSCLC and found that a substantial number of LUSC patients have genetic alterations in the PI3K-mTORC2-AKT signaling pathway. By using CRISPR/CAS-9, we showed that disrupting mTORC2 function in LUSC cells reduced glycolysis and lactate secretion, which in turn reduced tumor growth in vivo. Remarkably, the loss of mTORC2 also enhanced the activity of CD4+ and CD8+ T cells within the tumors. To further understand the metabolic and immune changes associated with mTORC2 loss of function, we performed RNA sequencing comparing wild-type (WT) and mTORC2-deficient cells. Our results confirmed a link between mTORC2 and HIF-2α, while regulating PSGL-1, a ligand of the VISTA/PD-1H checkpoint receptor. Furthermore, introducing a stable, non-degradable form of HIF-2α in mTORC2-deficient tumor cells restored PSGL-1 expression in vitro and in vivo. These results suggest that the interaction between PSGL-1 and VISTA plays a role in suppressing the anti-tumor immune response in LUSC tumors. Indeed, anti-VISTA treatment inhibited the growth of LUSC WT tumors in vivo, suggesting that mTORC2 plays a role in regulating PSGL-1 expression in the tumor microenvironment. Together, these data demonstrate that targeting mTORC2 or inhibiting VISTA checkpoint receptor may serve as a potential therapeutic strategy for improving immunotherapy in LUSC. Citation Format: Verra M. Ngwa, Yoonha Hwang, Deanna N. Edwards, Wenqiang Song, Jin Chen. Lung squamous cancer cell mTORC2 signaling suppresses antitumor immunity by up-regulation of PSGL-1, a ligand of VISTA/PD-1H checkpoint receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5555.

Abstract 3903: Discovery of ULBP6 as a novel immuno-oncology target using pleiotropic signals from 23andMe’s genetic and health survey database

Abstract 23andMe has assembled one of the largest platforms for human genetics research that combines genotypes from 14 million individuals, 80% of which are consented to participate in research, with billions of phenotypic data points collected from health survey data. Using these large scale genetic and phenotypic datasets, we have developed a unique target discovery platform that has identified hundreds of pleiotropic genetic variants with opposing directionality of effects in cancer and immune diseases. These immune-oncology (I/O) genetic associations point to already clinically validated immune checkpoint receptors (e.g., CTLA4) and those currently in clinical trials (e.g., CD200R1). This suggests that these I/O genetic associations could be linked to genes that are broadly utilized by tumor cells to evade the immune system and could be used to identify novel therapeutic targets involved in regulating anti-tumor immune response. Here, we utilized expression quantitative trait loci (eQTLs) and annotation of coding single nucleotide polymorphisms (SNPs) to link one of these signals to a causal gene, and identified ULBP6, a stress-induced ligand for the activating immunoreceptor NKG2D found on NK and T cells. ULBP6 is known to be shed from the cell surface of tumor cells to block its interaction with NKG2D to evade immune surveillance. Expression profiling of ULBP ligands in various tumor types using MSD, IHC, bulk and single-cell RNA-seq revealed tumor-intrinsic up-regulation of ULBP6 in squamous cancer subtypes. Collectively, these data suggest that ULBP6 is a promising therapeutic target, and that can potentially enhance anti-tumor immunity. Citation Format: Susanne Tilk, Pierre Fontanillas, Wei-Jen Chung, Clifford Hom, Shi Shi, Anh Diep, Kim Gerrick, Mauro Poggio, Pranidhi Sood. Discovery of ULBP6 as a novel immuno-oncology target using pleiotropic signals from 23andMe’s genetic and health survey database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3903.

Abstract 3134: SDP03923-000-9106, a novel and optimized LIV-1 ADC with superior anti-tumor efficacy in breast cancer xenograft models

