V. Craig Jordan, CMG, OBE | |
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Born | July 25, 1947 |
Alma mater | University of Leeds |
Known for | "Father of Tamoxifen"; Research on SERMs, particularly tamoxifen and raloxifene |
Awards |
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Scientific career | |
Fields | Pharmacology, Cancer Research |
Institutions | University of Texas MD Anderson Cancer Center; University of Leeds; Ludwig Institute, Bern, Switzerland; University of Wisconsin–Madison; Northwestern University; Fox Chase Cancer Center; Georgetown University |
Virgil Craig Jordan, CMG , OBE , FMedSci , is a scientist with American and British citizenship specializing in drugs for breast cancer treatment and prevention. [1] Currently, he is Professor of Breast Medical Oncology, and Professor of Molecular and Cellular Oncology at the University of Texas MD Anderson Cancer Center, Houston, Texas. Previously, he was Scientific Director and Vice Chairman of Oncology at the Lombardi Comprehensive Cancer Center of Georgetown University. Jordan was the first to discover the breast cancer prevention properties of tamoxifen and the scientific principles for adjuvant therapy with antihormones. [2] More recently his work has branched out into the prevention of multiple diseases in women with the discovery of the drug group, selective estrogen receptor modulator (SERMs). Currently, he plans to develop a new Hormone Replacement Therapy (HRT) for post-menopausal women that prevents breast cancer and does not increase the risk of breast cancer. [3]
Jordan's paper The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women: Results from the More Randomized Trial [4] was one of the top 20 most cited papers in breast cancer research during 2003 and 2004. [5]
Born in New Braunfels, Texas, US, Jordan moved to England with his family as a child. He went to school at Moseley Hall Grammar School in Cheshire before attending the University of Leeds where he received BSc, PhD and DSc degrees in pharmacology.
Jordan began working on the structure-activity of anti-estrogens as part of his PhD program at Leeds University. During that time, he met Arthur Walpole, the patent holder for the drug that became tamoxifen.
In September 1972, Jordan became a visiting scientist at the Worcester Foundation for Experimental Biology, Massachusetts. While there he began researching the idea that tamoxifen, a selective estrogen receptor modulator (SERM), could block estrogen receptors in breast tumors. Estrogen receptors in breast tumors attract estrogen which is then absorbed into the cancerous cell and encourages the cell to divide, causing the cancer to grow. Until this time, the treatment for this type of breast cancer was oophorectomy.
Jordan returned to Leeds University as a lecturer in Pharmacology between 1974 and 1979, after which he spent one year at Ludwig Institute for Cancer Research at the University of Bern, Switzerland.
In 1980, Jordan joined the University of Wisconsin–Madison where he started to look at the effects of tamoxifen and another SERM, raloxifene, on bone density and coronary systems. This was needed because of the concern that long term use of SERMs could lead to osteoporosis and heart disease. Jordan's research showed that post-menopausal women who took these drugs did not suffer from a lowering of bone density or an increase in blood cholesterol. Raloxifene is now used in the prevention of osteoporosis. Jordan gained a full Professorship at Wisconsin in 1985, the same year his alma mater awarded him a DSc.
In 1993, Jordan became Professor of Cancer Pharmacology at Northwestern University Medical School in Chicago, IL., and director of the Breast Cancer Research Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. He was the inaugural holder of the Diana Princess of Wales Professor of Cancer Research (1999–2004).
In January 2005, Jordan was the inaugural Alfred G. Knudson Chair of Cancer Research at the Fox Chase Cancer Center in Philadelphia, PA. He has recently published work showing that estrogen, given at the right time, causes the destruction of cancer cells rather than feeding their growth. Jordan was the Scientific Director of the Lombardi Comprehensive Cancer Center, Professor of Oncology and Pharmacology, Vice Chair of the Department of Oncology, and the Vincent T. Lombardi Chair of Translational Cancer Research, Georgetown University, Washington, D.C., prior to moving to Texas.
Jordan was appointed Companion of the Order of St Michael and St George (CMG) in the 2019 Birthday Honours for services to women's health. [6]
Jordan is the father of two daughters, Helen Turner and Alexandra Noel.
Military Service: Captain Intelligence Corps (V) (On the staff of the Deputy Chief Scientist (Army) UK (1971–75)), Attached NBC Officer Region 1 US Mobilization Designee, DEA Officers' Course and UK Police Narcotics Squad Training (1973–78), 23 Special Air Service (1975–79) (Commanding Officer Rory Walker (1975-1978)),(Commanding Officer Tony Hunter-Choat(1978-1979)), (Director SAS Group, Brigadier Johnny Watts (1975-1979)), RARO SAS (1979–97). SAS Regimental Association (2008–present).
