Squamous Cancer Research Articles

MRNA vaccines in cancer clinical trials: HPV16 tumor-derived antigens (e6 and e7 oncoproteins) associated with head and neck squamous cell carcinoma (HNSCC), oropharyngeal and cervical cancers

Human papillomavirus (HPV) induces the most common sexually transmitted disease and has been classified in the Alphapapillomavirus genus, Papillomaviridae family. They are non‒enveloped viruses presenting a closed circular double‒stranded non‒segmented DNA genome of approximately 8 kb that infect the anogenital epithelium causing cervical cancer, anal and penis cancer. There are viral groups based on their oncogenic activity as high‒risk types, low‒risk types and types of undetermined‒risk. mRNA vaccines are being evaluated in people with HPV-related cancers. This study described how mRNA cancer vaccines work and their applications recruiting several strategies for HPV cancer immunotherapy. Several biopharmaceuticals are developing mRNA vaccines encoding neoepitopes that can induce immune responses against target tumors. One trial is testing a personalized mRNA vaccine in combination with an immune checkpoint inhibitor in patients with advanced head and neck cancer. The production of therapeutic mRNA proteins for development of vaccine cancer have been manufactured by upstream and downstream methods. Several stages are processed in bioreactors using input and output parameters to measure the quality control of purified substance. Thus, novel technologies using different mRNA delivery system can be able to be integrated in clinical trials of HPV16 tumor-derived antigens associated cervical intraepithelial lesions of different stages until head and neck squamous cell carcinoma, oropharyngeal and cervical cancers.

Cervical Squamous Intraepithelial Lesions: A Comparison of Diagnostic Approaches

Aim. To compare the effectiveness of Papanicolaou test, screening for oncogenic human papillomavirus (HPV) strains, and colposcopy in diagnosis of cervical squamous intraepithelial lesions and cervical cancer.Materials and Methods. We conducted a retrospective study which included 101 patients aged 21-65 years (mean age 36.9 ± 8.2 years). All patients underwent cytological examination, screening for 14 high-risk HPV types, and colposcopy. The prognostic value of the methods was calculated using standard formulas for determining the sensitivity, specificity, and prognostic value of positive and negative results. Cervical biopsy was accepted as the gold standard.Results. Among the examined women (n = 101), high-risk HPV types were detected in 78 women (77.2%). According to the results of cytological examination, cervical intraepithelial neoplasia (CIN) I, CIN II, CIN III, and cancer were detected in 24 (23.8%), 24 (23.8%), 22 (21.7%), and 2 (2%) cases, respectively. Abnormal colposcopy results of the 1st and 2nd degree were found in 33 (32.7%) and 51 (50.5%) women, respectively. The highest sensitivity in the diagnosis of low-grade squamous intraepithelial lesion was demonstrated by colposcopy (81.3%), whilst HPV testing and cytological examination had lower sensitivity values (75.0% and 58.3%, respectively). However, HPV testing had the highest sensitivity (85.7%) in diagnosis of high-grade squamous intraepithelial lesion and cervical cancer, whereas colposcopy and Papanicolaou test were behind (82.9% and 63.6%, respectively).Conclusion. Detection of high-risk HPV types has a high sensitivity in detecting both low- and highgrade squamous intraepithelial lesions and cervical cancer.

Metachronous Multiple Primary Inoperable Squamous Cancer of the Esophagus: Case Report

The incidence of primary multiple malignant neoplasms (PMMN) in Russia is steadily increasing due to the increasing frequency of detection of metachronous tumors. A similar trend is observed in esophageal cancer (EC). Advances in the diagnosis and treatment of cancer have led to an increase in the life expectancy of patients after a cured primary tumor and, in turn, to an increase in the detection rate of a second tumor. The longer life expectancy of patients with cancer, the higher the likelihood of developing a second tumor. PMMN of the esophagus is one of the least studied problems in modern oncology, which complicates the choice of treatment tactics, since there are no standards for the management of such patients. This article reflects a multidisciplinary and individual approach to the treatment of a patient with primary multiple metachronous inoperable squamous cell carcinoma of the middle and lower thoracic esophagus. The patient underwent chemoradiotherapy (CRT) with full effect, with no post-radiation damage and improved quality of life.

