MDV3100
Encyclopedia
MDV3100 is an experimental androgen receptor
antagonist drug developed by the pharmaceutical company Medivation for the treatment of castration-resistant prostate cancer
currently in Phase 3 clinical trials. Results so far have been encouraging; Medivation has reported up to an 89% decrease in prostate specific antigen
serum levels after a month of taking the medicine. Early preclinical studies also suggest that MDV3100 inhibits breast cancer
cell growth.
who is now at Memorial Sloan–Kettering Cancer Center and Michael Jung
at UCLA
.
. As opposed to bicalutamide, MDV3100 does not promote translocation
of AR to the nucleus and in addition prevents binding of AR to DNA and AR to coactivator
proteins.
When LNCaP
cells (a prostate cancer cell line) engineered to express elevated levels of AR (as found in patients with advanced prostate cancer) were treated with MDV3100, the expression of androgen dependent genes PSA
and TMPRSS2
was down regulated in contrast to bicalutamide where the expression was upregulated. In VCaP cells which over express androgen receptors, MDV3100 induced apoptosis
whereas bicalutamide did not. Furthermore MDV3100 behaves as an antagonist of the W741C mutant androgen receptor in contrast to bicalutamide which behaves as a pure agonist when bound to the W741C mutant.
Medivation is conducting an international phase III trial that began in September 2009 known as AFFIRM. The trial will determine the effectiveness of MDV3100 in patients who have previously failed chemotherapy treatment with docetaxel. In November 2011, this trial was halted after an interim analysis revealed that patients given the drug lived for approximately 5 months longer than those taking placebo. Medivation is expected to file for FDA approval sometime in 2012.
There is another phase III trial, known as PREVAIL, that is investigating the effectiveness of MDV3100 with patients who have not yet received chemotherapy. As of October 2011, this trial is still open to accrual. In addition, a phase II trial began in March 2011 comparing MDV3100 with a commonly used anti-androgen, bicalutamide, in prostate cancer patients who have progressed while on LHRH
analogue therapy (e,g., leuprorelin) or surgical castration.
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
antagonist drug developed by the pharmaceutical company Medivation for the treatment of castration-resistant prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
currently in Phase 3 clinical trials. Results so far have been encouraging; Medivation has reported up to an 89% decrease in prostate specific antigen
Prostate specific antigen
Prostate-specific antigen also known as gamma-seminoprotein or kallikrein-3 is a glycoprotein that in humans is encoded by the KLK3 gene. KLK3 is a member of the kallikrein-related peptidase family that are secreted by the epithelial cells of the prostate gland...
serum levels after a month of taking the medicine. Early preclinical studies also suggest that MDV3100 inhibits breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
cell growth.
Discovery
MDV3100 was discovered by Charles SawyersCharles Sawyers
Charles L. Sawyers is an investigator of the Howard Hughes Medical Institute and a physician-scientist at Memorial Sloan-Kettering Cancer Center. His work in the lab builds on the success of molecularly targeted cancer drugs with a focus on developing a new generation of treatment options for...
who is now at Memorial Sloan–Kettering Cancer Center and Michael Jung
Michael E. Jung
Michael E. Jung is Professor of Chemistry in the Department of Chemistry and Biochemistry at the University of California at Los Angeles.Michael Jung was born May 14, 1947 in New Orleans, Louisiana. He received a B.A. from Rice University in Houston, Texas in 1969 and a Ph.D. from Columbia...
at UCLA
University of California, Los Angeles
The University of California, Los Angeles is a public research university located in the Westwood neighborhood of Los Angeles, California, USA. It was founded in 1919 as the "Southern Branch" of the University of California and is the second oldest of the ten campuses...
.
Preclinical pharmacology
MDV3100 has approximately fivefold higher binding affinity for the androgen receptor (AR) compared to the antiandrogen bicalutamideBicalutamide
Bicalutamide is an oral non-steroidal anti-androgen used in the treatment of prostate cancer and hirsutism...