Abstract Background: LIV-1, also known as SLC39A6 or ZIP6, is a transmembrane protein belonging to the zinc transporter family. LIV-1 is a promising target for antibody-drug conjugate (ADC) therapy due to its broad expression in tumors and limited normal tissue expression. Ladiratuzumab vedotin, a LIV-1 targeting ADC with payload of MMAE, is now in phase I clinical trial stage and is the only LIV-1 ADC under clinical development worldwide. The preliminary clinical results demonstrated promising efficacy in TNBC (ORR=32%) but no response in HR+/HER2- breast cancer (ORR=0%), and typical MMAE-related adverse events were observed. Herein, we presented a novel LIV-1 directed ADC, SDP03923-000-9106, consisting of a LIV-1 mAb developed in house conjugated to a proprietary topoisomerase I inhibitor via a cleavable linker with an optimized average drug-to-antibody ratio (DAR) of 6. Method: The in vitro binding affinity of SDP03923-000-9106 against LIV-1 protein was measured by Surface Plasmon Resonance (SPR) assays. The expression levels of LIV-1 in different cancer cell lines were detected by flow cytometry and IHC staining. In vitro activity against cancer cell lines was analyzed by CellTiter Glo assays following 10 days of treatment. The in vivo anti-tumor activities were investigated in both CDX and PDX models of breast cancer. Results: SDP03923-000-9106 is a novel anti-LIV-1 ADC comprised of a humanized LIV-1 monoclonal antibody conjugated to the potent topoisomerase I inhibitor (a novel exatecan derivative designed by Hengrui with a better liposolubility and cellular permeability) by a cleavable linker. SDP03923-000-9106 had an optimal drug-to-antibody ratio (DAR) of 6 and showed strong binding affinity to LIV-1 and favorable internalization. SDP03923-000-9106 exhibited robust anti-tumor activity in cell lines across breast cancer, esophageal squamous cancer, gastric cancer, prostate cancer and non-small cell lung cancer. In the LIV-1 highly expressed breast cancer cell line of MCF-7, SDP03923-000-9106 demonstrated a strong inhibitory effect with IC50 of 5.36 nM. Moreover, in a LIV-1 high-expressing patient-derived xenograft model of breast cancer, SDP03923-000-9106 showed pronounced tumor regression at both doses of 3 and 10 mg/kg and showed stronger anti-tumor activity (TGI: 109%) at the same dose of 3 mg/kg versus BMK-MMAE (TGI: 75%; BMK-MMAE is synthesized by Hengrui using the published structure of Ladiratuzumab vedotin). Conclusion: In summary, SDP03923-000-9106 is a novel LIV-1 targeted ADC with a highly permeable payload demonstrating great anti-tumor activity across multiple types of tumors in preclinical studies. The promising preclinical data support advancing SDP03923-000-9106 into clinical testing, and Investigational New Drug (IND) application to NMPA has been submitted. Citation Format: Yanling Gong, Xing Sun, Changyong Yang, Simeng Chen, Wei Zhang, Cheng Liao. SDP03923-000-9106, a novel and optimized LIV-1 ADC with superior anti-tumor efficacy in breast cancer xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3134.

Dickkopf-1 drives perineural invasion via PI3K-AKT signaling pathway in head and neck squamous cancer.

Perineural invasion (PNI) leads to the poor prognosis of head and neck squamous cancer (HNSCC) patients, but the mechanism of PNI remains unclear. Dickkopf-1 (DKK1), a secretory protein in the Wnt signaling pathway, was found indeed upregulated in HNSCC cells and tissues. Higher expression of DKK1 was statistically relevant to T stage, N stage, PNI, and poor prognosis of HNSCC. DKK1 overexpression enhanced the migration abilities of cancer cells. Moreover, DKK1-overexpressing cancer cells promoted cancer cells invasion of peripheral nerves in vitro and in vivo. Mechanistically, DKK1 could promote the PI3K-AKT signaling pathway. The migration abilities of neuroblastoma cells, which were enhanced by DKK1-overexpressing HNSCC cell lines, could be reversed by an inhibitor of Akt (MK2206). The association of DKK1 with PNI was also confirmed in HNSCC samples. Variables, including T stage, N stage, DKK1 expression, and PNI, were used to establish a nomogram to predict the survival probability and disease-free probability at 3 and 5years. In summary, DKK1 can promote the PI3K-AKT signaling pathway in tumor cells and then could induce neuritogenesis and facilitate PNI. MK2206 may be a potential therapeutic target drug for HNSCC patients with PNI.

Reciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer

Squamous cell carcinomas (SCCs) are common and aggressive malignancies. Immune check point blockade (ICB) therapy using PD-1/PD-L1 antibodies has been approved in several types of advanced SCCs. However, low response rate and treatment resistance are common. Improving the efficacy of ICB therapy requires better understanding of the mechanism of immune evasion. Here, we identify that the SCC-master transcription factor TP63 suppresses interferon-γ (IFNγ) signaling. TP63 inhibition leads to increased CD8+ T cell infiltration and heighten tumor killing in in vivo syngeneic mouse model and ex vivo co-culture system, respectively. Moreover, expression of TP63 is negatively correlated with CD8+ T cell infiltration and activation in patients with SCC. Silencing of TP63 enhances the anti-tumor efficacy of PD-1 blockade by promoting CD8+ T cell infiltration and functionality. Mechanistically, TP63 and STAT1 mutually suppress each other to regulate the IFNγ signaling by co-occupying and co-regulating their own promoters and enhancers. Together, our findings elucidate a tumor-extrinsic function of TP63 in promoting immune evasion of SCC cells. Over-expression of TP63 may serve as a biomarker predicting the outcome of SCC patients treated with ICB therapy, and targeting TP63/STAT/IFNγ axis may enhance the efficacy of ICB therapy for this deadly cancer.

Predictors of disease recurrence after radical resection and adjuvant chemotherapy in patients with stage IIb-IIIa squamous cell lung cancer: A retrospective analysis.

Lung cancer (LC) is a global medical, social and economic problem and is one of the most common cancers and the leading cause of mortality from malignant neoplasms. LC is characterized by an aggressive course, and in the presence of disease recurrence risk factors, patients, even at an early stage, may be indicated for adjuvant therapy to improve survival. However, combined treatment does not always guarantee a favorable prognosis. In this regard, establishing predictors of LC recurrence is highly important both for determining the optimal treatment plan for the patients and for evaluating its effectiveness. To establish predictors of disease recurrence after radical resection and adjuvant chemotherapy in patients with stage IIb-IIIa lung squamous cell carcinoma (LSCC). A retrospective case-control cohort study included 69 patients with LSCC who underwent radical surgery at the Orenburg Regional Clinical Oncology Center from 2009 to 2018. Postoperatively, all patients received adjuvant chemotherapy. Histological samples of the resected lung were stained with Mayer's hematoxylin and eosin and examined under a light microscope. Univariate and multivariate analyses were used to identify predictors associated with the risk of disease recurrence. Receiver operating characteristic curves were constructed to discriminate between patients with a high risk of disease recurrence and those with a low risk of disease recurrence. Survival was analyzed using the Kaplan-Meier method. The log-rank test was used to compare survival curves between patient subgroups. Differences were considered to be significant at P < 0.05. The following predictors of a high risk of disease recurrence in patients with stage IIb-IIa LSCC were established: a low degree of tumor differentiation [odds ratio (OR) = 7.94, 95%CI = 1.08-135.81, P = 0.049]; metastases in regional lymph nodes (OR = 5.67, 95%CI = 1.09-36.54, P = 0.048); the presence of loose, fine-fiber connective tissue in the tumor stroma (OR = 21.70, 95%CI = 4.27-110.38, P = 0.0002); and fragmentation of the tumor solid component (OR = 2.53, 95%CI = 1.01-12.23, P = 0.049). The area under the curve of the predictive model was 0.846 (95%CI = 0.73-0.96, P < 0.0001). The sensitivity, accuracy and specificity of the method were 91.8%, 86.9% and 75.0%, respectively. In the group of patients with a low risk of LSCC recurrence, the 1-, 2- and 5-year disease-free survival (DFS) rates were 84.2%, 84.2% and 75.8%, respectively, while in the group with a high risk of LSCC recurrence the DFS rates were 71.7%, 40.1% and 8.2%, respectively (P < 0.00001). Accordingly, in the first group of patients, the 1-, 2- and 5-year overall survival (OS) rates were 94.7%, 82.5% and 82.5%, respectively, while in the second group of patients, the OS rates were 89.8%, 80.1% and 10.3%, respectively (P < 0.00001). The developed method allows us to identify a group of patients at high risk of disease recurrence and to adjust to ongoing treatment.

Exploratory Assessment of Galectin-1, -3, and -9 in Non-Small Cell Lung Cancer.