Characterization of cell cycle, inflammation, and oxidative stress signaling role in non-communicable diseases: Insights into genetic variants, microRNAs and pathways

Non-Communicable Diseases (NCDs) significantly impact global health, contributing to over 70% of premature deaths, as reported by the World Health Organization (WHO). These diseases have complex and multifactorial origins, involving genetic, epigenetic, environmental and lifestyle factors. While Genome-Wide Association Study (GWAS) is widely recognized as a valuable tool for identifying variants associated with complex phenotypes; the multifactorial nature of NCDs necessitates a more comprehensive exploration, encompassing not only the genetic but also the epigenetic aspect. For this purpose, we employed a bioinformatics-multiomics approach to examine the genetic and epigenetic characteristics of NCDs (i.e. colorectal cancer, coronary atherosclerosis, squamous cell lung cancer, psoriasis, type 2 diabetes, and multiple sclerosis), aiming to identify novel biomarkers for diagnosis and prognosis. Leveraging GWAS summary statistics, we pinpointed Single Nucleotide Polymorphisms (SNPs) independently associated with each NCD. Subsequently, we identified genes linked to cell cycle, inflammation and oxidative stress mechanisms, revealing shared genes across multiple diseases, suggesting common functional pathways. From an epigenetic perspective, we identified microRNAs (miRNAs) with regulatory functions targeting these genes of interest. Our findings underscore critical genetic pathways implicated in these diseases. In colorectal cancer, the dysregulation of the “Cytokine Signaling in Immune System” pathway, involving LAMA5 and SMAD7, regulated by Hsa-miR-21-5p, Hsa-miR-103a-3p, and Hsa-miR-195-5p, emerged as pivotal. In coronary atherosclerosis, the pathway associated with “binding of TCF/LEF:CTNNB1 to target gene promoters” displayed noteworthy implications, with the MYC factor controlled by Hsa-miR-16-5p as a potential regulatory factor. Squamous cell lung carcinoma analysis revealed significant pathways such as “PTK6 promotes HIF1A stabilization,” regulated by Hsa-let-7b-5p. In psoriasis, the “Endosomal/Vacuolar pathway,” involving HLA-C and Hsa-miR-148a-3p and Hsa-miR-148b-3p, was identified as crucial. Type 2 Diabetes implicated the “Regulation of TP53 Expression” pathway, controlled by Hsa-miR-106a-5p and Hsa-miR-106b-5p. In conclusion, our study elucidates the genetic framework and molecular mechanisms underlying NCDs, offering crucial insights into potential genetic/epigenetic biomarkers for diagnosis and prognosis. The specificity of pathways and related miRNAs in different pathologies highlights promising candidates for further clinical validation, with the potential to advance personalized treatments and alleviate the global burden of NCDs.

Human Papillomavirus-Induced Chromosomal Instability and Aneuploidy in Squamous Cell Cancers.

Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer. CIN is defined as a continuous rate of chromosome missegregation events over the course of multiple cell divisions. CIN causes aneuploidy, a state of abnormal chromosome content differing from a multiple of the haploid. Human papillomavirus (HPV) is a well-known cause of squamous cancers of the oropharynx, cervix, and anus. The HPV E6 and E7 oncogenes have well-known roles in carcinogenesis, but additional genomic events, such as CIN and aneuploidy, are often required for tumor formation. HPV+ squamous cancers have an increased frequency of specific types of CIN, including polar chromosomes. CIN leads to chromosome gains and losses (aneuploidies) specific to HPV+ cancers, which are distinct from HPV- cancers. HPV-specific CIN and aneuploidy may have implications for prognosis and therapeutic response and may provide insight into novel therapeutic vulnerabilities. Here, we review HPV-specific types of CIN and patterns of aneuploidy in squamous cancers, as well as how this impacts patient prognosis and treatment.

Abstract 279: Iatrogenic immunosuppression emplaces tacrolimus to drive squamous skin cancer progression and influence the microenvironment

