Methods for characterizing bladder cancer
Inventors
Kim, Jaegil • Getz, Gad • Lerner, Seth Paul • Kwiatkowski, David • Meeks, Joshua • Bellmunt, Joaquim • McConkey, David
Assignees
Baylor College of Medicine • Brigham and Womens Hospital Inc • General Hospital Corp • Johns Hopkins University • Northwestern University • US Department of Veterans Affairs • Broad Institute Inc
Publication Number
US-11814687-B2
Publication Date
2023-11-14
Expiration Date
2039-02-08
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Abstract
The present invention features methods for characterizing mutational profiles in patients with bladder cancer.
Core Innovation
The invention features methods for characterizing mutational profiles in patients with bladder cancer. It involves detecting alterations in the expression of specific biomarkers, including luminal markers (such as uroplakin genes UPK2, UPK1A, and urothelial differentiation markers FOXA1, GATA3, and PPARG), luminal-papillary markers (including FGFR3-TACC3 fusions and lncRNAs like DANCR, GAS5, MALAT1), luminal-infiltrated markers (such as CD274 (PD-L1) and PDCD1 (PD-1)), basal-squamous markers (including CD44, KRT5, TP63, and immune markers CD274 and CTLA4), and neuronal markers (such as MSI1, SOX2, TUBB2B, CHGA, CHGB, SYP, ENO2). These markers enable stratification of bladder cancer into multiple mRNA expression subtypes: luminal, luminal-infiltrated, basal-squamous, neuronal, and luminal-papillary.
The problem being addressed is the heterogeneity of urothelial bladder cancer, which presents most commonly as an exophytic tumor confined to the mucosa or lamina propria, but 25% of patients have muscle-invasive bladder cancer (MIBC) or metastatic disease at diagnosis, leading to worse prognosis. There is an urgent need for improved methods to identify such patients and select appropriate aggressive treatments. This invention provides a comprehensive molecular classification into expression subtypes that may inform prognosis and therapeutic strategies.
The invention further provides probes, primers, and nucleic acid arrays for detecting expression of these markers as well as methods of analyzing expression profiles compared to reference controls. It includes methods of selecting patients for treatments such as immune checkpoint inhibitors or tyrosine kinase inhibitors based on subtype stratification, and identifies therapeutic regimens suitable for each subtype, including cisplatin-based chemotherapy, checkpoint inhibitors like atezolizumab, and FGFR3 inhibitors for luminal-papillary subtypes with FGFR3 mutations or fusions.
Claims Coverage
The patent includes eight independent claims directed to methods of treating bladder cancer by selecting patients based on biomarker expression and administering atezolizumab.
Method of selecting patients for atezolizumab treatment by detecting expression of neuronal markers SOX2, TUBB2B, and PEG10
Selecting subjects for atezolizumab administration based on detecting increased levels of polynucleotide markers SOX2, TUBB2B, and PEG10 in a biological sample, using probes, primers, or nucleic acid arrays compared to a reference.
Supplementary detection methods for patient characterization
Detecting proteins GATA3, EGFR, CDH1, HER2; miRNAs miR-200s, miR-99a, miR-100; TP53 and RB1 mutations; and mutations/homozygous deletions in RB1, CDKN1A4, CDKN2A, ATM, ERCC, FGFR3, PIK3CA, RAS, ERBB2, KDM6A, KMT2A, KMT2C, KMT2D, CREBBP, EP300, KANSL1, ARID1A, ASXL1, and ASXL2 to further characterize subjects.
Use of urothelial tumor samples
The biological sample for detecting marker levels can be a urothelial tumor sample.
Expression-based profiling and comparison to reference
Determining polynucleotide marker levels by measuring expression of SOX2, TUBB2B, and PEG10 transcripts to create an expression profile, which is then compared to a reference profile.
Expression profile comparison for marker detection
Determining marker levels by comparing the expression profile from a subject's sample to a control or standard expression profile.
Method of treating bladder cancer by measuring neuronal marker levels and administering atezolizumab
Measuring PEG10, SOX2, and TUBB2B neuronal marker polypeptides or polynucleotides in a subject's bladder cancer sample, comparing the expression profile to a standard to select the patient, then administering atezolizumab.
Method of treating bladder cancer by detecting increased neuronal marker levels and administering atezolizumab
Detecting increased expression of neuronal markers SOX2, TUBB2B, and PEG10 in a bladder cancer sample relative to a reference, selecting the subject accordingly, and administering atezolizumab.
The claims cover methods for selecting bladder cancer patients for treatment with atezolizumab based on increased expression of neuronal markers SOX2, TUBB2B, and PEG10, measured using nucleic acid probes, primers, or arrays, and methods of administering atezolizumab accordingly. Additional claims cover supplemental detection of proteins, miRNAs, and mutations to characterize patients, use of urothelial tumor samples, comparison to reference expression profiles, and the treatment methods that follow from such molecular characterization.
Stated Advantages
The methods provide highly specific drug targets and enable identification of safe therapies for patients.
They allow high-throughput, high-sensitivity, and low-complexity analyses of compounds for effects on bladder cancer.
The classification into expression subtypes can stratify patients' responses to therapy, potentially enhancing personalized treatment strategies.
Documented Applications
Characterizing mutational profiles and expression subtypes in bladder cancer patients for prognosis and therapy selection.
Selecting patients for treatment with atezolizumab based on expression of neuronal markers SOX2, TUBB2B, and PEG10.
Selecting patients for tyrosine kinase inhibitor therapy targeting FGFR3 based on luminal-papillary subtype status.
Selecting patients for immune checkpoint therapy based on luminal-infiltrated subtype characterization.
Selecting patients for cisplatin-based neoadjuvant chemotherapy or immune checkpoint therapy based on basal-squamous subtype identification.
Selecting patients for etoposide-cisplatin therapy based on expression of neuroendocrine/neuronal markers.
Using nucleic acid primers, probes, and microarrays in kits for analyzing bladder cancer expression profiles and subtype classification.
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