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Method for predicting anti-cancer efficacy of compound targeting apoptosis pathway and composition

A biomarker, cancer technology, applied in the field of cancer treatment

Pending Publication Date: 2021-05-28
ASCENTAGE PHARMA SUZHOU CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, identification of predictive biomarkers capable of predicting response to anticancer therapies remains a challenge

Method used

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  • Method for predicting anti-cancer efficacy of compound targeting apoptosis pathway and composition
  • Method for predicting anti-cancer efficacy of compound targeting apoptosis pathway and composition
  • Method for predicting anti-cancer efficacy of compound targeting apoptosis pathway and composition

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0476] This example shows the correlation between Noxa expression and compound efficacy of compound A15 in gastric cancer PDX model and esophageal cancer PDX model.

[0477] Materials and Methods

[0478] 12 PDX models of gastric cancer and 4 PDX models of esophageal cancer were selected for efficacy study. Mice bearing patient-derived xenografts (PDX) were randomly assigned to 2 different study groups according to their tumor volume. The average tumor volume at randomization was 100-200mm 3 . On Day 1, randomization was performed based on the "Matched distribution" randomization method (StudyDirector™ software). Mice were administered vehicle or compound A15 for 21 days (iv, twice a week).

[0479] Tumor volume was measured in two dimensions using calipers twice a week and expressed in mm3 using the following formula: tumor volume (mm3) = 0.5a x b2 (where a and b are the long and short diameters of the tumor, respectively). Relative tumor volume (RTV) was calculated us...

example 2

[0486] This study shows that compound B4 is more dependent on Bcl-xL than on Bcl-2 to function as a dual Bcl-2 / Bcl-xL inhibitor.

[0487] ABT-737 (IUPAC name: 4-{4-[(4'-chloro-2-biphenyl)methyl]-1-piperazinyl}-N-[(4-{[(2R)-4- (Dimethylamino)-1-(phenylsulfanyl)-2-butyl]amino}-3-nitrophenyl)sulfonyl]benzamide) was developed by Abbott Laboratories (now One of the first BH3 mimics developed by Abbvie. It acts as a dual BCl-2 / Bcl-xL inhibitor and promotes tumor cell apoptosis. This study compared the binding of Bcl-2 and BCl-xL between compound B4 or ABT-737.

[0488] The diffuse large B-cell lymphoma line Toledo and the acute lymphoblastic leukemia line RS4;11 were chosen for this study. Cells were treated with Compound B4 or ABT-737 at the indicated concentrations (0.025uM, 0.04uM and 0.06uM, respectively) for 24 hours and harvested for complex analysis. Both Bcl-2:BIM and Bcl-xL:BIM complexes were analyzed using the MSD advanced ELISA method.

[0489] The results show that ...

example 3

[0492] This study shows the antitumor activity of compound A15 in ASCL-1-high and Noxa-high SCLC PDX models.

[0493] SCLC is a heterogeneous disease with an extremely high mutation rate but lacks identified driver oncogenes for molecularly targeted therapies. It is currently treated in the clinic as a single disease entity. Recent studies have improved our understanding of SCLC and characterized distinct subtypes based on mutually exclusive expression of ASCL1, NEUROD1, POU2F3, or YAP1 (Rudin et al., 2019). SCLC expressing ASCL1 is the most common subtype, accounting for 70% of cases.

[0494] Noxa expression levels were obtained from 58 commercially available PDX models of SCLC (PDX models available from Crownbio). The Noxa expression levels of these 58 PDX models have been determined by RNA-sequencing and plotted in Figure 5A , where each point represents a PDX model. Based on RNA-sequencing data, Noxa expression levels ranged from below 2 to above 6 (expressed by Log2...

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Abstract

The invention relates to a biomarker for predicting the efficacy of an MDM2 inhibitor or a Bcl-2 / Bcl-xL dual inhibitor or a Bcl-2 inhibitor or a Bcl-xL inhibitor in the treatment of a cancer patient. The invention also provides a composition, e.g. a kit, for assessing the gene levels of biomarkers, and a method for using such gene levels to predict the response of a cancer patient to the MDM2 inhibitor or the Bcl-2 / Bcl-xL dual inhibitor or the Bcl-2 inhibitor or the Bcl-xL inhibitor. The information can be used to determine prognosis and treatment selection for cancer patients.

Description

technical field [0001] The present invention relates generally to cancer treatment. Background technique [0002] Evasion of apoptosis is a hallmark of human cancer and is a common cause of therapy resistance (Hanahan D et al, Cell [cell] (2000) 100:57-70; Delbridge AR et al, Cold Spring Harb Perspect Biol Perspectives in Biology] (2012) 4). Therefore, targeting key apoptotic players in human cancers is an attractive new strategy for the development of entirely new classes of anticancer therapies. [0003] Clinical response to anticancer therapy is usually limited to a subset of patients. To maximize the efficiency of anticancer therapies, molecular biomarker-based personalized chemotherapy has been proposed. However, the identification of predictive biomarkers capable of predicting response to anticancer therapies remains a challenge. Therefore, there is a continuing need to develop biomarkers for predicting the anticancer efficacy of compounds targeting apoptotic pathw...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6886G01N33/574C07F9/6509C07D471/04C07D487/10A61P35/00
CPCC12Q1/6886G01N33/57488G01N33/57484C07F9/650952C07D471/04C07D487/10A61P35/00C12Q2600/106C12Q2600/158A61K31/407A61K31/496C07D401/12C07D471/20C07D403/12C07D211/62G01N2800/52G01N33/57496G01N2333/4703A61K45/06A61K2300/00A61K31/519
Inventor 翟一帆杨大俊方东陶然
Owner ASCENTAGE PHARMA SUZHOU CO LTD
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