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Application of metformin in treatment of KRAS mutant type colorectal cancer

A colorectal cancer, mutant technology, applied in the treatment of KRAS mutant colorectal cancer, in the field of metformin, can solve the unexplained mechanism, can not improve the overall survival time and progression-free survival time of colorectal cancer patients, no Clarify the effective treatment types and individuals of metformin in the treatment of rectal cancer, and achieve far-reaching and enhanced effects of inhibiting tumor cell proliferation

Inactive Publication Date: 2020-02-07
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, some studies have also reported that metformin cannot improve the overall survival time and progression-free survival time of patients with colorectal cancer.
[0006] The above studies suggest that there may be type and individual differences in the therapeutic effect of metformin on colorectal cancer. At present, the effective treatment type and individual of metformin in the treatment of rectal cancer have not yet been clarified, nor has the mechanism been elucidated

Method used

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  • Application of metformin in treatment of KRAS mutant type colorectal cancer
  • Application of metformin in treatment of KRAS mutant type colorectal cancer
  • Application of metformin in treatment of KRAS mutant type colorectal cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 2

[0072] Example 1 Effect of metformin on the prognosis of patients with metastatic colorectal cancer

[0073] 1. Grouping and clinical characteristics of metastatic colorectal cancer patients with type 2 diabetes mellitus

[0074] 1. Experimental samples

[0075] Among the 4,751 patients with metastatic colorectal cancer (mCRC) admitted to Sun Yat-sen University Cancer Center from 2004 to 2016, 282 patients with type 2 diabetes (T2DM) before diagnosis were included. They were divided into those taking metformin (metformin use, n=109), insulin or insulin-releasing (insulin or insulin-releasing, n=141) taking other anti-diabetic drugs (n=22) and Untreated group (without anti-diabetic treatments, n=32). Patient inclusion group see figure 1 .

[0076] 2. Experimental method

[0077] Collect general clinical characteristics of patients, such as gender, age, body mass index (BMI); and clinical characteristics that have been reported to affect the prognosis of mCRC (such as prima...

Embodiment 2

[0199] Example 2 Verification of the therapeutic effect of metformin on KRAS mutant tumors in tumor animal models

[0200] 1. Construction of PDX model

[0201] Use the PDX model: take clinical KRAS wild-type and mutant colorectal cancer patient tumor tissues, digest and culture tumor cells, identify KRAS mutations, and plant tumor cells in the axilla of nude mice.

[0202] 1. Experimental method

[0203] 1) Collection of tumor specimens from patients: For specimens after surgical resection, cancer tissues with non-necrotic margins were taken, soaked in 5% fetal bovine serum, PRMI1640 culture medium containing 1× penicillin and streptomycin, and transported at 4°C;

[0204] 2) Cut the tumor tissue into small pieces about 2×2×2mm in size in the ultra-clean workbench, wash with the above culture medium for 3 times, and remove the congestion;

[0205] 3) BALB / C nude mice aged 4-6 weeks were anesthetized with 4.8% chloral hydrate. After anesthesia, a small incision of about 3 mm...

Embodiment 3

[0216] Example 3 Metformin inhibits the proliferation of KRAS mutant colorectal cancer cells

[0217] 1. The effect of metformin on the apoptosis of colorectal cancer cells

[0218] On KRAS wild-type cells SW48 and KRAS(G13D) mutant cells LoVo, Annexin V / PI double staining was used to detect the effect of metformin on colorectal cancer cell apoptosis.

[0219] 1. Experimental method

[0220] 1) Cells were planted in a 6-well plate, after 12 hours of attachment, they were starved overnight, treated with drugs for 24 hours, digested with EDTA-free trypsin, washed once with PBS, and did not need to be fixed.

[0221] 2) Add 300 μl Binding Buffer to resuspend the cells, add 3 μl Annexin V-FITC and 3 μl Propidium Iodide (PI), mix well, incubate at room temperature in the dark for 30 minutes, and perform flow cytometry on the machine.

[0222] 3) Antibody detection by flow cytometry: the apoptosis kit (A211-02) was purchased from KGI; the cell cycle PI single-staining detection ki...

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Abstract

The present invention discloses a marker for determining a treatment plan for colorectal cancer. The marker is a KRAS gene and / or protein. For KRAS mutant type colorectal cancer, metformin is used totreat the colorectal cancer. For the first time, use of the metformin in patients with the KRAS mutant type colorectal cancer is determined to have more significant benefits, down-regulation of META1expression in a metformin discharge channel is further determined to be a key mechanism for KRAS mutant colorectal cancer cells to be sensitive to the metformin, a transcription level of META1 is reduced to increase concentration of the metformin in tumor cells, and thus an effect of the metformin on inhibiting tumor cell proliferation is enhanced. A novel idea and method for the treatment of thecolorectal cancer are provided, have far-reaching significance and are deserved to be vigorously promoted.

Description

technical field [0001] The present invention relates to the technical field of colorectal cancer treatment, more specifically, relates to the application of metformin in the treatment of KRAS mutant colorectal cancer. Background technique [0002] Colorectal cancer (CRC) is one of the most common malignant tumors. Currently, chemotherapy based on oxaliplatin or irinotecan combined with anti-epidermal growth factor receptor (EGFR) monoclonal antibody can increase the median overall survival time of colorectal cancer patients to more than 2 years . However, about 1 / 4 of the patients in China have already developed tumor metastasis at the time of diagnosis, and the effect of chemotherapy is not good. In addition, colorectal cancer is a genetically heterogeneous disease. Changes (mutation or deletion) in genes such as APC, KRAS, TP53, BRAF, and PIK3CA, as well as microsatellite instability (MSI) and chromosomal instability (chromosomal instability) , CIN) and other epigenetic...

Claims

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Application Information

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IPC IPC(8): C12Q1/6886G01N33/68G01N33/574A61K31/155A61P35/00
CPCA61K31/155A61P35/00C12Q1/6886G01N33/57419G01N33/57446G01N33/68
Inventor 高国全周倜杨霞谢晋烨夏良平何文卓
Owner SUN YAT SEN UNIV
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