Galectins play a pivotal role in lung cancer oncogenic pathways, influencing apoptosis, angiogenesis, and tumor metastasis. Biomarkers that diagnose, prognose, and guide cancer treatment are crucial, with galectins having the biomarker potential for non-small cell lung cancer (NSCLC). Using enzyme-linked immunosorbent assay (ELISA), we assessed serum galectin-1, -3, and -9 levels in NSCLC patients. A retrospective chart review was performed to examine patient demographics, cancer stage, tumor biology, cancer treatment, and patient outcomes. Galectin levels were then compared across these factors. In this exploratory analysis, galectin-3 levels were significantly lower in patients with squamous cell lung cancer (p = 0.0019) and in patients exposed to chemotherapy (p = 0.0375). Galectin-1 levels were significantly lower in patients with previous metastasis but had no correlation with future metastasis. Abnormal galectin-1 levels were significantly correlated with decreased overall survival (OS) in NSCLC (p = 0.0357) and specifically in patients with surgically resectable NSCLC (p = 0.0112). However, abnormal galectin-1 levels were not found to correlate with decreased OS in multivariable analysis (p = 0.0513). These findings may have clinical implications as galectin-3 inhibitors are in trials for NSCLC. Additionally, they suggest that galectin-1 has potential as a prognostic marker for surgically resectable NSCLC.

A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors.

Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56-62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.

Immune Gene Networks from Lung Cancer Patients Treated with Immune Checkpoint Inhibitors.

The association between immune checkpoint inhibitors (ICIs) and immune gene networks in squamous lung cancer (LUSC) and lung adenocarcinoma (LUAD) was studied. Immune gene networks were constructed using RNA-seq data from the gene expression omnibus (GEO) database. Datasets with more than 10 samples of normal control and tumor tissues were selected; of these, GSE87340, GSE120622, and GSE111907 were suitable for analysis. Gene set enrichment for pathway analysis was performed. For immune gene network construction, 998 unique immune genes were selected from 21 pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG). Gene function annotation was performed based on the KEGG, Gene Ontology, and Reactome databases. Tumor tissues showed decreased coagulation, hematopoiesis, and innate immune pathways, whereas complement- and coagulation-related genes were prominent in the tumor immune gene network. The average numbers of neighbors, clustering coefficients, network diameters, path lengths, densities, and heterogeneities were highest for normal tissue, followed by LUAD and LUSC. Decreased coagulation genes, which were prominent in tumor immune networks, imply functional attenuation. LUAD was deviated from normal tissue, based on network parameters. Tumor tissues showed decreased immune function, and the deviation of LUSC from normal tissue might explain LUSC's better therapeutic response to ICI treatment.

Photodynamic therapy of Bowen’s disease

Bowen’s disease is a form of non-invasive (in situ) squamous cell skin cancer localized in the non-genital area. Russian and European clinical guidelines include photodynamic therapy (PDT) in the standard of care for patients with Bowen’s disease. In the present review, the efficacy and safety profile of different PDT regimens for Bowen’s disease are analyzed according to the available literature data. PDT can be used to treat large Bowen’s disease lesions localized in areas of the body characterized by severe healing and in cases where surgery is not feasible. Analysis of the results of studies shows that PDT is superior in efficacy and cosmetic results to traditional local treatments such as 5-fluorouracil or cryotherapy. In all analyzed studies in patients with Bowen’s disease, PDT achieved a significant clinical effect. Complete regression of pathologic foci was achieved in 67-100% of patients. In studies evaluating the recurrence rate of Bowen’s disease after PDT, this value ranged from 2-28% with the range of 6-18% in most of the studies. Most often, 5-aminolevulinic acid and its methyl ester are used for PDT in Bowen’s disease. According to some researchers, aminolevulinic acid allows to achieve a more long-term positive clinical effect with a lower incidence of painful reactions during treatment

Cost-effectiveness of immunotherapies for advanced squamous non-small cell lung cancer: a systematic review

BackgroundThere are differences in the pharmacoeconomics of Immune checkpoint blocking (ICB) therapies for the treatment of lung squamous cell carcinoma (LSCC). However, no corresponding review studies have fully discussed the cost-effectiveness of ICBs in treating LSCC. The aim of this paper is to systematically review and evaluate all available pharmacoeconomic studies of ICBs for LSCC.MethodThe inclusion criteria were based on the population, intervention, comparator, outcomes, and study designs. An electronic search was conducted by June 2023, and the following databases were used: PubMed, EMBASE, Cochrane Library, and Web of Science. Search keywords included ‘Carcinoma’, Non-Small-Cell Lung’, ‘Immunotherapy’, and ‘Economics, Medical’. The primary outcome was the cost-effectiveness analysis of ICB therapy in LSCC patients. Drummond Checklist was used to assess quality problems and possible bias in the study design of included pharmacoeconomic studies.ResultsThis review searched 15 articles on the economic evaluation of ICB treatment for LSCC. After a qualitative review of 15 studies, we concluded that nivolumab is more cost-effective as a monotherapy than chemotherapy alone. In the combination regimen, pembrolizumab combined with chemotherapy appears to be the most cost-effective option at present, but for Chinese payers with LSCC, locally developed treatments such as sintilimab or toripalimab in combination with chemotherapy are more cost-effective.DiscussionThe inclusion of economic evaluation has heterogeneity in research design and outcomes, which can only support qualitative synthesis. Therefore, The results of this paper need to be treated with caution. For the Chinese market, instead of imported drugs, the possible cost-effectiveness of locally developed ICB therapies should be the focus of future research.

