Zie ook literatuurlijst niet-toxische middelen en behandelingen specifiek bij blaaskanker van arts-bioloog drs. Engelbert Valstar

Zie ook in gerelateerde artikelen.

11 februari 2021: Bron: ASCO GI februari 2021

Enfortumab vedotin (EV) is een zogeheten antilichaam-geneesmiddelconjugaat gericht tegen Nectin-4 dat is goedgekeurd voor behandeling van uitgezaaide blaaskanker en urineleiderkanker (urotheelkanker). Maar welke factoren precies maken dat Enfortumab vedotin aanslaat is niet helemaal duidelijk. Dit medicijn richt zich op de NECTIN-4 expressie, maar tot nu toe is niet helemaal duidelijk of een hoge of juist lage expressie de behandeling positieef of negatief beïnvloed..

In een studie hebben onderzoekers geprobeerd:

1) heterogeniteit van NECTIN4-genexpressie te onderzoeken over moleculaire subtypes van blaaskanker
2) te bepalen of Nectin-4-expressie gevoeligheid of resistentie voor Enfortumab vedotin bewerkstelligt.

Voor een leek is denk ik moeilijk te begrijpen wat de onderzoekers precies hebben gevonden, maar het studieabstract is op ASCO GI 2021 gepresenteerd en artsen en onderzokers begrijpen dit beter dan ik mag ik hopen:

Heterogeneity in Nectin-4 expression across molecular subtypes of urothelial cancer mediates sensitivity to enfortumab vedotin.

Authors:

Carissa Chu, Martin Sjöström, Emily A Egusa, Ewan Gibb, Michelle L Badura, Vadim S Koshkin, Bradley A. Stohr, Maxwell Meng, Raj Pruthi, Terence W. Friedlander, Yair Lotan, Peter C. Black, Sima P. Porten, Felix Y Feng, Jonathan Chou; University of California, San Francisco, CA; Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA; UCSF, San...

Abstract Disclosures

Research Funding:

None

Background:

Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting Nectin-4 (encoded by the PVRL4/NECTIN4 gene) approved for treatment-refractory metastatic urothelial cancer. Factors that mediate sensitivity or resistance to EV are unknown. In the present study, we sought to 1) examine heterogeneity of NECTIN4 gene expression across molecular subtypes of bladder cancer and 2) determine if Nectin-4 expression mediates EV sensitivity or resistance.

Methods:

NECTIN4 expression data from seven muscle-invasive bladder cancer clinical cohorts (n = 1912 total patients) were used to compare relative NECTIN4 expression across molecular subtypes. The outcome of the gene expression analysis was relative NECTIN4 expression in the consensus molecular subtypes of bladder cancer. Expression of NECTIN4 was validated in multiple bladder cancer cell lines. NECTIN4 was stably over-expressed or knocked down in basal (TCCSUP and UMUC-3) and luminal (HT-1376, HT-1197 and UMUC-9) bladder cancer cell lines, respectively, and EV dose-response assays were performed, as measured by cell proliferation and clonogenic assays.

Results:

NECTIN4 expression is heterogenous across molecular subtypes of bladder cancer and significantly enriched in luminal subtypes (p < 0.001). NECTIN4 expression is positively correlated with the luminal markers GATA3, FOXA1, and PPARG across cohorts (Spearman’s rank correlation r = 0.57, p < 0.0001 for GATA3, r = 0.37, p < 0.0001 for FOXA1, and r = 0.56, p < 0.0001 for PPARG). NECTIN4 expression is both necessary and sufficient for EV sensitivity in luminal and basal subtypes of urothelial bladder cancer cells. Downregulation of NECTIN4 led to EV resistance, and EV-resistant cell lines expressed decreased levels of Nectin-4.

Conclusions:

Results of this pre-clinical study suggest that sensitivity to EV is mediated by expression of NECTIN4, which is significantly enriched in luminal subtypes of bladder cancer. Downregulation of NECTIN4 leads to resistance to EV. These findings have implications for biomarker development, patient selection and the inclusion of molecular subtyping in ongoing and future EV clinical trials. Further investigation into Nectin-4 loss as a mechanism of resistance in patients treated on EV is warranted.