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Durable Objective Response to Lurbinectedin in Small Cell Bladder Cancer with TP53 Mutation: A Molecular-Directed
Mohammad Jad Moussa1, Jaanki Khandelwal2, Nathaniel R Wilson3
1Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
Small cell bladder cancer (SCBC) is a rare and aggressive disease, often treated with platinum/etoposide-based chemotherapy. Key molecular drivers include the inactivation of onco-suppressor genes (TP53, RB1) and amplifications in proto-oncogenes (MYC). We report a patient with SCBC who achieved an objective and prolonged response to lurbinectedin, which has been approved for metastatic small cell lung cancer, after developing disease progression on cisplatin/etoposide and nivolumab/ipilimumab. A genomic analysis of a metastatic biopsy prior to lurbinectedin initiation revealed a TP53 mutation and amplification of the cell cycle regulators E2F3 and MYCL. A repeat biopsy following the development of lurbinectedin resistance showed a new actionable ERBB2 alteration without significant change in the tumor mutation burden (six mutations/Mb). The present report suggests that lurbinectedin may be active and should be further explored in SCBC harboring TP53 mutations and amplifications in E2F3 and MYC family complexes.
Insights
This study reports a small cell bladder cancer (SCBC) patient who responded well to lurbinectin after standard chemotherapy failure. Genomic analysis revealed key mutations and amplifications, suggesting lurbinectin
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Small cell bladder cancer (SCBC) is aggressive, typically treated with platinum/etoposide chemotherapy.
- Key molecular alterations include TP53/RB1 inactivation and MYC proto-oncogene amplification.
- Limited treatment options exist for platinum-refractory SCBC.
Observation:
- A patient with advanced SCBC progressed on cisplatin/etoposide and nivolumab/ipilimumab.
- The patient achieved an objective and prolonged response to lurbinectin.
- Genomic analysis revealed TP53 mutation and E2F3/MYCL amplification prior to lurbinectin.
Findings:
- A subsequent biopsy after lurbinectin resistance identified an ERBB2 alteration.
- Tumor mutation burden remained low (six mutations/Mb).
- Lurbinectin demonstrated activity in this SCBC patient.
Implications:
- Lurbinectin may be a viable treatment option for SCBC.
- Further investigation is warranted in SCBC with TP53 mutations and E2F3/MYC amplifications.
- Identifying actionable alterations like ERBB2 is crucial for resistance mechanisms.
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