2020 Honorary Doctor of Science degree from the University of Wisconsin–Madison [7] [8]
2012 Louis S. Goodman and Alfred Gilman Award in Receptor Pharmacology, American Society for Pharmacology and Experimental Therapeutics [9]
2011 St. Gallen Prize for Clinical Breast Cancer Research, Switzerland [10]
2008 David A. Karnofsky Award from the American Society of Clinical Oncology [11]
2006 American Cancer Society Award and Lecture from the American Society for Clinical Oncology. [12]
2003 Kettering Prize [13]
2002 American Cancer Society Medal of Honor for basic research. [14]
2002 made an Officer of the Order of the British Empire by Queen Elizabeth II for services to international breast cancer research. [15]
2001 Umberto Veronesi Award for the Future Fight Against Breast Cancer (2001 [16] )
2001 Bristol-Myers Squibb Award for Distinguished Achievement in Cancer Research. [17]
2001 Doctor of Medicine, honoris causa from the University of Leeds [18]
1993 Cameron Prize for Therapeutics of the University of Edinburgh
1993 ASPET Award from the American Society of Pharmacology and Experimental Therapeutics. [19]
1993 The Gaddum Memorial Award from the British Pharmacological Society [20]
1992 Brinker International Breast Cancer Award for Basic Science from Susan G. Komen for the Cure. [21]
Total Citations as of January 11, 2021: 59,204 h-index score as of January 11, 2021: 122
Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.
Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.
Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors, which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors. This article refers to the former (ER).
Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to reduce the risk of breast cancer in those at high risk. It is taken by mouth.
Toremifene, sold under the brand name Fareston among others, is a medication which is used in the treatment of advanced breast cancer in postmenopausal women. It is taken by mouth.
Lasofoxifene, sold under the brand name Fablyn, is a nonsteroidal selective estrogen receptor modulator (SERM) which is marketed by Pfizer in Lithuania and Portugal for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy, and the result of an exclusive research collaboration with Ligand Pharmaceuticals (LGND). It also appears to have had a statistically significant effect of reducing breast cancer in women according to a study published in The Journal of the National Cancer Institute.
Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhibiting or suppressing estrogen production. Antiestrogens are one of three types of sex hormone antagonists, the others being antiandrogens and antiprogestogens. Antiestrogens are commonly used to stop steroid hormones, estrogen, from binding to the estrogen receptors leading to the decrease of estrogen levels. Decreased levels of estrogen can lead to complications in sexual development. Antiandrogens are sex hormone antagonists which are able to lower the production and the effects that testosterone can have on female bodies.
Arzoxifene is a selective estrogen receptor modulator (SERM) of the benzothiophene group which was never marketed. It is a potent estrogen antagonist in mammary and uterine tissue while acting as an estrogen agonist to maintain bone density and lower serum cholesterol. Arzoxifene is a highly effective agent for prevention of mammary cancer induced in the rat by the carcinogen nitrosomethylurea and is significantly more potent than raloxifene in this regard. Arzoxifene is devoid of the uterotrophic effects of tamoxifen, suggesting that, in contrast to tamoxifen, it is unlikely that the clinical use of arzoxifene will increase the risk of developing endometrial carcinoma.
Antihormone therapy is a type of hormone therapy that suppresses selected hormones or their effects, in contrast with hormone replacement therapy, which encourages hormone activity.
Nafoxidine or nafoxidine hydrochloride is a nonsteroidal selective estrogen receptor modulator (SERM) or partial antiestrogen of the triphenylethylene group that was developed for the treatment of advanced breast cancer by Upjohn in the 1970s but was never marketed. It was developed at around the same time as tamoxifen and clomifene, which are also triphenylethylene derivatives. The drug was originally synthesized by the fertility control program at Upjohn as a postcoital contraceptive, but was subsequently repurposed for the treatment of breast cancer. Nafoxidine was assessed in clinical trials in the treatment of breast cancer and was found to be effective. However, it produced side effects including ichthyosis, partial hair loss, and phototoxicity of the skin in almost all patients, and this resulted in the discontinuation of its development.
A nonsteroidal estrogen is an estrogen with a nonsteroidal chemical structure. The most well-known example is the stilbestrol estrogen diethylstilbestrol (DES). Although nonsteroidal estrogens formerly had an important place in medicine, they have gradually fallen out of favor following the discovery of toxicities associated with high-dose DES starting in the early 1970s, and are now almost never used. On the other hand, virtually all selective estrogen receptor modulators (SERMs) are nonsteroidal, with triphenylethylenes like tamoxifen and clomifene having been derived from DES, and these drugs remain widely used in medicine for the treatment of breast cancer among other indications. In addition to pharmaceutical drugs, many xenoestrogens, including phytoestrogens, mycoestrogens, and synthetic endocrine disruptors like bisphenol A, are nonsteroidal substances with estrogenic activity.
