CN113951212A - HER2 positive gastric cancer drug-resistant PDX model and construction method and application thereof - Google Patents
HER2 positive gastric cancer drug-resistant PDX model and construction method and application thereof Download PDFInfo
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- CN113951212A CN113951212A CN202011192778.9A CN202011192778A CN113951212A CN 113951212 A CN113951212 A CN 113951212A CN 202011192778 A CN202011192778 A CN 202011192778A CN 113951212 A CN113951212 A CN 113951212A
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- 206010066896 HER-2 positive gastric cancer Diseases 0.000 title claims abstract description 21
- 239000003560 cancer drug Substances 0.000 title claims abstract description 15
- 238000010276 construction Methods 0.000 title description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 28
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 28
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 28
- 229940079593 drug Drugs 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000011282 treatment Methods 0.000 claims abstract description 17
- 229960000575 trastuzumab Drugs 0.000 claims abstract description 15
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims abstract description 14
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims abstract description 14
- 238000007920 subcutaneous administration Methods 0.000 claims abstract description 6
- 241000699666 Mus <mouse, genus> Species 0.000 claims description 17
- 238000011081 inoculation Methods 0.000 claims description 5
- 241000699670 Mus sp. Species 0.000 claims description 4
- 238000012216 screening Methods 0.000 claims description 4
- 238000002054 transplantation Methods 0.000 claims description 4
- 230000002146 bilateral effect Effects 0.000 claims description 3
- 238000001727 in vivo Methods 0.000 claims description 3
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 claims description 2
- 238000001574 biopsy Methods 0.000 claims description 2
- 238000002651 drug therapy Methods 0.000 claims description 2
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- 230000009456 molecular mechanism Effects 0.000 abstract description 3
- 238000011269 treatment regimen Methods 0.000 abstract description 3
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0271—Chimeric vertebrates, e.g. comprising exogenous cells
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2207/00—Modified animals
- A01K2207/12—Animals modified by administration of exogenous cells
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2207/00—Modified animals
- A01K2207/15—Humanized animals
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/0331—Animal model for proliferative diseases
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Abstract
The invention relates to a method for constructing a HER2 positive gastric cancer drug-resistant PDX model, which comprises the following steps: fresh gastric cancer tissues of a drug-resistant HER2 positive gastric cancer patient after drug treatment are transplanted to the subcutaneous of a mouse. According to the invention, the gastric cancer tissue of a patient with drug resistance after HER2 positive trastuzumab treatment is obtained clinically, and a gastric cancer PDX model is successfully established. The scheme provided by the invention has a crucial role in understanding the potential molecular mechanism of trastuzumab acquired resistance, searching for a new treatment strategy for overcoming the resistance and making the next effective treatment scheme.
Description
Technical Field
The invention relates to a cancer treatment model and application thereof, in particular to a HER2 positive gastric cancer drug-resistant PDX model and a construction method and application thereof.
Background
Gastric cancer is the fourth most common cancer, with its cancer-related mortality ranking second. Although early treatment at early diagnosis can reduce mortality, there are about 40% of patients with poor prognosis due to late stage inoperable or metastatic disease, requiring palliative treatment. Human epidermal growth factor receptor 2(HER2, also known as ERBB2) is a transmembrane receptor tyrosine kinase whose overexpression/amplification (HER2 positive, HER2+) accounts for approximately 6.1% -23.0% of GC. Several studies have demonstrated the efficacy of trastuzumab on HER2+ metastatic gastric cancer. The ToGA study was the first clinical trial showing that trastuzumab in combination with chemotherapy can significantly improve Overall Survival (OS) in HER2+ metastatic gastric cancer patients. However, while survival benefits can be realized with trastuzumab, the addition of trastuzumab in a chemotherapy regimen only improved the overall remission rate by 12.8% and the Progression Free Survival (PFS) by 1.2 months. For HER2+ metastatic gastric cancer patients, limited response to initial treatment or acquired resistance to trastuzumab may account for limitations in efficacy. For the exploration of the drug resistance mechanism and the formulation of the next diagnosis and treatment plan of trastuzumab drug-resistant patients, an alternative method capable of evaluating the curative effect response is needed.