Abstract One in thirteen organ transplant recipients (OTRs) develop post-transplant cutaneous squamous cell carcinoma (cSCC), leading to significant morbidity upon disease progression. Although chronic ultraviolet (UV) exposure primarily underlies keratinocyte carcinogenesis, long-term immunosuppression is a critical etiologic risk factor due to reduced systemic surveillance of dysplasia. Calcineurin inhibitors such as tacrolimus are commonly administered to suppress the immune system by blocking T-cell proliferation and preventing donor organ rejection. Contrarily, studies have evinced the off-target effects of immunosuppressives, namely azathioprine and cyclosporine, but not tacrolimus — the most widely used in all immunosuppression. In addition, the preclinical research literature has overlooked the contribution of stromal fibroblasts in the cSCC tumor microenvironment (TME). Hence, we hypothesize that tacrolimus exerts direct carcinogenic effects on keratinocytes and fibroblasts in the skin. We further postulate that tacrolimus enables a tumor-permissive microenvironment by activating dermal fibroblasts to cause aggressive and invasive keratinocyte carcinoma in OTRs. To examine this cellular crosstalk phenomenon, we used human keratinocytes, primary dermal fibroblasts and cSCC cells in mono- and co-cultures to mimic cutaneous and tumor complexities. Next, we assessed the molecular mechanisms utilized by tacrolimus to potentiate tumorigenesis pertinent to cell survival, proliferation and invasion. Herein, we show that tacrolimus promotes cell survival dose-dependently in cSCC cells. We also found that a fibroblast-cSCC spheroid co-culture significantly enhances cell invasion. In a wound-healing migration assay, tacrolimus increased the migratory capacity of normal keratinocytes and cSCC cells. However, cell proliferation remains nebulous due to cyclical dose-response effects in vitro. We then queried whether cell proliferation is affected in vivo using immunodeficient mice, and similar results were observed. We confirmed via immunoblotting that tacrolimus induced elevated expression of proliferation markers at distinct drug concentrations. Altogether, our findings illuminate keratinocyte-stroma interactions and particularly isolate the contributory role of tacrolimus in non-immune mediated cSCC pathogenesis. This knowledge suggests newer immunosuppressives that do not inhibit calcineurin activity may help relieve cutaneous malignancies in transplant recipients. Citation Format: Edwin Kumah, Yash Chhabra, Vania Wang, Agrani Dixit, Ashani Weeraratna, Kristin Bibee. Iatrogenic immunosuppression emplaces tacrolimus to drive squamous skin cancer progression and influence the microenvironment [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 279.

Abstract 3495: Multi-omic landscape of squamous cell lung cancer

Abstract Patients with lung squamous cell carcinoma (LSCC) require new drug targets and improved biomarkers due to a lack of targetable genomic drivers and low response rates to immune checkpoint blockade. In a previous study, we analyzed a cohort of 108 LSCC patients by integrating DNA copy number variation, somatic mutations, RNA-sequencing, and expression proteomics. The principal discovery was the identification of three proteomic subtypes, with the majority (87%) of tumors comprising two of these subtypes. The "Inflamed" subtype showed enrichment for B-cell-rich tertiary lymphoid structures, while the "Redox" subtype exhibited enrichment for redox pathways and NFE2L2/KEAP1 alterations but had notably lower immune infiltration. We hypothesized that these subtypes would result in distinct metabolic signatures. Using ultra-high-performance liquid chromatographic separation on a HILIC column, followed by analysis on a Q Exactive HF high resolution mass spectrometer, we performed untargeted metabolomics on 87 tumors from the same LSCC proteogenomics cohort. A total of 7,392 features were obtained from this analysis, leading to the identification of 446 metabolites through m/z and retention time matching against an internal reference library. To understand if metabolomics could recapitulate our proteomic subtypes, we applied consensus clustering and non-negative matrix factorization (NMF) and assessed the resulting clusters using a Random Forest (RF) supervised classifier. Area Under the Curve (AUC) values for consensus clustering (5 clusters, AUC = 0.72), NMF (4 clusters, AUC = 0.73), and proteomics subtypes (Stewart et al. Nature communications. 2019:10:3578) (3 clusters, AUC = 0.74) suggest that metabolite abundances do indeed recapitulate the proteomic subtypes. Differential expression between Redox and Inflamed yielded 29 differentially expressed metabolites (p-value < 0.05 and 1.5 fold change). Glutathione, a key redox metabolite, was modestly elevated in the Redox proteomic subtype (0.58 log2 ratio, p = 1.14E-05). Notably, we identified glutathione metabolism (p = 1.29-5) and arginine biosynthesis (p = 5.22-4) as among the most significant pathways among differentially expressed metabolites. Glutathione, a key redox metabolite, was modestly elevated in the Redox proteomic subtype (0.58 log2 ratio, p = 1.14E-05). In conclusion, metabolomics recapitulates the proteomic subtypes, and there are distinct differences between these subtypes at the metabolite level. Ongoing work is developing a novel, network-based analysis framework to integrate these data quantitatively. Citation Format: Isis Y. Narvaez-Bandera, Ashley Lui, Eric Welsh, Dalia Ercan, Vanessa Rubio, Hayley Ackerman, Guohui Li, Lancia Darville, Min Liu, Bin Fang, Steven Eschrich, Brooke Fridley, John Koomen, Eric Haura, Gina M. DeNicola, Elsa Flores, Paul Stewart. Multi-omic landscape of squamous cell lung cancer [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 3495.

