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Combination of JNK inhibitor and TGF beta inhibitor

A technology of β inhibitors and inhibitors, applied in the field of combined use of NK inhibitors and TGFβ inhibitors, can solve the problems of dependence, failure to meet the clinical needs of patients with multiple target organ metastasis risks, and patient harm

Inactive Publication Date: 2018-11-13
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Past studies identified several associated genes specific to bone or lung metastases 1-3 , but the specific associated genes targeting only a single target organ still cannot meet the clinical needs of simultaneously predicting the risk of metastasis in patients with multiple target organs
Moreover, even if these genes are used as biological markers, they mostly rely on invasive detection methods such as puncture, which are likely to cause additional harm to patients
[0003] In addition, although there were some drug regimens for the treatment of organ-specific metastases in the past, they only targeted a single target organ.

Method used

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  • Combination of JNK inhibitor and TGF beta inhibitor
  • Combination of JNK inhibitor and TGF beta inhibitor
  • Combination of JNK inhibitor and TGF beta inhibitor

Examples

Experimental program
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Effect test

Embodiment 1

[0321] Expression patterns of DKK1 in breast cancer samples

[0322] Through the enzyme-linked immunosorbent assay (ELISA) of the patient's serum, it was found that the serum DKK1 protein level of breast cancer patients in the bone metastasis group was significantly higher than that of the control group without metastasis, while the DKK1 protein level of patients in the lung metastasis group was significantly lower than that of the control group ( figure 1 a). Moreover, the lung metastasis-free survival rate of patients in the high serum DKK1 group was significantly higher than that in the low DKK1 group, and the opposite was true in the bone metastasis-free survival rate ( figure 1 b). Previous studies have almost never reported biomarkers similar to DKK1 with opposite expression patterns in different tissue-specific metastases, indicating that DKK1 has the potential to become a new class of biomarkers that simultaneously predict bone and lung metastases in breast cancer. P...

Embodiment 2

[0326] Functional study of DKK1 in group-specific metastasis of breast cancer

[0327] To test whether DKK1 is functional in breast cancer tissue-specific metastasis, DKK1 was overexpressed in the luciferase-labeled MDA-MB-231 breast cancer cell line (obtained from Joan Massague's lab), and the cells were passed through tail Intravenous and left atrium injection into immunodeficient mice (purchased from Shanghai Slack Experimental Animal Co., Ltd.), through the injection of luciferase substrate, the light signal corresponding to the transfer load can be observed. Consistent with clinical relevance, light signaling from tumor cells revealed that overexpressed DKK1 significantly suppressed breast cancer lung metastasis and significantly enhanced bone metastasis ( figure 1 c, d, e).

Embodiment 3

[0329] Mechanism of action of DKK1

[0330] DKK1 is an inhibitory protein of the canonical WNT signaling pathway. The study of the present invention found that DKK1 regulates the recruitment and important cytokines of microenvironmental cells (macrophages and myeloid-derived immunosuppressive cells, MDSC) in lung metastases through non-canonical WNT signaling pathways—JNK and NF-κB pathways. TGFβ secretion affects the growth of lung metastases. DKK1 can inhibit the phosphorylation level of the transcriptional regulator JUN downstream of the JNK pathway, thereby reducing its transcriptional activity, resulting in a decrease in the expression of downstream genes, and inhibiting the ability of tumor cells to produce factors that attract macrophages / MDSCs ( figure 2 a); at the same time, DKK1 can also inhibit the phosphorylation level of RELA, an important transcriptional regulator of the NF-κB pathway, thereby reducing the secretion of downstream TGFβ ( figure 2 b), jointly i...

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Abstract

The invention provides combination of a JNK inhibitor and a TGF beta inhibitor. Concretely, the invention provides a product combination including a first pharmaceutical composition (i). The first pharmaceutical composition contains first activity components (a). The first active components are the JNK inhibitor and a pharmaceutically acceptable carrier. The product combination also includes a second pharmaceutical composition (ii). The second pharmaceutical composition contains second activity components (b). The second active components are the TGF beta inhibitor and a pharmaceutically acceptable carrier. The first pharmaceutical composition and the second pharmaceutical composition are different pharmaceutical compositions or the same pharmaceutical composition. The product of the invention also includes a DKK1 molecular detection reagent (iii). The invention also provides a medicine box. The product combination and medicine box can reduce the risk of bone metastasis and lung metastasis in breast cancer.

Description

technical field [0001] The invention relates to the field of biomedicine. More specifically, the present invention relates to combinations of NK inhibitors and TGFβ inhibitors. Background technique [0002] Distant metastasis of breast cancer is the main cause of breast cancer treatment failure and patient death. The main distant metastatic target organs of breast cancer are bone and lung. An important clinical phenomenon is that the metastasis of breast cancer is organ-specific, that is, tumor cells that invade and migrate from tumor in situ in some patients are prone to bone metastasis, while other patients are prone to lung metastasis. Therefore, the development of biomarkers specific to metastatic organs plays an important role in predicting patients' risk of metastasis and determining treatment options. Past studies identified several associated genes specific to bone or lung metastases 1-3 , but the specific associated genes targeting only a single target organ sti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61P35/04
CPCA61K45/06
Inventor 胡国宏壮雪倩
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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