The tumor animal model is always an effective tool for the preclinical efficacy prediction and toxicity evaluation of the antitumor drug. The PDX (Patient-derived xenograde, PDX) model is a transplanted tumor model of fresh tumor tissue derived from a tumor Patient, and is a tumor formed by inoculating fresh tumor tissue (puncture specimen or surgical specimen) of the Patient under the skin or kidney capsule of an immunodeficient mouse. The model can reflect the biological characteristics of human tumor more than the traditional cell line model, not only retains the proliferation and histopathological characteristics similar to the primary tumor tissue, but also has high consistency with the original tumor tissue in biological behavior, including molecular characteristics such as tumor genes, proteins and the like. There is a great deal of research evidence that PDX-transplanted tumor models are one of the ideal models for predicting tumor treatment response. Due to the high clinical relevance of the PDX model, the PDX model can provide an effective research tool for researchers in the aspects of patient population screening, drug sensitivity prediction, new drug preclinical tests and the like.
However, in the prior art, the genome maps of the primary tumor and the metastatic tumor are not always consistent, and the genome may form new drug-resistant mutations after multi-line treatment, especially trastuzumab treatment. Because the treated tumor tissue is difficult to obtain, the successful establishment of a drug-resistant gastric cancer PDX model after HER2 positive trastuzumab treatment does not exist.
Disclosure of Invention
A first object of the present invention is to provide a method for constructing a HER2 positive gastric cancer drug-resistant PDX model, comprising the steps of: fresh gastric cancer tissues of a drug-resistant HER2 positive gastric cancer patient after drug treatment are transplanted to the subcutaneous of a mouse.
As a preferred embodiment of the invention, the drug therapy is a therapy with a monoclonal antibody against HER 2. The monoclonal antibody against HER2 is further preferably trastuzumab.
In a preferred embodiment of the present invention, the fresh gastric cancer tissue is obtained at the time of biopsy of a patient, and is rapidly put into a centrifuge tube containing a tissue preservation solution, and is transported and preserved at a low temperature. The provider of the fresh gastric cancer tissue should comprehensively detect and record pathological information, immunohistochemical results and medication information.
In a preferred embodiment of the present invention, the fresh gastric cancer tissue is cut into (1-3) mmX (2-4) mm or 10m before being transplanted under the skin of a mouse3～20m3Size of the pieces to facilitate smooth inoculation.
As a preferred embodiment of the present invention, the mouse is an immunodeficient mouse (NOD-SCID), preferably an immunodeficient mouse of 4-6 weeks of age. The site of transplantation is preferably the back of the mouse, bilateral subcutaneous inoculation.
As a preferred embodiment of the present invention, after the transplantation, various growth factors can be used to assist the growth of tumor cells to increase tumorigenicity, and the condition of transplanted tumors can be observed and measured at least twice a week to monitor the tumor growth.
As a preferred aspect of the present invention, the method further comprises: the stomach cancer tissue to be transplanted under the skin of the mouse is 1000mm long3～1500mm3Size, and taking out for in vivo passage. And (3) freezing and storing the stomach cancer tissues which are successfully inoculated and passaged and preferably generate 2-3 generations by adopting liquid nitrogen for recovery inoculation again.
As a preferred aspect of the present invention, the method further comprises: and (4) freezing and storing the successfully-passaged gastric cancer tissues or the stomach cancer tissues which are successfully passaged and then revived, and inoculating other mice again.
The HER2 positive gastric cancer drug-resistant PDX model obtained by the method needs to be subjected to gastric cancer histopathological identification, such as routine pathological examination and immunohistochemical staining, and also needs to be subjected to gastric cancer histogenetic identification, such as exome deep sequencing of tumor-related genes, mutation, amplification, copy number variation, insertion/deletion, point mutation and the like, and especially needs to pay attention to target point mutation targeted by the existing targeted drugs and molecular characteristics related to chemotherapy drug sensitivity.
The second purpose of the invention is to provide a HER2 positive gastric cancer drug-resistant PDX model constructed by the method.
The third purpose of the invention is to provide the application of the HER2 positive gastric cancer drug-resistant PDX model. Specifically, the model can be used for the next treatment scheme exploration of the drug resistance after HER2 positive gastric cancer drug treatment, can be used for exploring a potential molecular mechanism of acquired drug resistance, and can also be used for searching a new treatment strategy for overcoming the drug resistance. Furthermore, the model can also be used for screening other drugs with anti-cancer activity, in particular drugs with anti-HER 2 positive gastric cancer activity.
