Researchers at Baylor College of Medicine have conducted a molecular analysis to understand why some muscle-invasive bladder cancers (MIBC) are resistant to chemotherapy. Their findings, published in Cell Reports Medicine, may help identify which patients are more likely to benefit from the current standard chemotherapy and suggest new treatment strategies.
“One of our goals was to identify molecular markers in patient tumors that would help us predict which patients were most likely to benefit from chemotherapy and which ones might not,” said first co-author, Dr. Matthew V. Holt, director of the Lester and Sue Smith Breast Center Proteomics Laboratory at Baylor.
The study analyzed 60 MIBC tumor samples using a multi-omics approach. This included examining the genetic makeup of the tumors, analyzing gene activity, identifying proteins produced by the tumor cells, and studying modified proteins that can control cell behavior.
“By computationally analyzing the vast information generated by the multi-omics approach, we produced a molecular profile for each tumor sample and hoped to uncover patterns linked to resistance to chemotherapy,” said co-first author Dr. Yongchao Dou, assistant professor in the Breast Center at Baylor.
The research team found differences in protein isoforms—slightly different forms of the same protein—in tumors that responded well to chemotherapy compared with those that did not. “We were excited about the findings,” Holt said. “For instance, we investigated protein isoforms, which refers to slightly different forms of the same protein, which can behave differently. We found that certain isoforms – especially of proteins like ATAD1 and the RAF family – were more common in tumors that responded well to chemotherapy. These isoforms weren’t detectable by looking at genes or RNA alone, highlighting the importance of studying proteins directly.”
Further analysis identified active molecular pathways related to resistance: “We also identified molecular pathways linked to resistance,” Dou said. “Wnt signaling, involving a protein called GSK3B, was more active in resistant tumors. The JAK/STAT pathway, especially the protein STAT3, was also more active in resistant cases. These data reveal these pathways as potential therapeutic targets to overcome chemoresistance.”
The study looked at how new cancer drugs called antibody-drug conjugates (ADCs) could be combined with existing treatments based on specific patterns found across tumor subtypes. Certain target proteins such as PD-L1, TROP2, and NECTIN-4 appeared differently depending on subtype.
Additionally, comparisons between pre- and post-treatment samples revealed changes after chemotherapy; some tumors shifted their subtype or showed increased activity in proteins related to cell recycling and energy use.
“This study identified specific proteins and pathways linked to treatment resistance, as well as potential new ways to treat resistant tumors,” said senior author Dr. Seth P. Lerner, professor of urology and Beth and Dave Swalm Chair in Urologic Oncology at Baylor College of Medicine who also directs its Multidisciplinary Bladder Cancer Program. “This is important because it provides insights that can help expand the population that can be treated effectively and improve overall patient outcomes.”
The work involved several contributors from Baylor College of Medicine including Meggie N. Young, Alexander B. Saltzman, Meenakshi Anurag among others.
Funding for this research came from sources such as Bladder Cancer Advocacy Network Innovation Award; Partnership in Bladder Cancer Research; Dan L Duncan Comprehensive Cancer Center Award; CPRIT Core Facility Awards; NIH High-End Instrumentation Award; McNair Medical Institute at Robert and Janice McNair Foundation; and U01CA214125.
