Drug composition for treating B cell lymphoma

A composition and B cell technology, which can be used in drug combinations, anti-tumor drugs, active ingredients of heterocyclic compounds, etc., and can solve problems such as low success rate, death, and patient recurrence.

Active Publication Date: 2018-11-06
FUDAN UNIV SHANGHAI CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although more than half of DLBLC patients can be cured by R-CHOP (rituximab / R, cyclophosphamide / C, doxorubicin / H, vincristine / O, and prednisone / P) regimen, many Up to one third of patients eventually relapse
The remaining treatment options for these patients, including high-dose chemotherapy and autologous stem cell transplantation, are extremely limited, with very low success rates and ultimately death

Method used

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  • Drug composition for treating B cell lymphoma
  • Drug composition for treating B cell lymphoma
  • Drug composition for treating B cell lymphoma

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] Example 1 SOX2 regulates the drug resistance of stem cell-like drug-resistant DLBCL cells

[0128] Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) are the main mechanisms for the therapeutic effect of rituximab. Resistance to ADCC may arise from intrinsic characteristics of the individual patient's immune cells; whereas resistance to CDC results from low expression levels of CD20 and / or high expression levels of membrane-bound complement regulatory proteins (mCRP) (including CD46, CD55 and especially CD59) mediated. CHO chemotherapeutics inhibit tumor cell replication by inducing DNA damage or binding to tubulin, and cyclophosphamide must be metabolically activated in cells to 4-hydroxycyclophosphamide (4-HC) to exert this effect. Therefore, using rituximab plus normal human serum (NHS, as a source of complement), 4-HC plus doxorubicin plus vincristine, and their combinations, we constructed drug-resistant LY8 (GCB subtype) o...

Embodiment 2

[0130] Example 2 PI3K / AKT signaling phosphorylates and thereby stabilizes SOX2 against ubiquitination-mediated degradation

[0131] We next investigated the mechanism of SOX2 upregulation in drug-resistant DLBCL cells. Unexpectedly, SOX2 mRNA levels were significantly decreased in drug-resistant cells, especially in drug-resistant LY8 cells ( Figure 15 ), suggesting that transcriptional regulation is not involved in the overexpression of SOX2. Interaction scores from KEGG pathway analysis based on RNA-seq data from naive and drug-resistant cells showed that PI3K / AKT signaling pathway and steroid biosynthesis were the most enriched pathways ( Figure 15 ). Furthermore, gene set enrichment analysis (GSEA) revealed that gene signatures of the PI3K / AKT signaling pathway were significantly activated in both RCHO-resistant cell lines ( Figure 16 ). It was confirmed experimentally that the phosphorylation of AKT(S473) increases with the degree of drug resistance, thereby enhanc...

Embodiment 3

[0132] Example 3 Multiple signaling events activate PI3K / AKT pathway in drug-resistant cells

[0133] The study of the key regulators upstream of the PI3K / AKT pathway helps to find potential drug targets that can reduce the expression of SOX2. Therefore, we identified 124 upregulated genes in the PK3K / AKT pathway ( Figure 16 ) and classify them according to cell subtype ( Figure 22 ). Due to the limited number of overlapping genes (only 18) in the two cell subtypes, we used all 124 genes for KEGG pathway analysis. Figure 23 The top 10 pathways are listed, and the PI3K / AKT pathway is ranked first. PI3Kα / β isoforms are widely expressed, while PI3Kγ / δ isoforms are only expressed in hematopoietic cells, in which PI3Kδ plays a key role in the development and function of B cells, and in B cell malignancies through the expression of BCR and other The receptor remains hyperactive at all times for signaling to various integrins and cytokines / chemokines. Consistently, we found t...

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Abstract

The invention discloses a drug composition for treating B cell lymphoma. The drug composition comprises a PI3K/AKT signal pathway inhibitor and a chemotherapeutic drug, and further comprises targetedCD20 infliximab, such as rituximab. The drug composition provided by the invention is especially suitable for treating relapsed or refractory B cell lymphoma. In view of the key effect of a CSC (cancer stem cell) in the transferring and drug resisting process, the invention provides a new pro-differentiation therapy strategy for the CSC, that is, a decisive signal conduction pathway for maintaining the dryness of the stem cell is determined, and then the pathway is interfered to promote CSC differentiation. The differentiation cell is finally sensitive to a routine treatment method (such as chemotherapy). Under the condition, the PI3K/AKT signal pathway inhibitor is combined with an R-CHOP scheme to exert a good effect of treating drug-resisting DLBCL (diffuse large B cell lymphoma).

Description

technical field [0001] The invention relates to a pharmaceutical composition for treating B-cell lymphoma, in particular to a pharmaceutical composition for treating relapsed / refractory B-cell lymphoma. Background technique [0002] The problem of drug resistance has always been a major problem in cancer treatment. This acquired drug resistance is at least partially derived from the heterogeneity of cell types within the tumor, including a variety of fast-growing differentiated cancer cells and a very small number of slow-growing cancer stem cells. (Cancer Stem Cell, CSC). Although traditional cancer treatments, such as radiotherapy and chemotherapy, can eliminate most of the differentiated cells in tumors, cancer stem cells still survive, which may be an important reason for promoting the development of drug resistance. CSCs were initially discovered in leukemias in a very low proportion, but they can seed new tumors, which were further confirmed in solid tumors. CSCs hav...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K39/395A61P35/00
CPCA61K39/395A61K45/06A61P35/00A61K2300/00C07K16/2887A61K2039/505A61K39/3955A61P35/02A61K31/52A61K31/675A61K31/704A61K31/475A61K31/496
Inventor 胡维国陈剑锋
Owner FUDAN UNIV SHANGHAI CANCER CENT
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