ABSTRACT
Metastatic urothelial cancer is a lethal disease. Although recent advances in immunotherapies and targeted therapy against fibroblast growth factor receptor (FGFR)2/3 mutation (erdafitinib) have improved patient survival, there is still a critical need for novel therapeutic strategies for patients who do not benefit from these treatments. Evasion of apoptosis through amplifying anti-apoptotic Bcl-2 family proteins (Mcl-1, Bcl-xL, Bcl-2) is one mechanism responsible for treatment resistance in urothelial cancers, suggesting that targeting anti-apoptotic proteins may be a possible therapeutic strategy for urothelial cancers. Here, we showed that erdafitinib increased Mcl-1 degradation mainly through previously unknown mechanisms and synergized with a BH3 mimetic drug targeting Bcl-xL/Bcl-2 to induce apoptosis in FGFR wild-type urothelial cancer cells. Strikingly, clinical sequencing data showed amplification of MCL1 or BCL2L1 (encoding Bcl-xL) in subsets of FGFR mutation-negative bladder cancer tissues. In conclusion, these findings suggest that exploiting apoptosis pathways may be a promising treatment strategy for patients with FGFR wild-type metastatic urothelial cancer with Mcl-1 or Bcl-xL overexpression.
Subject(s)
Antineoplastic Agents , Carcinoma, Transitional Cell , Myeloid Cell Leukemia Sequence 1 Protein , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Apoptosis Regulatory Proteins/metabolism , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/metabolism , Cell Line, Tumor , Humans , Myeloid Cell Leukemia Sequence 1 Protein/drug effects , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-bcl-2/drug effects , Proto-Oncogene Proteins c-bcl-2/metabolism , Pyrazoles/pharmacology , Quinoxalines/pharmacology , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , bcl-X Protein/drug effects , bcl-X Protein/metabolismABSTRACT
We report a case of primary central nervous system lymphoma (PCNSL) in an 81-year-old man who had undergone radical cystectomy with an ileal conduit urostomy due to a diagnosis of muscle-invasive bladder cancer. The postoperative diagnosis was invasive urothelial carcinoma (pT2bN1M0, stage IV). Gemcitabine-cisplatin therapy was provided as adjuvant chemotherapy, and there was no recurrence during follow-up. Four years after surgery, he visited the emergency department because of weakness of the lower extremities and stuttering. He was found to have a parietal lobe mass on magnetic resonance imaging (MRI) and hospitalized with suspicion of brain metastasis. Despite examination by a neurosurgeon, it was not possible to make a clinical diagnosis, and the patient gradually deteriorated and died 21 days later. The pathology results were diagnostic of PCNSL.
Subject(s)
Carcinoma, Transitional Cell , Lymphoma , Urinary Bladder Neoplasms , Aged, 80 and over , Central Nervous System , Cystectomy , Humans , Male , Urinary Bladder Neoplasms/surgeryABSTRACT
(Purpose) We created an image reconstructing multiparametric MRI system called VIVID (Visualization of Various Integration with Diffusion) and examined the efficacy of VIVID in detecting prostate cancer. (Methods and materials) The subjects were 80 patients who underwent one target biopsy with reference to MRI images in addition to 8-20 biopsies. (Results) The significant cancer detection rate was 61%, the significant cancer detection rate of PI-RADS 4 or 5 was 55%, and the significant cancer detection rate of VIVID score 4 or 5 was 55%. Three cases with PI-RADS 4 at TZ lesion with positive T2WI only were evaluated as having VIVID scores 1 or 2. Cancer was not detected with target biopsy from the site. (Conclusion) Our finding suggest that VIVID correctly excludes TZ lesions with only T2WI positively in multiparametric MRI.