Repeated tracheal resection for endotracheal metastasis after sleeve pneumonectomy for squamous cell lung cancer

The incidence of endotracheal and endobronchial metastases of both pulmonary and non-pulmonary primary malignancies is very rare. However, endotracheal metastasis may occur either as a result of recurrent lung cancer or of non-pulmonary originated neoplasia. Furthermore, reoperation on the trachea is a rare and challenging procedure. We here report a case of endotracheal metastasis from a squamous cell lung carcinoma, after previous tracheal sleeve pneumonectomy, which was resected via a “T” neck incision. The thorough observation of the trachea and bronchial tree over a long follow-up period is crucial for the early detection of endobronchial or endotracheal metastatic disease. Also, reoperation on the trachea can be carried out successfully by experienced surgeons.

Dual role of GRHL3 in bladder carcinogenesis depending on histological subtypes.

The effect of grainyhead-like transcription factor 3 (GRHL3) on cancer development depends on the cancer subtypes as shown in tumor entities such as colorectal or oral squamous cell carcinomas. Here, we analyzed the subtype-specific role of GRHL3 in bladder carcinogenesis, comparing common urothelial carcinoma (UC) with squamous bladder cancer (sq-BLCA). We examined GRHL3 mRNA and protein expression in cohorts of patient samples, its prognostic role and its functional impact on tumorigeneses in different molecular and histopathological subtypes of bladder cancer. We showed for GRHL3 a reverse expression in squamous and urothelial bladder cancer subtypes. Stably GRHL3-overexpressing EJ28, J82, and SCaBER in vitro models revealed a tumor-suppressive function in squamous and an oncogenic role in the urothelial cancer cells affecting cell and colony growth, and migratory and invasive capacities. Transcriptomic profiling demonstrated highly subtype-specific GRHL3-regulated expression networks coined by the enrichment of genes involved in integrin-mediated pathways. In SCaBER, loss of ras homolog family member A (RHOA) GTPase activity was demonstrated to be associated with co-regulation of eukaryotic translation initiation factor 4E family member 3 (EIF4E3), a potential tumor suppressor gene. Thus, our data provide for the first time a detailed insight into the role of the transcription factor GRHL3 in different histopathological subtypes of bladder cancer.

Intraoperative implantation of 125I seeds improves prognosis in refractory stage IIIB cervical cancer: a case report and literature review

BackgroundConcurrent chemoradiation is the standard treatment for advanced cervical cancer. However some patients still have a poor prognosis, and currently, there is no effective treatment for recurrence. In recent years, 125I seed implantation therapy has emerged as a treatment for advanced malignant tumors including surgically unresectable tumors, residual tumors after surgical resection, and metastatic tumors. However, the use of 125I seeds implantation in primary advanced cervical cancer has not been reported. In this study, we present a case of stage IIIB cervical cancer in a patient who had poor response to radiotherapy and chemotherapy. Subsequently, a radical hysterectomy was performed, and 125I radioactive seeds were successfully implanted during the surgery. This effectively controlled the lesions that were resistant to radiotherapy and had the potential to improve the prognosis.Case presentationA 56-year-old woman was diagnosed with stage IIIB (FIGO 2009) IIIC1r (FIGO 2018) squamous carcinoma of the cervix. After receiving 4 cycles of platinum-based chemotherapy and 30 rounds of radiotherapy, she underwent a radical hysterectomy. The localized cervical lesions were reduced, but there was no reduction in the size of the enlarged pelvic lymph nodes. Therefore, 125I seed implantation was performed under direct surgical vision for the right paracervical lesion and the enlarged pelvic lymph nodes on the right side. During the 18-month follow-up period, the enlarged lymph nodes subsided without any signs of recurrence or metastasis.ConclusionIntraoperative implantation of 125I seeds in lesions that are difficult to control with radiotherapy or in sites at high risk of recurrence is a feasible and effective treatment option for patients with advanced squamous cervical cancer, and it may contribute to improved survival.

