Lec 3: Antihormone Therapy & Prostate Cancer Flashcards
Drug List of Cancer Therapies: Anti-hormone Therapies…the 2 key MOA?
The Endocrine System and drugs that targets it . . .
Steroidogenesis & Inhibitors of CYPs . . . what are the two main ones and what CYP do they inhibit?
Steroid Hormone Receptor Superfamily & Cancer
Switching gears to Prostate cancer … The Prostate Gland..talk about it and the pathologies that can arise from it…what about mortality?
Prostate cancer is the #2 cancer in male = mortality! second to lung/ bronchus (in both men and women!)
Talk about CRPC (Castration resistant prostate cancer)
Sometimes when you castrate or remove ovaries/ testes cancer will regress as these are hormone
driven. We can also do “artificial” castration by using drugs like antihormones… in terms of prostate cancer? We use antiandrogen which stops testes from making hormone! = regression of cancer. However, CRPC is a more advanced disease … initial it’s very responsive to antihormone therapy but after a few years, the cancer becomes refracted and the therapy stops working!
Prostate Cancer Diagnosis & Therapy
- Therapy may be based on staging – AJCC TNM system (American Joint Committee on Cancer – Tumor, Nodes, Metastasized) – this is a complex and involved designation
. - Elements considered to determine therapy may include:
—— TNM designation
—— PSA level (controversial to some clinicians)
—— Grade (Gleason Score) – results from biopsy
.
-Initially, prostate cancer (CaP) is treated with androgen deprivation therapy (ADT)
—— May be used as neoadjuvant therapy (e.g., along with surgery or radiation therapy)
—— May be used as adjuvant therapy (e.g., after surgery or radiation therapy)
—— May be used to treat metastatic disease
—— May include antiandrogens (e.g., enzalutamide, bicalutamide), cytochrome P450 inhibitors (e.g., abiraterone acetate), and LHRH agonists (e.g., leuprolide)
.
-Chemotherapy for castration-resistant prostate cancer (CRPC)
The Endocrine System: LHRH agonists for prostate cancer
Leuprolide (Lupron®), Goserelin (Zoladex®)…. FYI: Triptorelin (Trelstar®), Histrelin (Vantas®)
.
- LHRH agonists (luteinizing hormonereleasing hormone agonists); also referred to as GnRH agonists
- Initially increase follicle stimulating hormone (FSH) and luteinizing hormone (LH) release, followed by suppression due to desensitization of pituitary
gonadotropin-releasing hormone resulting in reduced FSH and LH release
- LH and FSH stimulate testosterone release from testes, which can stimulate prostate cancer growth
- LHRH antagonists also available (e.g., Degarelix - Firmagon®)
Steroidogenesis: for prostate cancer
Abiraterone acetate (Zytiga®)
.
- Inhibits 17alpha-hydroxylase = CYP 17A1, which inhibits steroid hormone production that would
stimulate hormone-responsive prostate cancer cells
- Used for treatment of advanced, hormone-responsive prostate cancer; may be used in castrate resistant disease, as well
- Ketoconazole (Nizoral®) also used to block CYP function (with prednisone or hydrocortisone)
- will not only effect the release of hormones
in the testes but in the adrenal glands as well!
Model of Androgen Action: Drugs and how they work
NOTE: medicines to lower the levels of androgens made by the testicles.
Side Effects Associated with Androgen
Deprivation Therapy (ADT) may include:
- Impotence
- Hot flashes
- Reduced or absent sexual desire
- Breast tenderness (& growth of breast tissue)
- Osteoporosis
- Decreased mental sharpness
- Loss of muscle mass
- Weight gain
- Fatigue
- Depression
- Increased cholesterol levels
- Anemia
Advanced, Metastatic Castration-Resistant Prostate
Cancer (mCRPC) - Chemotherapy and other supportive drugs? What’s the classical drug for mCRPC?
Sipuleucel-T (Provenge®)
Mechanism of Action of Sipuleucel-T? What it? (generl)
- Autologous dendritic cells are isolated from a patient’s blood sample by leukapheresis.
- Cells are cultured ex vivo together with a fusion protein (PAP–GM-CSF), composed of prostate acid phosphatase (PAP), which is specifically expressed by prostatic cells; and granulocyte– macrophage colony-stimulating factor (GM–CSF), which enhances immune responses.
- Antigen-presenting cells (APCs) take up these antigens and are then reinfused into the same patient in order to stimulate a T-cell response against PAP–GM-CSF and consequently against cancerous prostatic cells.
- As Sipuleucel-T is composed of the patient’s own dendritic cells, the risk of inappropriate immune activation against vaccine components is low, while immune stimulation against the target antigen is maximized.