Triphenylethylene (TPE) is a simple aromatic hydrocarbon that possesses weak estrogenic activity. Its estrogenic effects were discovered in 1937. TPE was derived from structural modification of the more potent estrogen diethylstilbestrol, which is a member of the stilbestrol group of nonsteroidal estrogens.
Ethamoxytriphetol is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed. MER-25 was first reported in 1958, and was the first antiestrogen to be discovered. It has been described as "essentially devoid of estrogenic activity" and as having "very low estrogenic activity in all species tested". However, some estrogenic effects in the uterus have been observed, so it is not a pure antiestrogen but is, instead, technically a selective estrogen receptor modulator (SERM). For all intents and purposes, it is a nearly pure antiestrogen, however.
Etacstil is an orally active, nonsteroidal, combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) that was developed for the treatment of estrogen receptor-positive breast cancer. It was shown to overcome antiestrogen resistance in breast cancer by altering the shape of the estrogen receptor, thus exhibiting SERD properties. Etacstil is a tamoxifen derivative and one of the first drugs to overcome tamoxifen-resistance. It is the predecessor of GW-7604, of which etacstil is a prodrug. This is analogous to the case of tamoxifen being a prodrug of afimoxifene (4-hydroxytamoxifen).
Endoxifen, also known as 4-hydroxy-N-desmethyltamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group as well as a protein kinase C (PKC) inhibitor. It is under development for the treatment of estrogen receptor-positive breast cancer and for the treatment of mania in bipolar disorder. It is taken by mouth.
Triphenylchloroethylene, or triphenylchlorethylene, also known as chlorotriphenylethylene or as phenylstilbene chloride, is a synthetic nonsteroidal estrogen of the triphenylethylene group that was marketed in the 1940s for the treatment of menopausal symptoms, vaginal atrophy, lactation suppression, and all other estrogen-indicated conditions.
Droloxifene, also known as 3-hydroxytamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was developed originally in Germany and later in Japan for the treatment of breast cancer, osteoporosis in men and postmenopausal women, and cardiovascular disorders but was abandoned and never marketed. It reached phase II and phase III clinical trials for these indications before development was discontinued in 2000. The drug was found to be significantly less effective than tamoxifen in the treatment of breast cancer in two phase III clinical trials.
Zindoxifene is a nonsteroidal selective estrogen receptor modulator (SERM) that was under development in the 1980s and early 1990s for the treatment of breast cancer but was not marketed. It showed estrogenic-like activity in preclinical studies and failed to demonstrate effectiveness as a treatment for breast cancer in clinical trials. Zindoxifene was the lead compound of the distinct 2-phenylindole class of SERMs, and the marketed SERM bazedoxifene was derived from the major active metabolite of zindoxifene, D-15414. Zindoxifene was first described in 1984.
D-15414 is a nonsteroidal weak estrogen of the 2-phenylindole group which was never marketed. It is the major metabolite of the selective estrogen receptor modulator (SERM) zindoxifene (D-16726). D-15414 has high affinity for the estrogen receptor (ER) and inhibits the growth of ER-positive MCF-7 breast cancer cells in vitro. However, contradictorily, subsequent research found that the drug produced fully estrogenic effects in vitro similarly to but less actively than estradiol, with no antiestrogenic activity observed. The reason for the discrepancy between the findings is unclear, though may be due to methodology. The unexpected estrogenic activity of D-15414 may be responsible for the failure of zindoxifene in clinical trials as a treatment for breast cancer.
The antiestrogen withdrawal response is a paradoxical improvement in breast cancer caused by discontinuation of antiestrogen therapy for breast cancer. It has been documented rarely with the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene. The phenomenon indicates that these agents can somehow result in stimulation of breast cancer tumor progression under certain circumstances. One proposed theory for the mechanism is that the sensitivity of breast cells to estrogens shifts with estrogen deprivation, and upon antiestrogen withdrawal, endogenous estrogen acts in the manner of high-dose estrogen therapy in the breast to inhibit breast cancer growth and induce breast cancer cell death. The antiestrogen withdrawal syndrome is analogous to but less common and well-known than the antiandrogen withdrawal syndrome, a phenomenon in which paradoxical improvement in prostate cancer occurs upon discontinuation of antiandrogen therapy.