Gene signature predictive of hepatocellular carcinoma response to transcatheter arterial chemoembolization (TACE)
Inventors
Wang, Xin Wei • Miller, Valerie Fako
Assignees
US Department of Health and Human Services
Publication Number
US-11306362-B2
Publication Date
2022-04-19
Expiration Date
2037-02-07
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Abstract
This disclosure provides methods for predicting the likelihood that a hepatocellular carcinoma (HCC) will respond to transcatheter arterial chemoembolization (TACE) using a gene signature of 14 or 15 genes. Also provided are nucleic acid probes and kits for detecting the gene signature.
Core Innovation
This disclosure provides methods for predicting the likelihood that a hepatocellular carcinoma (HCC) will respond to transcatheter arterial chemoembolization (TACE) using a gene signature of 14 or 15 genes. The methods are based on detecting expression of specific TACE-associated genes in HCC tumor samples relative to controls, where modulation of expression indicates the tumor's responsiveness to TACE treatment. Also included are nucleic acid probes and kits for detecting this gene signature, as well as devices for carrying out the gene signature assay.
The problem addressed by the invention is the poor and heterogeneous outcome of HCC due to tumor heterogeneity and lack of effective treatment options for later-stage disease. Although TACE is considered the gold standard for intermediate to locally advanced tumors and has shown survival benefits, these benefits are only apparent when strict patient selection criteria are met. Current therapies lack reliable methods to predict patients' TACE response, leading to conflicting clinical trial results and limiting optimal therapeutic decisions.
The disclosed methods involve detecting differential expression of a gene signature comprising ASNS, CDK1, DNASE1L3, FBXL5, GOT2, GRHPR, IARS, LGALS3, LHFPL2, MFGE8, MKI67, PEBP1, TNFSF10, and UBB, with optional inclusion of GABARAPL3. Modulation of these gene expressions relative to control—such as housekeeping genes or non-tumor tissue—predicts whether an HCC will respond to TACE. The predictive capacity of the gene signature is independent of other clinical variables and applicable regardless of whether TACE is adjuvant or post-relapse therapy. The invention also provides a TACE Navigator Gene Signature Assay consisting of probes specific for these signature genes and housekeeping genes, for use in clinical diagnostics.
Claims Coverage
The patent discloses multiple independent claims centered on methods of detecting expression of specific genes to predict HCC response to TACE, methods of treating HCC based on gene expression, and use of probe sets for detecting these genes.
Method for detecting gene expression predictive of HCC response to TACE
Detecting an increase in expression of ASNS, CDK1, FBXL5, IARS, LGALS3, LHFPL2, MKI67, and UBB and a decrease in expression of DNASE1L3, GOT2, GRHPR, MFGE8, PEBP1, and TNFSF10 in an HCC sample obtained from a subject diagnosed with HCC relative to a control, thereby predicting TACE responsiveness.
Inclusion of GABARAPL3 in gene expression detection
Further comprising detecting a decrease in expression of GABARAPL3 in an HCC sample relative to a control as part of predicting TACE response.
Use of housekeeping genes or proteins for normalization
Including detection of expression of 1 to 10 housekeeping genes or proteins to normalize or control the assay.
Gene expression detection methods using a probe set
Utilizing a probe set comprising nucleic acid probes specific for the TACE-associated genes for measuring gene expression predictive of TACE response.
Method of treating HCC based on gene expression signature
Determining that HCC will respond to TACE by detecting the characteristic gene expression modulation and administering TACE treatment accordingly.
Employing gene expression values converted to statistical scores
Converting gene expression values to z-scores, applying a prognostic index equation, and using this to predict and treat TACE-responsive HCC patients.
Treatment methods with specified chemotherapeutic agents in TACE
Using TACE with agents such as cisplatin, adriamycin, mitomycin, and doxorubicin following gene signature evaluation.
The claims collectively cover methods for detecting specific gene expression modulations to predict HCC responsiveness to TACE, use of corresponding nucleic acid probes and probe sets for this detection, and treating patients based on these predictive results by administering TACE therapy. The invention ties gene expression signatures specifically to TACE response prediction and treatment.
Stated Advantages
Predicts patient response to TACE independent of other clinical variables.
Applicable regardless of whether TACE is used as adjuvant therapy or following tumor relapse.
Enables better selection of patients likely to benefit from TACE treatment.
Identifies the hypoxia response as a potential mechanism underlying TACE resistance, providing insight into tumor biology.
Allows integration of gene expression detection with clinical practice via kits and assays optimized for degraded RNA samples from FFPE tissues.
Documented Applications
Predicting responsiveness of hepatocellular carcinoma patients to transcatheter arterial chemoembolization (TACE).
Selecting HCC patients most likely to benefit from TACE treatment based on gene expression profiles.
Administering TACE treatment to patients identified as responders by the gene signature assay.
Using gene expression detection kits and probe sets for clinical diagnostic assays to guide HCC treatment decisions.
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