. As opposed to bicalutamide, MDV3100 does not promote translocation
Protein targeting
Protein targeting or protein sorting is the mechanism by which a cell transports proteins to the appropriate positions in the cell or outside of it. Sorting targets can be the inner space of an organelle, any of several interior membranes, the cell's outer membrane, or its exterior via secretion...
of AR to the nucleus and in addition prevents binding of AR to DNA and AR to coactivator
Coactivator (genetics)
A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
proteins.
When LNCaP
Lncap
LNCaP cells are a cell line of human cells commonly used in the field of oncology. LNCaP cells are androgen-sensitive human prostate adenocarcinoma cells derived from the left supraclavicular lymph node metastasis from a 50-year-old caucasian male in 1977...
cells (a prostate cancer cell line) engineered to express elevated levels of AR (as found in patients with advanced prostate cancer) were treated with MDV3100, the expression of androgen dependent genes PSA
Prostate specific antigen
Prostate-specific antigen also known as gamma-seminoprotein or kallikrein-3 is a glycoprotein that in humans is encoded by the KLK3 gene. KLK3 is a member of the kallikrein-related peptidase family that are secreted by the epithelial cells of the prostate gland...
and TMPRSS2
TMPRSS2
Transmembrane protease, serine 2 is an enzyme that in humans is encoded by the TMPRSS2 gene.-ERG Gene Fusion:TMPRSS2 protein's function in prostate carcinogenesis relies on overexpression of ETS transcription factors, such as ERG and ETV1 through gene fusion. TMPRSS2-ERG fusion gene is the most...
was down regulated in contrast to bicalutamide where the expression was upregulated. In VCaP cells which over express androgen receptors, MDV3100 induced apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
whereas bicalutamide did not. Furthermore MDV3100 behaves as an antagonist of the W741C mutant androgen receptor in contrast to bicalutamide which behaves as a pure agonist when bound to the W741C mutant.
Clinical studies
MDV 3100 was found clinically active for metastatic castration-resistant prostate cancer patients in ongoing phase I and II trials. PSA level decreased more than 50 percent in 40/65 chemo-naive patients and 38/75 chemotherapy-trated patients. Recent long-term follow up data from these early clinical studies, announced in February 2011, were positive. Median time to radiographic progression was 56 weeks for chemo-naive patients and 25 weeks for the post-chemotherapy population.Medivation is conducting an international phase III trial that began in September 2009 known as AFFIRM. The trial will determine the effectiveness of MDV3100 in patients who have previously failed chemotherapy treatment with docetaxel. In November 2011, this trial was halted after an interim analysis revealed that patients given the drug lived for approximately 5 months longer than those taking placebo. Medivation is expected to file for FDA approval sometime in 2012.
There is another phase III trial, known as PREVAIL, that is investigating the effectiveness of MDV3100 with patients who have not yet received chemotherapy. As of October 2011, this trial is still open to accrual. In addition, a phase II trial began in March 2011 comparing MDV3100 with a commonly used anti-androgen, bicalutamide, in prostate cancer patients who have progressed while on LHRH
Gonadotropin-releasing hormone
Gonadotropin-releasing hormone , also known as Luteinizing-hormone-releasing hormone and luliberin, is a tropic peptide hormone responsible for the release of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary. GnRH is synthesized and released from neurons within...
analogue therapy (e,g., leuprorelin) or surgical castration.
See also
- AbirateroneAbirateroneAbiraterone is a drug used in castration-resistant prostate cancer . It is formulated as the prodrug abiraterone acetate and sold under the trade name Zytiga...
- ARN-509, another 2nd generation anti-androgen currently in early clinical trials for treatment of castration resistant prostate cancer.
- GaleteroneGaleteroneGaleterone also known as TOK-001 or VN/124-1 is drug that being developed by Tokai Pharmaceuticals, Inc. for the treatment of prostate cancer. It is both an androgen receptor antagonist and CYP17A1 inhibitor. It is currently being tested in early phase I/II clinical trials for castration resistant...