Reference Detail

Ref Type

Journal Article

PMID

(26270481)

Authors

Pan CX, Zhang H, Tepper CG, Lin TY, Davis RR, Keck J, Ghosh PM, Gill P, Airhart S, Bult C, Gandara DR, Liu E, de Vere White RW

Title

Development and Characterization of Bladder Cancer Patient-Derived Xenografts for Molecularly Guided Targeted Therapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
PloS one	10	8	2015	e0134346	PLoS One

URL

Abstract Text

The overarching goal of this project is to establish a patient-derived bladder cancer xenograft (PDX) platform, annotated with deep sequencing and patient clinical information, to accelerate the development of new treatment options for bladder cancer patients. Herein, we describe the creation, initial characterization and use of the platform for this purpose.Twenty-two PDXs with annotated clinical information were established from uncultured unselected clinical bladder cancer specimens in immunodeficient NSG mice. The morphological fidelity was maintained in PDXs. Whole exome sequencing revealed that PDXs and parental patient cancers shared 92-97% of genetic aberrations, including multiple druggable targets. For drug repurposing, an EGFR/HER2 dual inhibitor lapatinib was effective in PDX BL0440 (progression-free survival or PFS of 25.4 days versus 18.4 days in the control, p = 0.007), but not in PDX BL0269 (12 days versus 13 days in the control, p = 0.16) although both expressed HER2. To screen for the most effective MTT, we evaluated three drugs (lapatinib, ponatinib, and BEZ235) matched with aberrations in PDX BL0269; but only a PIK3CA inhibitor BEZ235 was effective (p<0.0001). To study the mechanisms of secondary resistance, a fibroblast growth factor receptor 3 inhibitor BGJ398 prolonged PFS of PDX BL0293 from 9.5 days of the control to 18.5 days (p<0.0001), and serial biopsies revealed that the MAPK/ERK and PIK3CA-AKT pathways were activated upon resistance. Inhibition of these pathways significantly prolonged PFS from 12 day of the control to 22 days (p = 0.001). To screen for effective chemotherapeutic drugs, four of the first six PDXs were sensitive to the cisplatin/gemcitabine combination, and chemoresistance to one drug could be overcome by the other drug.The PDX models described here show good correlation with the patient at the genomic level and known patient response to treatment. This supports further evaluation of the PDXs for their ability to accurately predict a patient's response to new targeted and combination strategies for bladder cancer.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
PIK3CA	D549Y	missense	unknown	PIK3CA D549Y lies within the PIK helical domain of the Pik3ca protein (UniProt.org). D549Y has been identified in the scientific literature (PMID: 29106415, PMID: 26270481), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Mar 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA H1047R	urinary bladder cancer	sensitive	Dactolisib	Preclinical - Pdx	Actionable	In a preclinical study, BEZ235 inhibited tumor growth in a patient-derived xenograft (PDX) model of bladder cancer harboring PIK3CA H1047R (PMID: 26270481).	26270481
FGFR3 over exp	urinary bladder cancer	sensitive	Dactolisib + Sorafenib	Preclinical - Pdx	Actionable	In a preclinical study, the combination of BEZ235 and Nexavar (sorafenib) resulted in improved progression-free survival in an FGFR3-over expressing patient-derived xenograft (PDX) model of bladder cancer with secondary resistance to BGJ398 due to reactivation of downstream signaling, as evidenced by increased activation of Akt and Erk (PMID: 26270481).	26270481
FGFR3 over exp	urinary bladder cancer	sensitive	Infigratinib	Preclinical - Pdx	Actionable	In a preclinical study, treatment with Truseltiq (infigratinib) led to improved progression-free survival in a patient-derived xenograft (PDX) model of bladder cancer with FGFR3 over expression (PMID: 26270481).	26270481