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Method for normalizing neutrophil to lymphocyte proportion in cancer patients by selective glucocorticoid receptor antagonists

A technology of neutrophils and receptor antagonists, applied in organic chemistry, antineoplastic drugs, pharmaceutical formulations, etc., can solve problems such as unclear influence of NLR, and achieve the goal of promoting tumor elimination, improving health, and enhancing anticancer treatment Effect

Pending Publication Date: 2022-06-21
CORCEPT THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The effect, if any, of GR antagonism on the NLR is unknown

Method used

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  • Method for normalizing neutrophil to lymphocyte proportion in cancer patients by selective glucocorticoid receptor antagonists
  • Method for normalizing neutrophil to lymphocyte proportion in cancer patients by selective glucocorticoid receptor antagonists
  • Method for normalizing neutrophil to lymphocyte proportion in cancer patients by selective glucocorticoid receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0239] The following protocol describes the assay used to measure TAT induction by dexamethasone in HepG2 cells (a human hepatocellular carcinoma cell line; ECACC, UK). At 37°C, 5% / 95% (v / v) CO 2 HepG2 cells were cultured in MEME medium supplemented with 10% (v / v) fetal calf serum, 2 mM L-glutamine and 1% (v / v) NEAA under / air. HepG2 cells were then counted and adjusted to produce 0.125 x 10 in RPMI 1640 without phenol red, 10% (v / v) charcoal-stripped FBS, 2 mM L-glutamine 6 cells / ml and seeded in 96-well sterile tissue culture microtiter plates at 25,000 cells / well in 200 μl and incubated at 37°C, 5% CO 2 Incubate for 24 hours.

[0240] Then, the growth medium was removed and replaced with test medium {RPMI 1640, no phenol red, 2 mM L-glutamine + 10 μΜ forskolin}. Test compounds were then screened against 100 nM dexamethasone challenge. Compounds were then serially half-log diluted from 10 mM stocks into 100% (v / v) dimethyl sulfoxide. Then, an 8-point semi-log dilution c...

Embodiment 2

[0245] In healthy subjects, the neutrophil-to-lymphocyte ratio (NLR) in the blood is usually below 3( Figure 7A ). However, this ratio is much higher than 3 in many cancer patients, as Figure 7A NLR values ​​are indicated for patients with solid tumors. In this example, the effect of rilacoran administration on the NLR was determined in healthy subjects and cancer patients. The results of this rilacolan administration show that rilacolan administration reduces the NLR in cancer patients and can normalize the NLR.

[0246] method:

[0247] healthy object

[0248] Healthy subjects were recruited for the NCT03508635 study of Relakolan. Dosing and analysis of single and multiple ascending dose cohorts (SAD and MAD) as figure 1 The figure shows the dosing and assessment schedule for healthy subjects in this study, as described in . figure 1 Part (A) of the study shows the single ascending dose (SAD) prednisone challenge design of the study. figure 1 Part (B) of the stud...

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Abstract

Disclosed herein is a method of treating a cancer patient having a neutrophil to lymphocyte ratio (NLR) greater than 3, comprising administering to such cancer patient a non-steroid glucocorticoid receptor antagonist (GRA) effective to reduce NLR in the patient. Methods include administering non-steroid GRA and anti-cancer treatments to such cancer patients that are effective to reduce NLR in the patient and enhance treatment in the cancer patient. The GRA may be administered orally. The non-steroid GRA may be a non-steroid compound comprising a heteroaryl ketone fused aza-decalin structure (such as relacolan) or an octahydro fused aza-decalin structure (such as acicolan). The anti-cancer treatment may include chemotherapy, immunotherapy, radiotherapy, administration of an anti-angiogenic agent, administration of a growth factor inhibitor, surgery. The method can enhance anti-cancer treatment, improve prognosis of cancer patients, improve survival rate of cancer patients, and provide beneficial clinical effects and advantages for patients.

Description

Background technique [0001] Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells. Cancer is the leading cause of death in the United States and around the world. Pathways that regulate cell division and / or cell communication are altered in cancer cells such that the role of these regulatory mechanisms in controlling and limiting cell growth is disabled or bypassed. Through successive rounds of mutation and natural selection, a group of abnormal cells, usually derived from a single mutant cell, accumulates additional mutations that provide a selective growth advantage over other cells, thereby evolving to become dominant in the population cell type. As cancer cells further evolve, some of them become locally invasive and then metastasize to tissues other than the cancer cell's tissue of origin. This property, along with the heterogeneity of tumor cell populations, makes cancer a particularly difficult disease to treat and eradic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4738A61K31/337A61K31/7068A61K45/06A61P35/00C07D471/04
CPCA61K31/337A61K31/7068A61K45/06A61P35/00C07D471/04A61K31/4745A61K31/496A61K2300/00
Inventor A·格林斯坦L·陆J·卡斯托迪欧S·舍普赫德
Owner CORCEPT THERAPEUTICS INC
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