Ignite Creation Date:
2024-05-06 @ 4:32 PM
Last Modification Date:
2024-10-26 @ 2:11 PM
Study NCT ID:
NCT05016349
Status:
UNKNOWN
Last Update Posted:
2021-08-23
First Post:
2021-08-17
Brief Title:
Investigating the Potential Role of a Novel Quadrate Combination Therapy MifepristoneAntiprogestrone Tamoxifen Retinoic Acid and Cannabidiol Selective Cyp 26 Inhibitor for Treating Early Breast Cancer
Sponsor:
Mahmoud Ramadan mohamed Elkazzaz
Organization:
Kafrelsheikh University
Study Overview
Official Title:
Why Antiprogestrone Mifepristone and Cyp 26 Inhibitor Must be Combined With Tamoxifen or Tamoxifen and Retinoic Acid for Treating Early Breast Cancer
Status:
UNKNOWN
Status Verified Date:
2021-08
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Investigating the potential role of a novel quadrate combination therapy MifepristoneAntiprogestrone Tamoxifen Retinoic acid and Cannabidiol selective cyp 26 inhibitor for treating early breast cancer
Breast cancer is the main cause of mortality among women The disease presents high recurrence mainly due to incomplete efficacy of primary treatment in killing all cancer cells Therapy resistance remains a major problem in estrogen receptor-α ERα-positive breast cancer Half of estrogen receptor-positive breast cancers contain a subpopulation of cytokeratin 5 CK5-expressing cells that are therapy resistant and exhibit increased cancer stem cell CSC properties Here we propose a testable hypothesis that treatment of breast cancer with tamoxifen or retinoic acid or a combination of the two may result in induction or conversion of some ER-positive breast cancer cells to ER-negative cancer cells expressing the basal cytokeratin-5 CK5 via stimulation of progesterone receptors effect and production Therefore we raised an issue with the answer Why Antiprogestrone such Mifepristone and cyp 26 inhibitors must be combined with Tamoxifen or its combination with retinoic acid in the era of oncology for treating early breast cancer In fact limited evidence has indicated that induction of CK5 cells in ERα breast cancer is a unique effect of progestin Prg but many studies have demonstrated that progesterone P4 increases CK5 breast cancer cells In case-cohort study of 405 incident breast cancer cases elevated circulating progesterone levels were associated with a 16 increase in the risk of breast cancer A study demonstrated that tamoxifen induced progesterone receptors PGR in short term treatment Another study showed that High progesterone receptor expression correlates to the effect of adjuvant tamoxifen in premenopausal breast cancer patients These CK5-positive cells are therapy resistant and have increased tumor-initiating potential Also previous work has shown that retinoic acid a chemical that results from the bodys natural breakdown of vitamin A should act against these CK5 cells but clinical trials of retinoids against breast cancer have been largely unsuccessful Therefore we suggest that combination of retinoiac acid and tamoxifen was unsucssecful in treating breast cancer owing its ability to induce progesterone receptors and production leading to increasing numbers of CK5-positive cells which are therapy resistant Although retinoid fenretinide reduced the accumulation of CK5 cells during estrogen depletion A study investigated the effects of all-trans-RA atRA on progesterone production in immature rat GCs cultured without gonadotropin demonstrated that atRA enhanced progesterone production by upregulating the levels of steroidogenic acute regulatory protein StAR and cytochrome P450scc Cyp11a1 Here we suggest that tamoxifen or its combination with retinoic acid must be combined with anti-progesterone Mifepristone to achieve treatment with significant effect against early breast cancer Moreover Numerous studies have shown that CYP2D6 variant carriers around 50 CYP2D6 variant carriers in Chinese population will not benefit a lot from tamoxifen and combined use of CYP2D6 inhibitors will further affect the efficacy of tamoxifen In addition All-trans-retinoic acid acts as an inducer of CYP26A1 expression Which is the second expected cause of unsuccessful trial of Tamoxifen and retinoic acid in breast cancer treatment Furthermore The CYP26 inhibitor also induced expression of atRA-responsive genes All-trans retinoic acid ATRA significantly inhibited aromatase activity in a concentration-dependent manner in microsomes isolated from JEG-3 human placental carcinoma cells One study found that high retinol was significantly associated with reduced breast cancer risk Another found a significant trend of reduced retinol levels with more advanced disease stage A study showed that intake of vitamin A and retinol could reduce breast cancer risk Therefore we will take the benefit of cyp 26 inhibitor in this trial by combining Cannabidiol a major phytocannabinoid as a potent atypical inhibitor for CYP2D6
