About a quarter of patients with cancer of the Muscular Invasive bladder (MIBC) can be treated and draw an advantage with current standard chemotherapy. To better understand why some tumors are resisting chemotherapy and identifying better ways to treat these cancers, researchers from the Baylor College of Medicine have carried out a detailed molecular analysis of MIBC tumors. The results, published in Cell reports medicineOffer new potential ways to identify patients will benefit from chemotherapy and reveal new possible treatment strategies.
“One of our objectives was to identify the molecular markers of the tumors of patients who would help us to predict which patients were most likely to benefit from chemotherapy and who could not do so,” said the first co-author, Dr. Matthew V. Holt, director of the proteomics laboratory to Lester and Sue Smith Breast Center.
The researchers studied 60 samples of MIBC tumors using a complete multi-image approach which included genomics (sequencing of the tumor genes), the transcriptomic (analyzing which genes are lit or deactivated), proteomics (proteins produced by tumor) and phosphoproteins (proteins with chemical labels that control their activity).
By analyzing by calculating the vast information generated by the multi-ordinary approach, we produced a molecular profile for each tumor sample and hoped to discover models related to resistance to chemotherapy. “”
Dr Yongchao Dou, Co-Prime Author, Deputy Professor at the Baylor Breast Center
“We were enthusiastic about the conclusions,” said Holt. “For example, we have studied protein isoforms, which refer to slightly different forms from the same protein, which can behave differently. We found that some isoforms – Especially proteins like Atad1 and the RAF family – were more frequent in tumors that responded to chemotherapy. These isoforms were not detectable by looking at the genes or the RNA alone, stressing the importance of studying proteins directly. “”
“We have also identified molecular tracks related to resistance,” said Dou. “WNT signaling, involving a protein called GSK3B, was more active in resistant tumors. The Jak / Stat route, especially the Stat3 protein, was also more active in resistant cases. These data reveal these ways as potential therapeutic targets to overcome chemooresistance. »»
The study also analyzed proteins targeted by antibody conjugates (ADC) – A new class of cancer drugs. Proteins such as PD-L1, Tro TOP2 and Nectine-4 were found in different diagrams between the tumor subtypes. This suggests that the combination of ADC with chemotherapy or immunotherapy could be more effective, especially if it is adapted to the tumor’s subtype.
The researchers also compared the molecular profiles of patients who had pre- and post-treatment samples and found changes. Some tumors have changed their subtype after chemotherapy. They also found that certain proteins involved in cell recycling and energy consumption were more active after treatment, potentially helping the surviving tumor.
“This study has identified proteins and specific ways related to resistance to treatment, as well as new potential ways to treat resistant tumors,” said Dr. Seth P. Lerner, Urology Professor and Beth and Dave Swalm Chair in urological oncology. He is also the director of the multidisciplinary bladder cancer program in Baylor “This is important because it provides information that can help extend the population that can be treated effectively and improve the overall patients of patients.”
Other contributors to this work include Meggie N. Young, Alexander B. Saltzman, Meenakshi Anurag, Jonathan T. Lei, Antrix Jain, Mei Leng, Beom-Jun Kim, Lacey E. Dobrolecki, Stefanie F. Faucher, Sara Savage, Chenwei Wang, Zhiao Shi, Hugo Villanueva, Karoline Kremers, Kyle D. Drinnon, Patricia D. Castro, Michael M. Ittmann, Mehak Mehboob Khatani, Sung Han Kim, Matthew J. Ellis, Bing Zhang et Anna Malovannaya, tous au Baylor College of Medicine.
This study was supported by the price of innovation in the bladder arranging network, Partnership in Veshed Cancer Research; P30 Cancer Center Support Grant (NCI-CA125123); Dan L. Duncan understanding Cancer Center Award (P30 CA125123), CPrit Core Facility Awards (RP170005, RP210227, RP220646) and the high -end instrumentation price NIH (S10 OD026804). Additional support was provided by the McNair Medical Institute of the Robert and Janice McNair Foundation and U01CA214125.
