CN116254345B - Application of lenvatinib drug-resistant marker and related reagent thereof - Google Patents
Application of lenvatinib drug-resistant marker and related reagent thereof Download PDFInfo
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Abstract
The application provides an application of a lenvatinib drug-resistant marker and related reagents thereof, wherein the lenvatinib drug-resistant marker is JUN, and the JUN can be used for predicting the drug effect of the lenvatinib. The expression of related molecules is detected by sequencing the transcriptome of the tissue of a liver cancer patient or by PCR, a gene chip, a tissue chip, a NanoString technology and an immunohistochemical method, so that clues can be provided for the administration of the lenvatinib and the accurate treatment of the liver cancer.
Description
Technical Field
The application belongs to the technical field of biological medicines, and particularly relates to a lenvatinib drug-resistant marker and application of a related reagent thereof.
Background
Primary liver cancer is the fourth most common malignant tumor in China, and the second most common malignant tumor is the death rate, so that the life and health of people in China are seriously threatened. The treatment of early liver cancer patients (Barcolona 0 phase A), surgical excision, liver transplantation and the like can effectively improve the cure rate and survival prognosis of the liver cancer patients. However, since liver cancer is hidden, early symptoms lack specificity, and many patients are diagnosed with liver cancer already in the middle or late stage. For a long time, due to few drug treatment schemes and low clinical effective rate, the liver cancer in middle and late stages generally shows poor prognosis and low survival rate.
Sorafenib (Sorafenib) was the earliest drug for the treatment of liver cancer, however, sorafenib only increased median survival by three months and had low efficacy rates, which were less than 10%. Lenvatinib (Lenvatinib) is a first-line drug commonly used in clinic for primary liver cancer, and the applicable targets include VEGFR1-3, FGFR1-4, PDGFR alpha, KIT and RET, so that the Lenvatinib is suitable for liver cancer patients in IIb, IIIa, IIIb stage and liver function Child-PughA grade in unresectable Chinese liver cancer staging scheme (CNLC). Studies have shown that the median survival of liver cancer patients following treatment with lenvatinib is no worse than sorafenib. Guidelines of the national cancer Integrated network (NCCN), european oncology institute (ESMO), european liver research institute (EASL), china clinical oncology institute (CSCO), and the like recommend lenvatinib as a first-line standard treatment drug for advanced hepatocellular carcinoma in 2018. Although the clinical effective rate of the lenvatinib is obviously superior to that of sorafenib, the clinical effective rate of the lenvatinib is only 24.1%, and most of people are inapplicable, so that a plurality of ineffective treatment phenomena occur. Therefore, a drug sensitive molecular typing scheme for supplementing the lenvatinib is needed to improve the curative effect of liver cancer treatment.
Disclosure of Invention
The application relates to a division application of application number 202210636256.6, wherein the application date of the mother application is 2022, 6 and 7, and the application creates application of a' lenvatinib drug sensitive marker and related reagents.
Aiming at the problems in the prior art, the application aims to provide an application of a lenvatinib drug-resistant marker and related reagents thereof, and the application can be used for prompting a lenvatinib drug-resistant crowd so as to provide a basis for accurate treatment of liver cancer. A second object of the present application provides some applications of the related reagent of the lenvatinib drug-resistant marker, the related reagent of the marker includes: the application of the related reagents can fill the blank in the field of accurate diagnosis and treatment of liver cancer.
The application aims at realizing the following technical scheme:
the first aspect of the application: the high expression of JUN is found to be related to the drug resistance of the lenvatinib, so that the JUN gene expression can be used as a potential drug resistance biomarker for guiding the treatment of primary liver cancer. Namely, the application provides a lenvatinib drug-resistant marker, wherein the lenvatinib drug-resistant marker is JUN.
Further, the drug-resistant marker is RNA or its reverse transcribed cDNA, or protein.
The specific screening process is as follows:
the inventor collects a plurality of cases of operation specimens of primary liver cancer patients, samples the specimens at multiple points, and successfully establishes a liver cancer organoid biological library covering hundreds of sites by a three-dimensional culture method. Team confirmed that organoids retained the pathological features of the patient by Hematoxylin-Eosin (HE) staining. Through immunofluorescence and immunohistochemical staining of the organoids and corresponding patient specimens, the molecular markers of the liver cancer organoids and clinical liver cancer patients are found to be consistent.