Abstract 1244: Exploiting the pathogenesis of endogenous retrovirus to tackle squamous cancers

Abstract Retrotransposons are the evolution relic of ancestrally invaded retroviruses interspersed through our genome. Mostly domesticated as host regulome, retrotransposons shape lineage gene expressions or donate coding functions. A few rare evolutionarily young species remain virally active, leading to germline mutations and modulating immune functions. Aberrant retrotransposon activities have been widely observed in adult diseases, although the extent to which they ensue active viral form and function under those contexts is unclear. Their molecular trigger in adult pathophysiology is poorly defined. To address these questions, we use murine skin as our model, given its well-characterized, abundant and highly accessible adult stem cells, not only mediating postnatal remodeling and homeostatic regeneration, but also responding to stress by driving tissue repair and adaptations. By analyzing a genetic model lacking a known retrotransposon suppressor, histone methyltransferase Setdb1, which we found to be essential in the adult skin, we saw hair loss and hair follicle stem cell exhaustion phenotype, accompanied by a robust and selective surge of endogenous retroviruses (ERVs). When combined with squamous cell carcinoma drivers, Setdb1 loss significantly blocked tumor progression in vivo. Interestingly, compared to relatively mild or no induction of commonly observed evolutionarily young ERVs, the most induced species in our model is a class I ERV, murine leukemia virus (MuLV). We detected abundant retroviral peptides originated from its full-length copies through mass spectrometry and viral-like particles through transmission electron microscopy that are immunoreactive to a monoclonal MuLV env antibody. Similar viral-like particles were broadly evident across several epithelial tissues beyond skin, implicating its conserved function across squamous cancers. Epithelial originated ERVs elicit tissue wide inflammatory response, and can be ameliorated by pharmacological or genetic inhibition of retroviral activity. Physiologically, viral-coding ERVs arise as the epigenetic machinery declines in response to age-associated stress, and plummet when host safeguard prevails in UV induced skin hyperplasia. As an evolutionary conundrum, viral-coding ERVs pose a threat to host fitness and yet, they’ve resisted extinction persisting in the mammalian genome. Our findings suggest viral-coding ERVs wrestle with the host surveillance programs to regulate adult tissue physiology and pathology, thus providing a key target in eliciting innate immunity and tackling squamous cancers. Citation Format: Ying Lyu, Yejing Ge. Exploiting the pathogenesis of endogenous retrovirus to tackle squamous cancers [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 1244.

Abstract 4553: DXC004A, a novel EGFR antibody-tubulysin analog conjugate demonstrated potential to broaden therapeutic opportunities for non-small cell lung cancer

