MUC16 expression

Many drugs and trials targeting MUC16 have been developed, and MUC16 may be a new direction for future treatments. In this paper, the mechanism of action of MUC16 in the development of cancer, especially in the immune escape of tumor, is introduced in detail, indicating the potential of MUC16 in clinical treatment.

Collectively, these results suggested that MSLN-CAR T cells could potently eliminate MUC16- positive ovarian cancer tumor cells both in vitro and in vivo, thereby providing a promising therapeutic intervention for MUC16-positive patients.

We also found that the chemotherapy drug Vinorelbine was positively correlated with the three PPAR genes, showing the potential of Vinorelbine to serve as a treatment drug for STAD. Furthermore, cell experiments demonstrated that PPARG had higher expression in AGS and SGC7901 cells, and that inhibiting PPARG suppressed the viability, migration and invasion of AGS and SGC7901 cells. The current results confirmed that the three PPAR genes (PPARA, PPARD and PPARG) affected STAD development through mediating immune microenvironment and genome mutation.

Moreover, the glycopeptide-grafted nanovaccine candidate displayed minimal cytotoxicity and induced the activation of dendritic cells in vitro, even in the absence of an adjuvant. In vivo, the formulated nanovaccine candidate was also nontoxic and elicited the production of IgG specifically targeting MUC16 and MUC16-Tn glycoproteoforms in cancer cells and tumors, offering potential for precise cancer targeting, including targeted immunotherapies.

Additionally, we showed that [177Lu]Lu-CHX-A″-DTPA-huAR9.6 displayed strong antitumor effects in highly MUC16-expressing tumors. These findings demonstrate great potential for 89Zr- and 177Lu-labeled huAR9.6 as theranostic tools for the diagnosis and treatment of OC.

Together, our studies offer insight into antibody-MUC16 ectodomain interaction and advance our ability to design agents with potentially improved therapeutic properties over anti-CA125 moiety antibodies.

By knocking out the PGAP2 gene, the GPI-anchored form of CA125 was converted to a secretory form. Through the engineering of O-glycans and the use of a GPI-anchoring system, we successfully produced CA125 with Tn-antigen modification.

Vaccination with VLP displaying the 20 aa juxta-membrane MUC16 ectodomain, which includes the membrane proximal cleavage site, is likely to be well tolerated and induce IgG targeting ovarian cancer cells, even after CA125 is shed.

CONCLUSIONS A 10-year follow-up of patients with uterine sarcoma indicates that age above 60 years at diagnosis and high p53 expression and elevated CA125 levels before treatment can be independent prognostic factors. The high diagnostic sensitivity of sTNF RI and VEGF suggests the possibility of using these biomarkers in the early diagnosis of uterine sarcomas.

The current standard therapy of epithelial ovarian cancer (EOC) is the combination of surgery (primary cytoreductive surgery or interval cytoreductive surgery) and platinum-based chemotherapy (mainly using paclitaxel and carboplatin either by neoadjuvant chemotherapy and/or by postoperative adjuvant chemotherapy) with/without adding targeted therapy (mainly using anti-angiogenesis agent- bevacizumab)...It is well-known that overexpression of CA125 has been associated with attenuated cellular apoptosis, platinum chemotherapy resistance, tumor proliferation and disease progression, suggesting that anti-CA125 may play a role in the management of patients with EOC. The current review is a Part I which will focus on development of anti-CA125 monoclonal antibody, hoping that alternation of the front-line therapy by chemo-immunotherapy will be beneficial for prolonged survival of patients with EOC.

We show that ESK1 BiTE-secreting 4H11 CAR T cells exhibited enhanced anticancer activity against cancer cells with low Muc16 expression, compared to 4H11 CAR T cells alone, both in vitro and in mouse tumor models. Dual orthogonal cytotoxic modalities with different specificities targeting both surface and intracellular tumor-associated antigens present a promising strategy to overcome resistance to CAR T cell therapy in epithelial ovarian cancer and other cancers.

Moreover, the nomogram using the IPM and clinical prognostic factors also predicted the overall survival and clinical utility. Our project developed a robust risk signature depending on the MUC16 status and provided novel insights for individualized treatment options for LUAD patients.

Conclusion/Implications Ubamatamab +/- cemiplimab demonstrated acceptable safety and evidence of clinical activity in heavily pretreated OC. An ongoing randomised Phase 2 study is evaluating ubamatamab alone and with cemiplimab.

The impact of ubamatamab on QOL and physical functioning will be assessed. Current Trial Status: The study is currently recruiting patients to combination dose escalation, monotherapy dose expansion, and the randomized Phase 2 cohort.

Here we report a novel function of portal fibroblasts as drivers of cholestatic fibrosis, ductular reaction, inflammation, hepatocyte senescence, and HCC in aged mice, demonstrating the key role of the tumor microenvironment.

Finally, we found that Mesothelin expression significantly correlated with sensitivity to cytotoxic chemotherapy in pancreatic cancer cell lines. In conclusion, high Mesothelin expression is associated with enhanced proliferation, depressed immune response, and sensitivity to cytotoxic chemotherapy, which may explain there was no difference in survival in pancreatic cancer patients.

Further research is needed to explain differences in pathogenesis compared with other pNENs. In particular, multi-omics data such as RNASeq, methylation and whole genome sequencing could be informative.

CA125 has a high diagnostic value in the diagnosis of epithelial ovarian cancer. The detection of combined tumor markers in serum has higher sensitivity and specificity in epithelial ovarian cancer.