Near hundred sites are selected for sequencing the exons and transcriptomes of the tissues and the corresponding organoids, and genome characteristics of the tissues and the corresponding organoids are analyzed. The molecular characteristics of the tissue samples are highly preserved from the multi-dimensions of somatic mutation, copy number variation, transcriptome similarity and the like of the organoid biological library. In addition, the large-scale liver cancer tissue and organ queues established by the team are consistent with the previous liver cancer research, and have high mutation of liver cancer. In addition, the liver cancer data of the inventor reflect different degrees of inter-tumor (inter-tumor) and intra-tumor heterogeneity (intra-tumor heterogeneity), and provide a basis for researching liver cancer drug sensitivity heterogeneity.
The application selects liver cancer drugs such as sorafenib, lenvatinib and the like which are commonly used clinically, and carries out large-scale drug screening on the organoid biological library. The inventors compared organoid sensitization with clinical treatment effects, and found that the sensitization effect is highly consistent.
In order to study drug sensitive molecular typing of the first-line targeting drug of the lenvatinib in liver cancer, transcriptome sequencing is carried out on a plurality of organoid sites, and sensitive markers of the lenvatinib are analyzed to be ACOT6 and MT1X, NEDD L, PCYOX1 and drug resistant markers are JUN, HIST1H1E, WNT6, ZC3H12D, CHAC1, ANKRD37, CST1, SPNS3 and COX6A2 through a Lasso model and a belief analysis. The training set AUC was 0.86. Then, we collected a plurality of liver cancer specimens by the same method for organoid culture, drug sensitivity test and transcriptome sequencing, and molecular typing study, and obtained a verification set of 0.81 for lenvatinib.
The second aspect of the application: provides the application of the quantitative reagent of the JUN expression level of the lenvatinib drug resistance marker in preparing a detection reagent for the drug resistance of the lenvatinib.
Further, the detected sample is a liver cancer tissue sample, and the quantitative reagent is any one of a transcriptome sequencing reagent, a PCR (polymerase chain reaction), a gene chip, a tissue chip, a NanoString technology and an immunohistochemical reagent.
Further, a kit for evaluating the resistance of the lenvatinib is provided, which comprises a quantitative reagent for detecting the expression quantity of the lenvatinib resistance marker JUN.
Further, there is provided a system for analyzing resistance of lenvatinib to primary liver cancer, comprising:
target expression level detection device: the method is used for detecting the expression quantity of the lenvatinib drug-resistant marker JUN in a sample; the sample is liver cancer tissue of a patient;
drug resistance analysis device: determining the drug effect of liver cancer based on the expression quantity of a drug resistance marker JUN of lenvatinib;
result output means: and the device is used for outputting the analysis result of the drug resistance analysis device.
A third aspect of the application: a pharmaceutical composition for treating liver cancer is provided, which comprises lenvatinib and an inhibitor of a lenvatinib drug resistance marker JUN. The pharmaceutical composition improves the efficacy of the lenvatinib on a specific patient by inhibiting the expression of the lenvatinib drug-resistant gene.
Further, the inhibitor of the lenvatinib drug resistance marker JUN is shc-JUN.
Compared with the prior art, the application has the beneficial effects that:
the application determines that the JUN gene is related to the drug resistance of the lenvatinib, and the drug resistance marker JUN can be used for predicting the drug effect of the lenvatinib. The expression of related molecules is detected by tissue sequencing of liver cancer patients or by RT-qPCR and immunohistochemical methods, so that clues can be provided for the administration of the lenvatinib and the accurate treatment of the liver cancer.
Drawings
The application is further illustrated by the following examples in conjunction with the accompanying drawings:
fig. 1 shows the pathological features and tissue markers of a Hepatoma (HCC) patient with a organoid that retains the patient. Wherein, FIG. 1A, HE and immunohistochemical staining of different sites in HCC patients; FIG. 1B, microscopic status and HE staining of the organoids of HCC patients; FIG. 1C, immunofluorescent staining of organoids; FIG. 1D, immunohistochemical staining of organoids.
FIG. 2 retains the exonic and transcriptomic characteristics of a patient for organoids. Among other things, fig. 2A, exon sequencing revealed that organoids retained the mutational characteristics of the patient. Fig. 2B, transcriptome sequencing shows that the organoids retain the transcriptome characteristics of the patient.
Fig. 3 is an organoid drug sensitivity test. Fig. 3A, drug sensitivity curve of lenvatinib, fig. 3B, test of 376 organoids of 7 liver cancer targeted drugs. Figure 3C, in vitro drug susceptibility testing of organoids consistent with drug response in clinical patients.
