A novel combination targeted drug for the treatment of relapsed/refractory T-cell lymphoma

A lymphoma and cell technology, applied in the field of medicine, can solve the problems of differences in curative effects that need to be deepened, and achieve the effect of improving the current situation of clinical treatment and increasing the survival rate

Active Publication Date: 2022-04-29
SUN YAT SEN UNIV CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Since HDAC inhibitors are a new class of anti-tumor drugs, the specific mechanism of action, such as the difference in efficacy between different types of the same type of tumors, and the formation mechanism of acquired drug resistance, etc. still need to be further studied.

Method used

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  • A novel combination targeted drug for the treatment of relapsed/refractory T-cell lymphoma
  • A novel combination targeted drug for the treatment of relapsed/refractory T-cell lymphoma
  • A novel combination targeted drug for the treatment of relapsed/refractory T-cell lymphoma

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 evaluates the therapeutic effect of Chidamide on NKTL

[0048] 1. Our team recruited 20 NKTL patients and conducted clinical trials using Chidamide.

[0049] In order to evaluate the efficacy of chidamide in the treatment of relapsed and refractory NKTL patients, we enrolled 20 relapsed and refractory NKTL patients in Sun Yat-sen University Cancer Center (SYSUCC) from August 2016 to April 2018. Phase II prospective clinical trial. Refractory was defined as not achieving PR or CR according to the evaluation criteria for malignant lymphoma (Lugano2014 criteria) after at least two cycles of chemotherapy. Relapsed and refractory NKTL patients aged 18-75 who received asparaginase-based chemotherapy or radiotherapy and chemotherapy, ECOG score ≤ 2, normal organ and bone marrow function, no serious hematopoietic function, cardiac , lung, liver, kidney, and thyroid dysfunction, and at least one measurable or assessable lesion is eligible for inclusion. Patients wit...

Embodiment 2

[0055] Example 2 Study on the killing effect of HDAC inhibitors such as chidamide on NKTL cells

[0056] 1. Our team detected the IC50 of Chidamide in 11 NKTL cell lines, and treated the 11 NKTL cells with three HDAC inhibitors Chidamide, TrichostatinA (TSA), and SAHA, and evaluated the cells by ATP detection On this basis, two sensitive and two drug-resistant NKTL cell lines were selected for follow-up research. The killing effect of chidamide on NKTL cells was further demonstrated through cell viability detection, cell cycle and cell apoptosis experiments.

[0057] NKTL cell line sources: HANK1 and YT were provided by Dr. Yoshitoyo Kagami and Dr. C. Clayberger, respectively. SNK6, SNT8, SNK1 and NKYS were provided by Dr. Norio Shimizu. MEC04 was provided by Dr. Paul Coppo and Dr. Philippe Gaulard. KHYG1 and KAI-3 were purchased from JCRB Cell Bank, NK92 was purchased from ATCC, and NK-S1 was constructed from one NKTCL xenograft.

[0058] Cell viability assay: Luminesce...

Embodiment 3

[0085] Example 3 Perform chromatin immunoprecipitation sequencing and transcriptome sequencing on chidamide-resistant and sensitive NKTL cells, respectively

[0086] 1. Experimental method

[0087] H3K27ac is a marker of enhancer. Our team used two strains of sensitive and two strains of drug-resistant NKTL cells for H3K27ac ChIP-seq analysis, in order to analyze the chromatin in the state of tolerance to Chidamide. Gains and losses, and further combining RNA-seq and ChIP-seq data, identified signaling pathways enriched in chidamide-resistant states.

[0088] NKTL cell line source: KHYG1 was purchased from JCRB cell bank. MEC04 was provided by Dr. Paul Coppo and Dr. Philippe Gaulard. HANK1 was provided by Dr. Yoshitoyo Kagami. SNK6 was provided by Dr. Norio Shimizu.

[0089] Chromatin immunoprecipitation sequencing (Chip-seq): cells were collected, cross-linked with 1% formaldehyde for 10 min, and cross-linked with glycine. Centrifuge, wash the cells 3 times with TBSE, re...

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Abstract

The invention discloses a new combined targeted drug scheme for treating relapsed / refractory T-cell lymphoma. Firstly, the study proposed that TNFRSF8 (CD30), a downstream target of the JAK‑STAT signaling pathway, can be used as a biomarker to predict the sensitivity of NK / T cell lymphoma patients to HDAC inhibitors, and based on this, patients can be grouped before HDAC inhibitors treatment to maximize patient benefit. And further research on targets that can overcome drug resistance to HDAC inhibitors and the corresponding combination regimen, that is, the combination of JAK‑STAT signaling pathway inhibitors and HDAC inhibitors, which can remodel cellular chromatin to be sensitive to HDAC inhibitors status, thereby reversing drug resistance and enabling effective treatment of patients who cannot benefit from HDAC inhibitor therapy. The present invention helps to provide a personalized and precise treatment plan for T-cell lymphoma, improves the survival rate of patients, and is useful in promoting HDAC inhibitors in the treatment of relapsed / refractory T-cell lymphoma and improving the current situation of clinical treatment of T-cell lymphoma. important meaning.

Description

technical field [0001] The invention belongs to the technical field of medicine. More specifically, it relates to a novel combined targeted drug for the treatment of relapsed / refractory T-cell lymphoma. Background technique [0002] T-cell lymphoma is a highly heterogeneous and aggressive non-Hodgkin's lymphoma, including NK / T cell lymphoma (NK / T cell lymphoma, NKTL), peripheral T-cell lymphoma (Peripheral T-Cell Lymphoma, PTCL) and skin T-cell lymphoma (Cutaneous T-cell Lymphoma, CTCL), etc. Among them, NK / T cell lymphoma is a malignant tumor of the lymphatic system originating from mature NK / T cells. NK cells and T cells have a common progenitor cell, and the two have similarities in function and expression of certain antigens. NK / T cell lymphoma is named because it originates from these two cells. Similar to other types of lymphoma, progressive painless lymphadenopathy is the most common clinical presentation. The nasal cavity is the most common extra-nodal primary si...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/06A61K31/4406A61K39/395A61K31/167A61K31/165A61K31/519A61P35/00
CPCA61K45/06A61K31/4406A61K39/39558A61K31/167A61K31/165A61K31/519A61P35/00A61K2300/00
Inventor 谭静黄慧强陈竞红
Owner SUN YAT SEN UNIV CANCER CENT
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