Abstract EGFR is a member of the epidermal growth factor receptor (HER) family, and the over-expression of EGFR plays an important role in the growth and progression of various tumors, including non-small cell lung cancer. Monoclonal EGFR antibodies, such as cetuximab and panitumumab, have proven efficacy in various types of cancer. However, treatment with the anti-EGFR agents can be associated with toxicities of the skin, nails, hair, and eyes. Nimotuzumab (Nimo) is the first humanized monoclonal antibody targeting EGFR and has been granted approval for use in squamous cell carcinoma of head and neck (SCCHN), glioma and nasopharyngeal cancer in different countries. In contrast to cetuximab, Nimotuzumab is distinguished by achieving higher or similar complete remission rate (CRR) or overall remission rate (ORR) of the primary tumor in clinical applications but much less toxicity, resulting in a better safety profile, which has been attributed to its about 10-fold lower affinity. Paclitaxel combined with cisplatin is the first-line chemotherapy regimen for non-small cell lung cancer. A phase 2 clinical trial has confirmed that Nimotuzumab combined with concurrent chemoradiation therapy (radiation concurrent with docetaxel and cisplatin, CCRT) was well tolerated for locally advanced squamous cell lung cancer. However, the combination strategy of Nimo-CCRT has only demonstrated similar OS and PFS to those in the CCRT group. DXC004A is an ADC drug targeting EGFR, in which a Nimotuzumab derivative and a Tubulysin B analog is conjugated by a functional linker. DXC004A is in phase I clinical trial and has demonstrated clinical activity in advanced non-small cell lung cancers and good tolerability. In vitro and in vivo results had confirmed that DXC004A monotherapy had better anti-tumor activity than the combination of Nimotuzumab and Tubulysin analog in HCC827 cell lines with high EGFR expression. Meanwhile, a single injection of low-dose DXC004 (2.5 mg/kg) in HCC827 xenograft model showed very good durable anti-tumor effect. Moreover, the combination of DXC004A with Cisplatin exhibited significantly better activities than that of Nimo-CCRT combination, DXC004A or cisplatin alone, in vitro and in vivo, which might solve the predicament of poor efficacy of Nimo-CCRT combination therapy. This synergy results suggested that DXC004A plus cisplatin would possibly be a new adjuvant therapy for non-small cell lung cancer in further clinical studies. Citation Format: Xiaobo Cai, Min Cao, Huihui Guo, Qingliang Yang, Yongxiang Chen, Xiangfei Kong, Yong Du, Zhicang Ye, Zhixiang Guo, Lingli Zhang, Lu Bai, Junxiang Jia, Yunxia Zheng, Wei Zheng, Jun Zheng, Wenjun Li, Yuanyuan Huang, Zhongliang Fan, Binbin Chen, Meng Dai, Robert Y. Zhao. DXC004A, a novel EGFR antibody-tubulysin analog conjugate demonstrated potential to broaden therapeutic opportunities for non-small cell lung cancer [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 4553.

Abstract 6182: Artificial intelligence (AI)-powered quantification of glypican-3 (GPC3) expression facilitates patient selection for GPC3-targeted therapy in solid tumors

Abstract Introduction: GPC3 is a glycosyl-phosphatidylinositol-anchored cell surface glycoprotein that functions to control cell growth and differentiation in early development. Membrane GPC3 is highly expressed in hepatocellular carcinoma (HCC) and moderately in squamous non-small cell lung cancer (SQ-NSCLC) with limited expression in normal tissues which makes it an attractive target for immune cell engagers. This study aims to develop an AI-powered algorithm to evaluate GPC3 expression and compare it with manual immunohistochemistry (IHC) scoring in HCC, adeno-NSCLC and SQ-NSCLC. Methods: 147 NSCLC (94 SQ-NSCLC and 53 adeno-NSCLC) and 113 HCC FFPE tumor blocks were obtained from commercial sources. GPC3 protein level was quantified by a qualified IHC assay for tumor cell membrane and cytoplasm individually. PD-L1 expression is reported as tumor cell proportion score (TPS), combined positive score (CPS) and immune cell proportion score (IPS/IC) TPS, regardless of staining pattern and intensity. FFPE slides were stained for GPC3+ (GC33, Ventana), PD-L1+ (22C3, Dako) cells and then scanned at 20x using the Aperio Versa8 scanner. Machine learning (ML) models were developed using the digitized whole slide images to identify GPC3+ tumor area. Data-driven cutoffs were applied to model-generated human-interpretable features of GPC3+ percentage of tumor area to classify samples as positive and negative. As an orthogonal approach to the GPC3+ percentage cutoff method, tissue and cell annotations were used to train a convolutional neural network (CNN) to classify GPC3 positivity. Results: The epidemiology profiling results revealed that GPC3 protein is highly expressed in HCC (57.5% cases with > 1% positive cells), followed by SQ-NSCLC (52.1%) and adeno-NSCLC (5.7%). GPC3 expression was only detected in tumor cells with two staining patterns observed: membrane + cytoplasm and cytoplasm-only. There was no significant correlation between GPC3 and PD-L1 expression across tumor types, although a trend of lower level of PD-L1 was observed in the samples with GPC3 ≥50%. ML model quantification of GPC3+ and GPC3- showed high concordance with the consensus score of 2 independent pathologists on a test set of held-out samples not used in training. This concordance was comparable to that of individual annotators to consensus. Instead, GPC3 positivity results using both cutoff and CNN methods showed moderate concordance with 2-way pathologist consensus. Conclusions: Here we profiled GPC3 expression across tumor types and showed high level of expression in HCC followed by SQ-NSCLC. We have established an AI-powered digital pathology platform that can provide a standardized, scalable, and reproducible method of characterizing GPC3 positivity to support further patient selection in clinical study. Citation Format: Ellen Meng, Robin Meng, Ying Tong, Yuchen Li, Hong Wang, Paola Fiorentini, Elham Attieh, Qi Tang, Asma Kefsi, Serena Masciari, Giovanni Abbadessa, Cecile Combeau, Lei Tang, Benoit Pasquier, Rui Wang. Artificial intelligence (AI)-powered quantification of glypican-3 (GPC3) expression facilitates patient selection for GPC3-targeted therapy in solid tumors [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 6182.

