What are hormone receptors?
Hormone receptors are proteins in the interior (or on the surface) of a cell that bind to specific hormones. Estrogens and androgens are examples of hormones that bind with hormone receptors. Once a hormone binds with its receptor, a series of intracellular events occur that either stimulate or inhibit the actions of the hormone receptor and result in differing effects depending on the hormone, the tissue and a variety of other factors.
What is a selective receptor modulator?
Some drugs contain four fused chemical rings and are known as steroids. A nonsteroidal drug is a small molecule that does not contain the four fused chemical rings, but can interact with the same hormone receptor. When a drug can bind to the hormone receptor and elicit different effects in different tissues, it is called a selective receptor modulator. By blocking or stimulating a hormone receptor in a tissue-selective manner, it may be able to mimic the beneficial effects while simultaneously minimizing the unwanted effects of the natural or synthetic steroidal hormones. GTx is developing nonsteroidal selective receptor modulators.
What is the purpose of estrogens and androgens?
Estrogens and androgens are hormones that play critical roles in regulating not only the reproductive system, but also have important effects on the muscular, skeletal, cardiovascular and central nervous systems.
Although estradiol is commonly thought of as a female sex hormone, it plays a critical role in men’s health. Estradiol is the primary hormone responsible for bone turnover and bone quality. It is also important for cognition and the regulation of certain central nervous system and metabolic functions.
Testosterone is the predominant androgen in men and women. It is important for mental well-being and for masculine characteristics such as muscle size and strength, bone strength, sexual interest, potency, fertility and hair growth.
The balance between estrogens and androgens must exist in order for the body to function optimally. Testosterone levels decline in aging men. While absolute levels of estradiol also decrease, the ratio of estrogens to androgens gradually rises in aging men, especially in the prostate, leading to unwanted clinical effects. Estrogens are implicated in the development of benign enlargement of the prostate called benign prostatic hyperplasia (BPH) and prostate cancer and are known to cause gynecomastia.
What is a SERM?
A selective estrogen receptor modulator, or SERM, is a small molecule that binds to and selectively modulates estrogen receptors. These molecules have the potential to either stimulate or block estrogen's activity in different types of tissue:
- Stimulate estrogen's action in bone
- Stimulate estrogen’s effects in the hypothalamus-pituitary axis to block hot flashes in men on ADT
- Block estrogen's activity in the prostate
- Block estrogen’s activity in the breast
What is a SARM?
A selective androgen receptor modulator, or SARM, is a small molecule that binds to and selectively modulates androgen receptors depending on tissue type. In men, SARMs may be able to:
- Stimulate testosterone's action in bone, muscle and brain
- Block testosterone's action in the prostate and skin
- Either cross or not cross into the central nervous system to affect libido
What is high grade PIN?
High grade prostatic intraepithelial neoplasia, or PIN, is a precancerous lesion detected in more than 10% of patients who undergo biopsies looking for prostate cancer.1 High grade PIN is an independent histologic predictor of progression to invasive prostate cancer, and scientific evidence has shown that patients with high grade PIN are at high risk for prostate cancer. More than 40% of high grade PIN patients will progress to prostate cancer within three years of diagnosis and up to 80% within eight years.2,3
What is androgen deprivation therapy (ADT)?
Androgen deprivation therapy, or ADT, is the primary treatment for advanced prostate cancer. ADT reduces blood levels of testosterone, a primary growth factor for prostate cancer, by up to 95% and estrogen levels approximately 75%.4 ADT is accomplished either surgically by removal of the testes, or chemically by treatment with luteinizing hormone-releasing hormone (LHRH) agents.
LHRH agents work by shutting off luteinizing hormone secretion by the pituitary gland, which stops testosterone production by the testes. Examples of commercially marketed LHRH agents are Lupron Depot® (leuprolide acetate for depot suspension), Decapeptyl® (triptorelin pamoate for depot suspension), Zoladex® (goserelin acetate implant) and Eligard® (leuprolide acetate for injectable suspension).
What are the possible effects of depleted estrogen in men with prostate cancer on ADT?
A typical elderly man has higher estrogen levels than a postmenopausal woman. By reducing testosterone to castrate levels, ADT also depletes approximately 75% of a man's estrogen, resulting in the potential for multiple estrogen deficiency side effects.
Estrogen deficiency side effects of ADT include:
- Accelerated bone loss with an increased risk of skeletal fractures
- Adverse lipid changes and an increased risk of cardiovascular disease and heart attacks6,7
- Common symptomatic side effects such as hot flashes and bothersome gynecomastia (breast enlargement and pain)8,9
What is the risk of fracture in men with prostate cancer on ADT?
The incidence of fractures among men on ADT is high. Men on ADT have accelerated and continuous bone loss.10 Recent studies indicate that each year as many as 5% to 8% of men on ADT will fracture.11 Fractures are serious and can reduce survival in men on ADT by more than three years compared to men on ADT who do not fracture.12,13
What is chronic sarcopenia?
Chronic sarcopenia is a disease state of progressive skeletal muscle loss associated with impaired strength and mobility frequently accompanied by disability and a loss of independence. Chronic sarcopenia can exacerbate and be aggravated by comorbid illnesses, such as diabetes, depression and frailty in the elderly. Approximately 17 million Americans over the age of 65 are affected by chronic sarcopenia, with women being at greater risk than men.14 There are currently no FDA approved therapies for chronic sarcopenia.
What is cancer cachexia?
Cancer cachexia, or the unintentional loss of muscle mass and body weight, may lead to loss of protein stores, severe weakness and fatigue, immobility, loss of independence and an inability to tolerate and respond to cancer treatments. An estimated 1.3 million cancer patients in the United States have cancer cachexia.15 Cancer-induced muscle wasting is thought to be responsible for greater than 20% of cancer deaths.16 There are no drugs currently approved for the treatment of cancer wasting.
References
- GTx study of urologist and pathologist habits and practices, 2007.
- Huang G et al J Urol 2005, 173:397.
- Fleshner et al Presented at Prostate ASCO 2005.
- Smith MR et al N Engl J Med 2001, 345(13):948-55.
- Bruder JM et al J Urol 2006, 67:152-5.
- Smith MR et al J Clin Endo & Metab 2002, 87:599-603 PMID: 11836291.
- Keating NL et al J Clin Oncol 2006, 24:4448-56 PMID: 16983113.
- Harle LK et al Clin Adv Hematol Oncol 2006, 4(9):687-96 PMID: 17099626.
- Higano CS Urology 2003, 61(2a suppl 1):32-8 PMID: 12667885.
- Bruder JM et al J Urol 2006, 67:152-5.
- Shahinian VB et al N Engl J Med 2005, 352(2):154-64 PMID: 15647578.
- Oefelein MG et al J Urol 2002, 168:1005-7 PMID: 12187209.
- Krupski TL et al Cancer 2004, 101:541-9 PMID: 15274067.
- Mishra SK et al Acta Myologica 2003, 22:43-7.
- Tan BH and Fearon KC Current Opin Clin Nutr Metab Care 2008, 11:400-7.
- Tisdale MJ Journal of Supportive Oncology 2003, 1:157-68.