Compared with the prior art, the invention obtains the drug-resistant tumor tissue of a patient treated by HER2 positive trastuzumab clinically and successfully establishes a gastric cancer PDX model. The scheme provided by the invention has a crucial role in understanding the potential molecular mechanism of trastuzumab acquired resistance, searching for a new treatment strategy for overcoming the resistance and making the next effective treatment scheme.
Drawings
FIG. 1 is a graph of immunohistochemical results of patients in an example of the present invention;
FIG. 2 is a tumor-forming mouse with successful gastric cancer transplantation in an example of the present invention;
FIG. 3 is a graph showing the change in body weight of tumor-bearing mice in the example of the present invention;
FIG. 4 is a growth curve of a transplanted tumor in an example of the present invention.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Examples
The embodiment provides a HER2 positive gastric cancer drug-resistant PDX model, which is constructed by the following steps:
(1) taking the stomach cancer tissues of a clinically trastuzumab-resistant HER2 positive gastric cancer patient after treatment, performing immunohistochemical detection on the tissues of the stomach cancer patient (the result is shown in figure 1), and recording the medication information of the patient in detail;
(2) cutting fresh gastric cancer tissue into 2 × 2 × 3mm3The large and small fragments are inoculated under the back of a 4-6 week-old nude mouse in a bilateral subcutaneous inoculation mode, and a tumor forming mouse is shown in figure 2;
(3) the body weight of the nude mice was measured at least twice a week (results are shown in FIG. 3) and the condition of the transplanted gastric cancer tissues was observed and measured (results are shown in FIG. 4), when the tumor mass was 1000-1500mm3Size, taking out for in vivo passage;
(4) the stomach cancer tissues successfully passaged for 2 passages were re-inoculated to other mice.
Taking out part of tumor tissues aiming at the model constructed in the embodiment, and carrying out pathological identification on the tumor tissues, wherein the tumor tissues are proved to be gastric cancer tissues from patients by pathological experts; immunohistochemical staining of the tumor tissue, with HER-2(2 +); exome sequencing of the tumor tissue detected HER2 gene amplification. Therefore, this example successfully obtained a HER2 positive gastric cancer drug-resistant PDX model.
Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. A method for constructing a HER2 positive gastric cancer drug-resistant PDX model is characterized by comprising the following steps: fresh gastric cancer tissues of a drug-resistant HER2 positive gastric cancer patient after drug treatment are transplanted to the subcutaneous of a mouse.
2. The method of claim 1, wherein the drug therapy is treatment with a monoclonal antibody against HER 2;
preferably, the monoclonal antibody against HER2 is trastuzumab.
3. The method of claim 1, wherein the fresh gastric cancer tissue is taken at the time of biopsy by the patient.
4. The method according to claim 1 or 3, wherein the fresh gastric cancer tissue is sliced to (1-3) mmx (2-4) mm or 10m before being transplanted under the skin of the mouse3～20m3Size fraction.
5. The method according to claim 1, wherein the mouse is an immunodeficient mouse, preferably an immunodeficient mouse of 4-6 weeks of age.
6. The method according to claim 1 or 5, wherein the site of transplantation is preferably dorsal, bilateral subcutaneous inoculation of the mouse.
7. The method according to any one of claims 1 to 6, wherein the gastric cancer tissue to be transplanted under the skin of the mouse is 1000mm long3～1500mm3Size, and taking out for in vivo passage.
8. The method according to claim 7, wherein the gastric cancer tissues successfully passaged for 2 to 3 passages are re-inoculated into other mice.
9. A HER2 positive gastric cancer drug-resistant PDX model constructed by the method of any one of claims 1-8.
10. Use of the HER2 positive gastric cancer drug-resistant PDX model constructed by the method of any one of claims 1-8 or the HER2 positive gastric cancer drug-resistant PDX model of claim 9 in screening anti-cancer active drugs, preferably in screening anti-HER 2 positive gastric cancer active drugs.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116773790A (en) * | 2023-08-18 | 2023-09-19 | 南京普恩瑞生物科技有限公司 | Preparation method and application of tumor tissue HER2 gradient detection product |
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