Fig. 4 is a molecular typing of lenvatinib. Fig. 4A, drug sensitive molecular typing of lenvatinib. Fig. 4B, AUC of the lenvatinib training and validation sets. Fig. 4C, drug resistant targets of lenvatinib are plotted as each other.
Fig. 5 is a validation of molecular typing of lenvatinib in 100 liver cancer tissues.
Fig. 6 is a drug-sensitive effect of targeting JUN to enhance lenvatinib. The graph is shown as a drug sensitivity curve of 6 liver cancer patients, a curve marked by a circular point represents an original drug sensitivity curve of liver cancer organoids, and a curve marked by a square point represents a drug sensitivity curve of knockdown JUN (A) or over-expression JUN (B). The abscissa shows the different concentration of the lenvatinib drug and the ordinate shows the proportion of organoid survival at this concentration. Fig. 6A, knockdown of JUN in sites of resistance to lenvatinib can significantly enhance drug sensitivity of lenvatinib. Fig. 6B, over-expression of JUN in sites where lenvatinib is sensitive may also result in reduced sensitivity to lenvatinib.
Detailed Description
The technical scheme of the application is further described below in combination with experimental data.
Example 1
Screening of the lenvatinib drug sensitive marker: in the embodiment, a liver cancer organoid biological library covering 376 sites is successfully established by a 3D culture method. Taking a Hepatoma (HCC) patient as an example, the inventors confirmed that organoids retained the pathological characteristics of the patient by HE staining (fig. 1A, 1B). By immunofluorescence and immunohistochemical staining of the organoid and corresponding patient specimens, hepatocellular carcinoma patients and their organoid high-grade HCC diagnostic markers AFP, hepatocyte were found to be positive (fig. 1C, 1D), whereas the cholangiocarcinoma marker EPCAM was negative, consistent with the molecular markers of clinically hepatoma patients. It is shown that the organoid system established in this example well preserves the pathological characteristics of the patient.
In this example, 99 sites were selected for the sequencing of exons and transcriptomes of tissues and corresponding organoids, and genomic characteristics of tissues and corresponding organoids were analyzed. The molecular characteristics of the tissue samples are highly preserved from the multi-dimensions of somatic mutation, copy number variation, transcriptome similarity and the like of the organoid biological library. The large-scale liver cancer tissue and organoid queues established by the team are consistent with previous liver cancer studies, with high-incidence mutations in liver cancer (fig. 2A). At the transcriptome level, organoids and tissues of the corresponding patient also have a high correlation (fig. 2B).
In this example, drug sensitivity tests of first-line liver cancer drugs sorafenib and lenvatinib, commonly used two/three-line drugs regorafenib, apatinib and bevacizumab, and drugs Pemigatinib fused to bile duct cancer FGFR2 and drug Ivosidenib mutated to bile duct cancer IDH1 were performed on 376 organoids. This example plots the drug sensitivity profile of the first-line drug, lenvatinib (fig. 3A) and the heat map of all targeted drugs (fig. 3B). And the drug-sensitive reaction of the patient organoid is generally consistent with the clinical actual drug effect of the patient (figure 3C).
In order to study drug sensitive molecular typing of the first-line targeting drug of lenvatinib for liver cancer, transcriptome sequencing was performed on 106 organoid sites in this example, and sensitive markers of lenvatinib are ACOT6 and MT1X, NEDD and L, PCYOX1 and drug resistant markers are JUN, HIST1H1E, WNT6, ZC3H12D, CHAC1, ANKRD37, CST1, SPNS3 and COX6A2 (FIG. 4A) through Lasso model and biological analysis. The training set AUC was 0.86 (fig. 4B). Thereafter, 106 liver cancer specimens were collected for organoid culture, drug sensitive test and transcriptome sequencing by the same method, and molecular typing study was performed, resulting in a verification set of 0.81 for lenvatinib (fig. 4B). This example plots the interaction network for the drug resistance gene of lenvatinib revealing the link between these drug resistant molecules (fig. 4C).
This example demonstrates the effectiveness of this drug sensitive molecular typing in the tissues of 100 liver cancer patients. In liver cancer tissues, the drug sensitive molecular typing AUC of lenvatinib was 0.78 (fig. 5).