Abstract 1990: TIP60-mediated acetylation of ΔNp63α is associated with cisplatin resistance

Abstract The chemotherapeutic drug Cisplatin is often used to treat squamous cell carcinoma (SCC) patients, but low response rates and disease recurrence are common. About 5.4 million basal and squamous cell skin cancers are diagnosed each year in the US. ΔNp63α, a member of the p53 family of transcription factors, is overexpressed and considered oncogenic in non-melanoma skin cancer where it regulates cell survival, promotes proliferation, and inhibits cell apoptosis. ΔNp63α has also been shown to promote resistance to cisplatin by orchestrating the transcriptional regulation of several DNA damage response (DDR) genes. Our previous study showed that the histone acetyltransferase (HAT) TIP60 promotes SCC proliferation by positively regulating ΔNp63α protein levels in a manner reliant on the catalytic activity of TIP60. This observation suggested that TIP60 may contribute to the failure of platinum-based drugs in SCC and led us to hypothesize that TIP60-mediated acetylation of ΔNp63α regulates its stability and transcriptional activity to promote chemoresistance. We found that TIP60 levels positively correlated with ΔNp63α stability, protein levels, and cisplatin resistance. Further, silencing endogenous TIP60 led to a decrease in ΔNp63α transcript and protein levels in multiple cisplatin resistant SCC cell lines. Further, stable expression of TIP60 or ΔNp63α individually promoted resistance to cisplatin and reduced cell death, whereas loss of ΔNp63α or TIP60 induced G2/M arrest, increased cell death, and sensitized cells to cisplatin. Additionally, pharmacological inhibition of TIP60 reduced acetylation of ΔNp63α, decreased colony formation, and sensitized resistant cells to cisplatin. Finally, we demonstrated that ΔNp63α and TIP60 levels positively correlated with DNA repair capacity and negatively correlated with cisplatin-DNA adduct formation. Silencing of either TIP60 or ΔNp63α intensified cisplatin-DNA adduct formation and significantly reduced the expression of drug efflux transporters. Taken together, our data indicate that TIP60-mediated stabilization of ΔNp63α increases cisplatin resistance and provides critical insights into the mechanisms by which ΔNp63α confers cisplatin resistance in SCC. Our findings suggest that the inhibition of TIP60 may be therapeutically advantageous in overcoming cisplatin resistance in SCC and other epithelial cancers. Citation Format: Akshay Hira, Jin Zhang, Mike Kemp, Madhavi P. Kadakia. TIP60-mediated acetylation of ΔNp63α is associated with cisplatin resistance [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 1990.

Abstract 3365: Reliable detection of potentially therapeutically actionable ecDNA using clinical-grade NGS in a large pan-cancer cohort