62P First-line (1L) camrelizumab plus chemotherapy (chemo) for advanced squamous non-small cell lung cancer (sqNSCLC): 4-yr update from the phase III CameL-sq trial

62P First-line (1L) camrelizumab plus chemotherapy (chemo) for advanced squamous non-small cell lung cancer (sqNSCLC): 4-yr update from the phase III CameL-sq trial

68P Phase II results of ivonescimab (ivo) a novel PD-1/VEGF bispecific in combination with chemotherapy for first-line treatment of patients (pts) with advanced/metastatic squamous (Sq) non-small cell lung cancer (NSCLC)

68P Phase II results of ivonescimab (ivo) a novel PD-1/VEGF bispecific in combination with chemotherapy for first-line treatment of patients (pts) with advanced/metastatic squamous (Sq) non-small cell lung cancer (NSCLC)

Cysteine protease inhibitor 1 promotes metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer

Cysteine protease inhibitor 1 (CST1) is a cystatin superfamily protein that inhibits cysteine protease activity and is reported to be involved in the development of many malignancies. Mitochondrial oxidative phosphorylation (OXPHOS) also plays an important role in cancer cell growth regulation. However, the relationship and roles of CST1 and OXPHOS in esophageal squamous cell carcinoma (ESCC) remains unclear. In our pilot study, CST1 was shown the potential of promoting ESCC migration and invasion by the activation of MEK/ERK pathway. Transcriptome sequencing analysis revealed that CST1 is closely associated with OXPHOS. Based on a real-time ATP rate assay, mitochondrial complex I enzyme activity assay, immunofluorescence, co-immunoprecipitation, and addition of the OXPHOS inhibitor Rotenone and MEK/ERK inhibitor PD98059, we determined that CST1 affects mitochondrial complex I enzyme activity by interacting with the GRIM19 protein to elevate OXPHOS levels, and a reciprocal regulatory relationship exists between OXPHOS and the MEK/ERK pathway in ESCC cells. Finally, an in vivo study demonstrated the potential of CST1 in ESCC metastasis through regulation of the OXPHOS and MEK/ERK pathways. This study is the first to reveal the oncogenic role of CST1 in ESCC development by enhancing mitochondrial respiratory chain complex I activity to activate the OXPHOS/MEK/ERK axis, and then promote ESCC metastasis, suggesting that CST1/OXPHOS is a promising target for ESCC treatment.

Insight into the significance of Foxp3 + tumor-infiltrating lymphocytes in squamous cell lung cancer

PurposeAlthough developing a better understanding of tumor-infiltrating Foxp3 + lymphocytes (Foxp3 + TILs) might provide essential knowledge to predict response to immunotherapy and prognosis, our current knowledge about Foxp3 + TILs is inadequate. This study investigated the prognostic significance of tumor-infiltrating Foxp3 + lymphocytes (Foxp3 + TILs) in squamous cell lung cancer (SQ-LC) objectively.MethodsAmong patients with SQ-LC surgically resected in our institution between 2011 and 2017, those with pathological stage IA3-IIIA were immunohistochemically studied to evaluate Foxp3 + TILs in their tumor stroma. The impact of Foxp3 + TILs on relapse-free survival (RFS) was analyzed with Kaplan–Meier survival analysis and multivariate analysis using a Cox proportional hazards model/Fine-Gray model.ResultsThis study analyzed 100 patients. Multivariate analysis showed that a large number of Foxp3 + TILs in the stroma does not associate with a poor prognosis, rather that a large number of Foxp3 + TILs (≥ 64 cells) tend to be associated with a more favorable prognosis than a small number of Foxp3 + TILs (< 64 cells) (large vs small number: HR, 0.56; 95% CI, 0.17–1.83; P = 0.34). Exploratory analysis also showed that in the two populations divided by a difference in Foxp3 expression levels, similar trends to the main analysis were observed.ConclusionOur results showed that a large number of Foxp3 + TILs in the stroma may not associate with a poor prognosis in SQ-LC. To use the seemingly complicated information of Foxp3 + TILs as biomarkers, better understanding the diversity and heterogeneity of Foxp3 + TILs and analyzing their subpopulations that increase in the TME may be needed.