In order to further reveal the guidance of drug sensitive molecular typing on liver cancer drug administration, in the embodiment, as an example, according to the interaction diagram of drug resistance genes, a gene of JUN residing in a core area is selected as a key target point of drug resistance. Knocking down the JUN in the site of resistance to the lenvatinib can significantly enhance the drug sensitivity of the lenvatinib (FIG. 6A), and over-expressing the JUN in the site of sensitivity of the lenvatinib can also reduce the sensitivity of the lenvatinib (FIG. 6B) (note: JUN gene encodes c-JUN protein).
Example 2
Use of a label of lenvatinib in a study of administration of lenvatinib for non-therapeutic purposes. In this example, the activity of lenvatinib was studied: selecting specific liver cancer tissues, enabling different batches of the lenvatinib to act on the specific liver cancer tissues, and measuring quantitative expression of one or more of the selected lenvatinib drug-sensitive molecules in the example 1, thereby judging the biological activity of each batch of the lenvatinib.
Example 3
The embodiment provides an RT-qPCR (reverse transcription-quantitative polymerase chain reaction) lenvatinib drug sensitivity assessment kit, which comprises a quantitative reagent for detecting the expression quantity of the lenvatinib drug resistance marker JUN screened in the embodiment 1. The kit comprises upstream and downstream primers for the RNA of JUN. The kit provided by the application can be used for specifically detecting the expression quantity of JUN in a sample by combining a common RNA extraction reagent and a common reverse transcription reagent, and is beneficial to early judging the drug resistance of a liver cancer patient to lenvatinib. Can be measured immediately after a liver cancer patient performs surgery or performs pathological puncture to obtain liver cancer tissues, and the curative effect of the medicine can be evaluated before using the lenvatinib, so that a personalized and accurate treatment scheme is provided for the patient.
Example 4
The embodiment provides an RT-qPCR (reverse transcription-quantitative polymerase chain reaction) lenvatinib drug sensitivity assessment kit, which comprises a quantitative reagent for detecting the expression quantity of the lenvatinib sensitive marker MSRA and the like screened in the embodiment 1. The kit comprises primers upstream and downstream of the RNA of MSRA. The kit provided by the application can be used for specifically detecting the expression quantity of MSRA in a sample by combining with a common RNA extraction reagent and a common reverse transcription reagent, and is beneficial to early judging the sensitivity of a liver cancer patient to lenvatinib. Can be measured immediately after a liver cancer patient performs surgery or performs pathological puncture to obtain liver cancer tissues, and the curative effect of the medicine can be evaluated before using the lenvatinib, so that a personalized and accurate treatment scheme is provided for the patient.
Example 5
The embodiment provides a system for analyzing the drug resistance of pravastatin of primary liver cancer, which comprises:
RT-qPCR target expression quantity detection device: the method is used for detecting the expression quantity of a lenvatinib drug-resistant marker JUN and the like in a sample; the sample is liver cancer tissue of a patient; the target expression quantity detection device adopts RT-qPCR quantitative reagent including the upstream and downstream primers of the gene.
Drug resistance analysis device: determining the drug effect of liver cancer based on the expression quantity of the lenvatinib drug resistance marker JUN.
Result output means: and the device is used for outputting the analysis result of the drug resistance analysis device.
The curative effect of the medicine can be evaluated before the patient uses the lenvatinib, and a personalized and accurate treatment scheme is provided for the patient.
Finally, it should be noted that the above only illustrates the technical solution of the present application and is not limiting, and although the present application has been described in detail with reference to the preferred arrangement, it should be understood by those skilled in the art that modifications and equivalents may be made to the technical solution of the present application without departing from the spirit and scope of the technical solution of the present application.
Claims (2)
1. The application of a quantitative reagent for detecting the JUN expression level of a drug resistance marker of the lenvatinib in preparing a drug resistance detection reagent of the lenvatinib.
2. The use according to claim 1, wherein the sample to be detected is a liver cancer tissue sample and the quantitative reagent is any one of a transcriptome sequencing reagent, a PCR, a gene chip, and an immunohistochemical reagent.
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| CN114107509A (en) * | 2021-12-09 | 2022-03-01 | 江苏省肿瘤医院 | Liver cancer prognosis marker and application thereof |
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| Title |
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| "Posttreatment after Lenvatinib in Patients with Advanced Hepatocellular Carcinoma";Keisuke Koroki等;《Liver Cancer》;第10卷(第5期);全文 * |
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| CN116254345A (en) | 2023-06-13 |
| CN114959034A (en) | 2022-08-30 |
| CN114959034B (en) | 2023-05-12 |
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