Methods for overcoming glucocorticoid resistance and for determining glucocorticoid resistance potential in cancer
Patent Number: US20160230173
Executive Summary:
General Description:
Physiologically glucocorticoids are steroid hormones that are involved in numerous biological processes including inflammation, immunity and metabolism. They exert their effects via glucocorticoid receptors which once activated translocate to the nucleus and induce apoptotic cell death through transcriptional changes. Synthetic glucocorticoids are a key component in the treatment of acute lymphoblastic leukemia with 5 year survival rates above 85%. However, in instances where leukemia cells are resistant to glucocorticoids patient have a poor prognosis.
To tackle this the researchers involved with patent US20160230173 have identified a method for overcoming any resistance to glucocorticoids that a cancer cell may possess. They specifically found that in primary leukemia cells taken from 444 patients that were resistant to glucocorticoid based therapy, the levels of two pro-inflammatory genes CASP1 and its activator NLRP3 were elevated. Additionally, the promoter region of these genes showed significantly lower methylation providing a likely explanation for the increased expression. CASP1 and NLRP3 confer resistance by cleaving and thereby inactivation glucocorticoid receptors thereby eliminating the route through which synthetic glucocorticoids exert their effects.
Patent US20160230173 details methods for inhibiting CASP1 and NLRP3 activity in order to overcome glucocorticoid resistance. It additionally outlines methods for diagnosing which individuals display glucocorticoid resistance by measuring expression levels of both CASP1 and NLRP3 as well as the methylation status of their respective promoters.
Strengths:
Weaknesses:
Patent Status:
Inventor Bio: William E. Evans
https://www.stjude.org/directory/e/william-evans.html
Executive Summary:
- Invention Type: Diagnostic/Therapeutic
- Patent Status: Issued on 2012-06-26
- Patent Link: https://patents.google.com/patent/US20160230173/
- Research Institute: St. Jude Children's Research Hospital
- Disease Focus: Acute Lymphoblastic Leukemia (ALL) and other glucocorticoid resistant diseases
- Basis of Invention: A novel therapeutic target to treat glucocorticoid resistant cases of ALL and other diseases where glucocorticoid resistance hinders treatment. The invention may also be used as a predictive biomarker to determine response to glucocorticoid therapy
- How it works: Glucocorticoid resistance is overcome in cancer cells by inhibiting CASP1 (caspase-1), a pro-inflammatory gene that cleaves and inactivates glucocorticoid receptors. In glucocorticoid resistant leukemia cells, CASP1 expression and that of its activating gene NLRP3 are elevated explaining the decreased effectiveness of glucocorticoid based therapeutics. Accurate measurement of gene expression or promoter methylation levels for CASP1 and NLRP3 can be utilized to determine a patient’s response to glucocorticoid therapy
- Lead Challenge Inventor: William E. Evans
- Inventors: Steven W. Paugh, William E. Evans and Erik Bonten
- Development Stage: Lead optimization – target validated in 444 patient cell lines
- Novelty:
- Novel target for treatment of glucocorticoid resistant ALL
- Novel target for treatment of glucocorticoid resistant ALL
- Clinical Applications:
- Treatment of glucocorticoid resistant cancers particularly for ALL
- Diagnostic tool to determine effectiveness of glucocorticoid based treatment in cancer
- Could augment other inflammatory disorders where glucocorticoids are prescribed
- Treatment of glucocorticoid resistant cancers particularly for ALL
General Description:
Physiologically glucocorticoids are steroid hormones that are involved in numerous biological processes including inflammation, immunity and metabolism. They exert their effects via glucocorticoid receptors which once activated translocate to the nucleus and induce apoptotic cell death through transcriptional changes. Synthetic glucocorticoids are a key component in the treatment of acute lymphoblastic leukemia with 5 year survival rates above 85%. However, in instances where leukemia cells are resistant to glucocorticoids patient have a poor prognosis.
To tackle this the researchers involved with patent US20160230173 have identified a method for overcoming any resistance to glucocorticoids that a cancer cell may possess. They specifically found that in primary leukemia cells taken from 444 patients that were resistant to glucocorticoid based therapy, the levels of two pro-inflammatory genes CASP1 and its activator NLRP3 were elevated. Additionally, the promoter region of these genes showed significantly lower methylation providing a likely explanation for the increased expression. CASP1 and NLRP3 confer resistance by cleaving and thereby inactivation glucocorticoid receptors thereby eliminating the route through which synthetic glucocorticoids exert their effects.
Patent US20160230173 details methods for inhibiting CASP1 and NLRP3 activity in order to overcome glucocorticoid resistance. It additionally outlines methods for diagnosing which individuals display glucocorticoid resistance by measuring expression levels of both CASP1 and NLRP3 as well as the methylation status of their respective promoters.
Strengths:
- Target identified from 444 patients cell lines that display glucocorticoid resistance
Weaknesses:
- No in vivo data
- No suggested compound
Patent Status:
- Priority date: 2013-09-16
- Filing date: 2014-09-16
- Publication date: 2016-08-11
Inventor Bio: William E. Evans
https://www.stjude.org/directory/e/william-evans.html
