Antibody-drug conjugate for variant bladder cancesr

7 months 5 days ago #61624 by joea73
90% of bladder cancers are urothelial carcinomas.  The remaining 10% are so called variants. The recent WHO classification of bladder cancers lists 13 different histologic variants.  Squamous differentiation, Glandular differentiation, Nested variant, Microcystic Variant, Micropapillary Variant, Lymphoepithelioma-like carcinoma, Plasmacytoid and lymphoma-like variants, Sarcomatoid variant carcinoma , Giant cell variant, Trophoblastic differentiation, Clear cell variant, Lipid cell variant, Undifferentiated carcinoma.   Many of variant bladder cancers are known to be aggressive as often cancers are in advanced stage when patients are first diagnosed with variant bladder cancer.  In addition,  not enough research have been done for variant bladder cancers and new drug developments are more focused on   Most studies for variant bladder cancers are based upon single institution with retrospective data or based upon data base.  last year a group of researchers at Peking University Hospital in China, incidentally Peking University is ranked #12 top university in the world, tested  if muscle invasive bladder cancers with variant histology express  NECTIN-4, TROP-2, and HER  antigens (protein) on cancer cell membrane.  The reason for testing those antigens are expressed on bladder cancer cells is because there are three antibody-drug conjugates approved for advanced urothelial carcinoma and see if these drugs will also work for variant bladder cancers.    They investigated 5 different variants in addition to urothelial carcinoma.   

72 Urothelial Carcinoma           57/72 (79.2%) NECTIN+    65/72 (90.3%)  TROP-2+       26/72 (36.1%)  HER2+
10 squamous carcinomas        10/10 (100%)  NECTIN+         8/10 (80.0%)  TROP-2+              0/10 (0%)   HER2+
23 glandular carcinoma           15/23 (65.2%) NECTIN+       13/23 (56.5% ) TROP-2+       5/23 (21.7%)  HER2+
19 small cell carcinomas          4/19 (21.1%)   NECTIN+           3/19 (15.8%)  TROP-2+       6/19 (31.6%)   HER2+
19 micropapillary variants      15/19 (78.9%)  NECTIN+        16/19 (84.2%) TROP-2+      15/19 (78.9%)  HER2+
18 nested variants                    16/18 (88.9%)  NECTIN+       15/18 (83.3%) TROP-2+         7/18 (38.9%)  HER+
There are two FDA approved Antibody-drug conjugates for the use of advanced non variant urothelial cancers as shown below.

Enfortumab Vedotin (Padcev) is Antibody-drug conjugate targeting NECTIN-4.on membrane of cancer cells.' 
Ssacituzumab govitecan-hziy (Trodelvy) is  Antibody-drug conjugate targeting TROP-2.on cancer cells.

RC-48 is still ii is still in clinical trial.  RC-48 is also  Antibody-drug conjugate targeting HER2 on cancer cells.

Authors of this study is suggesting those three antibody-drug conjugates which had been approved for non variant urothelial carcinoma can be use for for variant histology bladder cancers with high ratio of  positive antigen,.e.g. high percentage of squamous carcinomas  has positive NECTIN-4 antigen, which enable Padcev and Trodelvy to reach to cancer cells.   Note that the study did not say if patients with variant bladder cancer were indeed treated with those drugs, so efficacy test is till required.  But I though the study was clever in such way that it would give clinical opportunities for patients with variant bladder cancers to be treated with available treatments.

Below is the link to the study report.

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