The developed immunoplatform involves functionalised magnetic microparticles (MBs), a set of specific antibody pairs (a capture antibody, cAb, and a biotinylated detector antibody b-dAb labelled with a streptavidin-horseradish peroxidase, Strep-HRP, polymer) for each target protein and amperometric detection at dual screen-printed carbon electrodes (SPdCEs) using the hydroquinone (HQ)/horseradish peroxidase (HRP)/HO system...The developed immunoplatform was employed to analyse CRC cell protein extracts (1.0 μg/determination) with different metastatic potential providing results in agreement with those obtained by blotting technologies but using affordable and applicable point-of-care instruments. This new biotool also emerges competitive in state-of-the-art electrochemical immunoplatforms seeking a compromise among simplicity, reduction of test time and analytical characteristics.

P1, N=18, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Aug 2023 --> Aug 2024 | Trial primary completion date: Aug 2023 --> Aug 2024

MUC16 acted on neutrophils by Siglec-9 leading to an inflammatory and immunosuppressive phenotype in ovarian cancer.

The overexpression of MUC16 plays a very obvious role in regulating inflammatory response, supporting immune suppression, and promoting the proliferation, division, and metastasis of cancer cells. In the next 20 years, there will be a luxuriant clinical application of MUC16 as a target for immune monitoring and immunotherapy.

The robust clinical correlations observed between MUC16 and N-cadherin in patient tumors and metastatic samples imply ch5E6 potential in targeting a complex and significantly occurring phenomenon of epithelial to mesenchymal transition (EMT) associated with disease aggressiveness. Our study supports evaluating ch5E6 with standard-of-care drugs, to potentially augment treatment outcomes in malignancies inflicted with MUC16-associated poor prognosis.

DAPI staining showed apoptosis induction upon exposure to targeted MSNP in MUC16 positive OVCAR-3 cells. According to our results, the engineered NSs could be considered an effective multifunctional targeted drug delivery platform for the mucin 16 overexpressing cells.

MUC16 may be a meaningful molecule reflecting the presence of distant metastasis in EMPD

In patients with lung adenocarcinoma, brain metastases, but not other sites of metastases, exhibited a relatively immune-suppressive TIME; this should be considered in the context of differential response to immunotherapy in brain metastases. Among patients with cancer antigen expression in the primary tumor, the majority had antigen expression in metastases; these data can inform the selection of antigen-targeted CARs to treat patients with metastatic lung adenocarcinoma.

The growth of these cells has also been studied after separation, demonstrating that nanoparticle size impacts cell-particle behavior and growth rate. These results present the successful isolation of "masked" CTCs enabling new strategies for the detection of cancer recurrence and select and monitor chemotherapy.

Mouse-specific CAR constructs have been validated to employ in a syngeneic model of pancreatic cancer to determine the mechanisms by which locally secreted VIPR antagonists can modulate the PDAC TME. The long-term goal of translating antVIPR-secreting CAR T cells for the treatment of PDAC.

Our study identified MUC16 as a TNBC lung metastasis promoter that acts through HuR/cMyc axis. This study will form the basis of future studies to evaluate the targeting of both MUC16 and HuR in TNBC patients.

LBL-033, a novel bispecific antibody targeting CD3 and MUC16 with a unique epitope, which is located at the MUC16 membrane-proximal domain, with affinity differentiation between anti-MUC16 and anti-CD3. It is shown a great anti-tumor efficacy in animal models, with a good safety profile in monkeys. These data support LBL-033 as a novel therapeutic bispecific antibody for ovarian cancer and other MUC16 positive tumors.

CA125 expression was also related to the immunosuppressive tumor-microenvironment through the infiltration of immunosuppressive immune cells, such as regulatory T-cells and M2 macrophages. These results suggest that the status of tumor-microenvironment associated with CA125 is involved in gemcitabine/cisplatin resistance in bladder cancer.

Although we found mesothelium-derivative stromal cells to be bystanders in normal pancreas, the proportion of these cells was higher in invasive PDAC, particularly in TP53 deficient tumors. Moreover, we also detail the regulation of MUC16, KRAS, and SOX9 by TP53 family members (TP53 and TP63) using multi-omics data from knockout models, PDAC cell lines, and human PDAC tissues.

The concurrent abnormality of serum CA125 before and after operation was an independent risk factor for GIST progression, suggesting its significance as a serum biomarker in the overall management of GIST patients.

Pharmacokinetic study shows a relatively short distribution (t) and elimination half-life (t) of 4.4 h and 99 h, respectively. In summary, Zr-DFO-M16Ab is an effective non-invasive imaging probe for ovarian and pancreatic cancers and shows promise for further development of theranostic radiopharmaceuticals.

Conversely, MUC16 mutation were related with worse prognosis in GBM patients upon analyzing those same parameters. Therefore, MUC16 mutations may assist in glioma diagnosis and prognosis and should be further studied in this tumor type.

Prominently deregulated pathways have been identified following MUC16 expression, overrepresented in cell cycle and immune system exhaustion processes. These findings suggest including MUC16 in clinical routine diagnostics as well as studying its molecular pathways to identify further mechanistic key players.

MM was a relatively common event that may occur selectively in specific oncogenes and is involved in aggressive malignant behavior.

The establishment of iOVCAR-3-OSKM not only allows us to fill the gap in the information on induced CICs in OC but also provides a potential strategy to develop personalized CICs and organoid models for treating OC in the near future.

MUC16 expression is a frequent feature in epithelioid sarcoma and may be identified in other INI-1-deficient malignancies. MUC16 is a possible therapeutic target and warrants further clinical trial development outside the ovarian cancer field.

P1, N=18, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Aug 2022 --> Aug 2023 | Trial primary completion date: Aug 2022 --> Aug 2023