Abstract Background Focal high-level oncogene amplifications (FH-amp) (e.g., MYC, EGFR) frequently occur on extrachromosomal DNA (ecDNA), highly transcribed units of circular non-chromosomal DNA. FH-amp on ecDNA promote intra-tumoral heterogeneity, resistance to therapies, and poor prognosis. Recently, a Phase 1 clinical trial exploring ecDNA-directed treatments has begun. However, to date, bioinformatic detection of ecDNA has relied on whole-genome sequencing data, and no standard method exists to detect ecDNA on targeted NGS. We thus sought to explore the feasibility of detecting ecDNA in a large cohort of patients with solid tumors sequenced with the targeted NGS panel, MSK-IMPACT, and describe the pan-cancer prevalence of oncogenes amplified on ecDNA. Methods We utilized a novel bioinformatic ecDNA-diagnostic algorithm, ECHO, to determine the presence of oncogene FH-amp on ecDNA (including HSR) vs. chromosomal in clinical-grade NGS data. 72,651 tumor samples profiled by MSK-IMPACT were queried for high level oncogene FH-amp (AR, CCNE1, CDK4/6, EGFR, FGFR1-4, KRAS, MDM2, MDM4, MET, MYC, MYCL, and MYCN) above a fold-change of three, and subsequently annotated with ECHO. Patients with concomitant oncogenic driver mutations or fusions (e.g., EGFR L858R, EML4-ALK) were excluded based on the hypothesis that they might be mutually exclusive with oncogene FH-amp. Results FH-amp of any above listed oncogene were found in 3065 (4.2%) samples. Cancer types with frequent FH-amp without concomitant driver alterations were liposarcoma (LPS) (61% FH-amp; 43% were ecDNA+), glioblastoma (GBM) (22%; 72%), gastroesophageal adenocarcinoma (GE AD) (10%; 57%) squamous cell lung cancer (7%; 18%), and breast cancer (BRCA) (7%; 23%). Among tumors with oncogene FH-amp, GBM and GE AD had high frequencies of ecDNA+ FH-amp of EGFR (39% and 15% of all EGFR ecDNA+). LPS had the highest frequency of ecDNA+ FH-amp of CDK4 (64%), followed by GBM (15%). The majority of ecDNA+ FGFR1 and FGFR2 FH-amp were in BRCA (75% and 47%). EGFR in GBM and EGFR or FGFR2 in GE AD were ecDNA+ in more than 90% of patients, while CDK4 in LPS and FGFR1 in BRCA were ecDNA+ in 45% and 39% respectively.Evaluation the relationship between ecDNA+ by ECHO and amp FC range showed higher ecDNA+ in samples with higher level amp (FC > 5; 58% ecDNA+) compared to lower level amp (FC 4~5; 12%, FC 3~4; 6% ecDNA+). Conclusions A novel ecDNA clinical diagnostic tool, ECHO, was successfully applied to a large clinical cohort of patients enriched for actionable oncogene amplifications sequenced with MSK-IMPACT. The results demonstrate that detection of ecDNA using clinical-grade NGS assays is feasible and that key oncogene FH-amp on ecDNA (e.g., EGFR, FGFR2) are common in select tumor types. ECHO may be developed as a clinical trial device to prospectively identify patients with oncogene ecDNA+ FH-amp for clinical testing of ecDNA-directed therapies. Citation Format: Matteo Repetto, Klaus Wagner, Shalabh Suman, Peter Krein, Pavitra Rao, Maria Arcila, Christian Hassig, Mark Donoghue, Alexander Drilon, Michael Berger. Reliable detection of potentially therapeutically actionable ecDNA using clinical-grade NGS in a large pan-cancer cohort [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 3365.

Abstract 1896: Therapeutic potential of TORL-4-500, an antibody-drug conjugate directed against delta like non-canonical notch ligand 1 (DLK1)

Abstract Delta like non-canonical Notch ligand 1 (DLK1) is a transmembrane protein that belongs to the NOTCH non-canonical ligand family. It has been implicated in adipogenesis, the regulation of stem cell pools, tissue differentiation during development, cancer differentiation, and cancer stem-like cell maintenance. DLK1 is highly expressed in adrenocortical, uterine, and testicular cancers as well as in a large portion of pancreatic, sarcoma, liver and squamous lung cancer patient samples. In contrast there is limited normal tissue expression beyond the normal adrenal gland, pituitary, and ovarian tissue samples. This expression profile makes DLK1 an attractive target for development of a therapeutic antibody-drug conjugate (ADC). This study describes the generation and preclinical characterization of TORL-4-500, an ADC consisting of a humanized anti-DLK1 monoclonal antibody coupled to monomethyl auristatin E (MMAE) via a cleavable linker. TORL-4-500 showed strong binding to DLK1 by flow cytometry in DLK1 native and artificial overexpressing cell lines. In contrast no binding was observed in DLK1 non-expressing cell lines. TORL-4-500 exhibits nanomolar binding affinity for both human and cynomolgus monkey DLK1 and is rapidly internalized in DLK1 expressing cells. TORL-4-500 exhibited selective efficacy in cell line xenograft models of DLK1 positive human cancers. Treatment with TORL-4-500 induced significant regressions in four DLK1 expressing human cancer cell line xenograft studies encompassing liver, small cell lung cancer (SCLC) and sarcoma cancer. Furthermore, anti-tumor responses were sustained in each of the DLK1 expressing models for several weeks post-final dose. In the case of the two SCLC cell lines, complete regressions of xenograft tumors were measured out past 100 days in the TORL-4-500 treated animals. No significant impact on xenograft tumor growth was observed in either a DLK1 non-expressing colon cell line xenograft or in a DLK1 non-expressing melanoma xenograft study. Each of the doses tested in this study was well tolerated in mice with no dose-limiting toxicity observed. The nonclinical pharmacokinetics and toxicokinetics of TORL-4-500 were characterized in mice and monkeys and results support dosing in humans. In summary, TORL-4-500 is a novel therapeutic for DLK1 positive cancers and on the basis of these promising preclinical efficacy results, a first in human trial to evaluate safety, tolerability, pharmacokinetics, and antitumor activity of TORL-4-500 has been launched in patients with advanced cancer and is currently ongoing (NCT06005740). Citation Format: Martina S. McDermott, Neil A. O'Brien, Ming Lu, Jun Zhang, KeWei Gong, Benjamin Hoffstrom, Tong Luo, Min Liang, Weiping Jia, Kevin Chau, Leonard Presta, John Glaspy, Dennis J. Slamon. Therapeutic potential of TORL-4-500, an antibody-drug conjugate directed against delta like non-canonical notch ligand 1 (DLK1) [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 1896.