Breast cancer is the main cause of mortality among women The disease presents high recurrence mainly due to incomplete efficacy of primary treatment in killing all cancer cells Therapy resistance remains a major problem in estrogen receptor-α ERα-positive breast cancer Half of estrogen receptor-positive breast cancers contain a subpopulation of cytokeratin 5 CK5-expressing cells that are therapy resistant and exhibit increased cancer stem cell CSC properties Here we propose a testable hypothesis that treatment of breast cancer with tamoxifen or retinoic acid or a combination of the two may result in induction or conversion of some ER-positive breast cancer cells to ER-negative cancer cells expressing the basal cytokeratin-5 CK5 via stimulation of progesterone receptors effect and production Therefore we raised an issue with the answer Why Antiprogestrone such Mifepristone and cyp 26 inhibitors must be combined with Tamoxifen or its combination with retinoic acid in the era of oncology for treating early breast cancer In fact limited evidence has indicated that induction of CK5 cells in ERα breast cancer is a unique effect of progestin Prg but many studies have demonstrated that progesterone P4 increases CK5 breast cancer cells In case-cohort study of 405 incident breast cancer cases elevated circulating progesterone levels were associated with a 16 increase in the risk of breast cancer A study demonstrated that tamoxifen induced progesterone receptors PGR in short term treatment Another study showed that High progesterone receptor expression correlates to the effect of adjuvant tamoxifen in premenopausal breast cancer patients These CK5-positive cells are therapy resistant and have increased tumor-initiating potential Also previous work has shown that retinoic acid a chemical that results from the bodys natural breakdown of vitamin A should act against these CK5 cells but clinical trials of retinoids against breast cancer have been largely unsuccessful Therefore we suggest that combination of retinoiac acid and tamoxifen was unsucssecful in treating breast cancer owing its ability to induce progesterone receptors and production leading to increasing numbers of CK5-positive cells which are therapy resistant Although retinoid fenretinide reduced the accumulation of CK5 cells during estrogen depletion A study investigated the effects of all-trans-RA atRA on progesterone production in immature rat GCs cultured without gonadotropin demonstrated that atRA enhanced progesterone production by upregulating the levels of steroidogenic acute regulatory protein StAR and cytochrome P450scc Cyp11a1 Here we suggest that tamoxifen or its combination with retinoic acid must be combined with anti-progesterone Mifepristone to achieve treatment with significant effect against early breast cancer Moreover Numerous studies have shown that CYP2D6 variant carriers around 50 CYP2D6 variant carriers in Chinese population will not benefit a lot from tamoxifen and combined use of CYP2D6 inhibitors will further affect the efficacy of tamoxifen In addition All-trans-retinoic acid acts as an inducer of CYP26A1 expression Which is the second expected cause of unsuccessful trial of Tamoxifen and retinoic acid in breast cancer treatment Furthermore The CYP26 inhibitor also induced expression of atRA-responsive genes All-trans retinoic acid ATRA significantly inhibited aromatase activity in a concentration-dependent manner in microsomes isolated from JEG-3 human placental carcinoma cells One study found that high retinol was significantly associated with reduced breast cancer risk Another found a significant trend of reduced retinol levels with more advanced disease stage A study showed that intake of vitamin A and retinol could reduce breast cancer risk Therefore we will take the benefit of cyp 26 inhibitor in this trial by combining Cannabidiol a major phytocannabinoid as a potent atypical inhibitor for CYP2D6
Detailed Description:
The study is a randomized interventional comparative Phase II trial which will Investigating and test the safety and effectiveness of a Novel Quadrate Combination Therapy MifepristoneAntiprogestrone Tamoxifen Retinoic Acid and Cannabidiol Selective Cyp 26 Inhibitor to learn whether this novel combination therapy works in treating Treating Early Breast Cancer The primary objective of the study is to 1 evaluate the anti-tumor activity of this combination therapy within the context of a phase II study Other objectives are 2 to determine the effect of this novel combination therapy on cytokeratin 5 CK5-expressing cells3 and to determine the expression of CK5 biomarkers of breast carcinogenesis before and after treatment160 adult female patients with breast cancer and fulfilling the below outlined inclusion criteria will be enrolled into the study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None