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 514: Salt-inducible kinase inhibitor OMX-0407 drives cell-cycle arrest in vitro and in vivo: An in-depth MoA analysis by phospho-proteomics

Abstract Based on iOmx’ proprietary iOTargTM genetic screening platform, salt-inducible kinase (SIK) 3 was identified as a novel cell signaling modulator in cancer biology. OMX-0407, an orally available, spectrum-selective kinase inhibitor targets several members of the SIK family and is known to prevent tumor-promoting function of the SIK-family through repolarization of the tumor microenvironment by enhancing caspase-mediated apoptosis upon death-receptor signaling. In addition, OMX-0407 inhibits individual key members of the tyrosine and tyrosine-like kinase family that are involved in cancer cell proliferation and cell cycle regulation. Via this dual mode of action, OMX-0407 has the potential to effectively fight solid tumors as exemplified by its striking single-agent efficacy in multiple pre-clinical tumor models. A comprehensive anti-tumor viability screen of >200 human cancer cell lines revealed striking effects of OMX-0407 on cancer cell viability across various cancer indications, resulting in a distinct sensitivity profile across various tumor indications with particularly strong effects on renal cell carcinoma (RCC) and squamous non-small cell lung cancer (sqNSCLC). Phospho-proteomics screening demonstrated pharmacodynamic activity of OMX-0407 in sensitive tumor cell lines via inhibition of key cellular processes such as cell motility, proliferation, and cell cycle regulation across different indications. Orthogonal functional in vitro assays confirmed the association of the OMX-0407-mediated anti-tumor efficacy with the arrest of G1/S transition and corresponding downregulation of cell cycle associated proteins PAK1/2 and ARHGAP35. The profound impact of OMX-0407 on fundamental regulatory mechanisms of cell division and cancer cell apoptosis translates into dose-dependent single-agent, anti-tumor efficacy in various pre-clinical tumor models of selected indications. Combination with Axitinib, a selective orally available inhibitor of vascular endothelial growth factor receptor 2, significantly enhanced anti-tumor efficacy and pharmacodynamic inhibition of cell growth as well as angiogenesis. These data further strengthen the potential of OMX-0407 in the treatment of RCC as well as other indications. In summary, OMX-0407 is a novel spectrum selective kinase inhibitor, currently under evaluation in a clinical Phase I trial (NCT05826600). OMX-0407 demonstrates strong anti-tumor efficacy in monotherapy in selected sensitive indications through a dual-pronged MoA, by modulating the tumor microenvironment and exerting direct anti-tumor activity in solid tumor indications with high unmet medical need. Citation Format: Ilona-Petra Maser, Marisa Stebegg-Wagner, Bettina Bauer, Filippos Konstantinidis, Andreas Schirmer, Moritz Zulley, Sonja Lacher, Barbara Kracher, Parastou Kohvaei, Murray Yule, Hannes Loferer, Stefan Bissinger. Salt-inducible kinase inhibitor OMX-0407 drives cell-cycle arrest in vitro and in vivo: An in-depth MoA analysis by phospho-proteomics [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 514.

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.