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Oncology Exam 3
Hormone Therapy Smith B
| Term | Definition |
|---|---|
| Why are estrogen, progesterone, and testosterone bad for some breast and prostate cancers? | ER ad PR+ are usually breast cancer; ovarian, uterine, and why testosterone bad? prostate cancer; not going to give horomones but we give drugs to prevent the production of thesehoromes or block those receptors that those horomones would be binding and hormones will have less of a chance to stimulate those cancers |
| Synthesis Inhibitors: GnRH agonists and Antagonists are for? | prostate cancer; *Testosterone production in males may be suppressed by using GnRH agonists or GnRH antagonists |
| What is the MOA of GnRH agonoists? | -GnRH is normally released from hypothalamus in pulses to control LH and FSH release -If the hypothalamus were to release GnRH continuously, LH and FSH secretion would be suppressed ⭐ by pituitary -Therefore, we administer the GnRH agonists continuously to suppress LH/FSH pituitary secretion which then reduces testosterone production |
| What is the MOA of GnRH antagonists? | -GnRH receptor antagonists interfere with GnRH stimulation of pituitary, preventing the secretion of LH/FSH from the pituitary which then reduces testosterone production *block GnRH receptor on the pituitary |
| We can get a ____ _____ with GnRH agonists | disease flare (using a GnRH agonist will take awhile for them to down regulate) ⭐️ -Can cause initial surge in LH and FSH release, resulting in transient flare of disease -Prevent surge by temporary (2 to 4 weeks) administration of androgen receptor antagonists⭐ with the GnRH agonist *can often find prostate cancer going to the spinal column compressing spinal cord⭐️ |
| Efficacy of GnRH agonists? | -Can reduce testicular production of testosterone to castration levels |
| What are our GnRH agonists? | Goserelin; Leuprolide; Triptolerin |
| GnRH is prodiuced by the _______ (goanadotripoin releassing hromone | hypothalamus -lots of feedback inhibition; finds anterior pututriatry--> calse release of LH and FSH from anterior petutiray--> hormones go to ovaries and testes to produce androsterndipen (ovaries) and protesterone, and testoseterone. |
| GnRH agonists and antagonists act on _____ | pituitary gland |
| GnRH prevention of disease flare---> will add? | androgen receptor antagonists to prevent the flare since we get a surge and stop effects of production; *will need to use for 2-4 weeks while starting. pt on a GnRH agonist. |
| Will a disease flare occur with a GNRH antagonist? | No, its an antagonist |
| What is the efficacy of our GnRH antagonists? | -Rapidly reduces serum testosterone levels within a week in most patients -No initial increase in testosterone levels -Other than avoidance of the initial flare, GnRH antagonists have no advantage over GnRH agonists |
| What are cautions to conisder for our GnRH receptor antagonists? | -Potential teratogen⭐️; Males with female partners who can become pregnant must use an effective birth control during treatment and after the last dose -Preexisting QTc prolongation; do not use with class Ia or class III antiarrhythmics |
| What are our GnRH antagonists agents? | -Relugolix (Oral medication; do not crush or chew) -Degarelix (Given SQ) |
| which is more potent? Androsterone or Dihydrotestosterone? | DHT (10x more potent) |
| MOA of 5a-reductase? | -Inhibits 5A-reductase, preventing conversion of testosterone to DHT |
| PD of 5a-reductase? | -Indicated for moderate to severe BPH -Preferred over α1-adrenergic antagonists for patients with -Uncontrolled arrhythmias -Poorly controlled angina -On multiple antihypertensives -Unable to tolerate the hypotensive effects of adrenergic antagonists -Slow onset: can take 6 months to maximally shrink prostate -Normal doses reduce serum PSA levels by 50% |
| why do we use 5a-reductase inhibitors in prostate cancer? | prevent the growth of potent DHT (lowering presence of hormone that would get those prostate cancer cells to grow *Type II is expressed in urogenital tract; Type 1 expressed more systemically |
| Finasteride use? | -Competitively inhibits Type II 5α-reductase -Suppresses intraprostatic DHT by 80% to 90% -Decreases serum DHT by 70% |
| Dutasteride use? | -Nonselective Type I and Type II 5α-reductase inhibitor -Quickly and (more) completely suppresses intraprostatic DHT production -Decreases serum DHT by 90% |
| PK of 5a-reductase? | Finasteride -Plasma t1/2 approximately 8 hrs -Dutasteride -Up to 5 weeks *dont forget these meds are teratogenic |
| AE of 5a-reductase inhibitors? | -ED may be secondary to nitric oxide synthase inhibition -Nausea, abdominal pain, asthenia, dizziness, flatulence, headache, rash, muscle weakness, gynecomastia; DI: No clinically relevant drug interactions known; ⭐️TERATOGENIC! Do not allow pregnant females to handle broken or crushed tablets⭐️ |
| CYP 17 inhibitrs (17a-hydroxylase and 17-20 ligase act where on the production of testosterone? | removing hydroxyl groups (drugs will inhibit both enzymes) -inhibiting CYP 17 (stop conversion of progesterone to the 17 OH progesterone bc its a 17a hydroxylase |
| A CYP 17 inhibitor, Abiraterone acetate MOA is? | -It blocks 17α-hydroxylase (P450c17) and 17,20-lyase, reducing synthesis of cortisol in the adrenal and gonadal testosterone precursors (dehydroepiandrosterone (DHEA) and androstenedione) in the gonads⭐ -A compensatory increase⭐ occurs in ACTH and aldosterone synthesis, but this can be prevented by concomitant administration of dexamethasone or prednisone |
| Indication of CYP 17 inhibitors | -Metastatic castration-resistant prostate cancer⭐ in patients who had docetaxel⭐ -PO once daily on empty stomach in combination with twice daily prednisone ⭐ |
| PK of Abiraterone acetate is? | Is a prodrug, activated by CYP3A4; -⭐️metabolized by 2D6 |
| AE of Abiraterone acetate? | -Adrenocortical insufficiency, hepatotoxicity, hypertension, hypokalemia, fluid overload, and heart failure -CYP3A4 substrate; inhibits p-glycoprotein and CYP2D6 |
| C19 inhibitors are used to decrease the production of ______ | androgens |
| Aromatase inhibitors profoundly suppress? cause increased risk of? | estrogen formation, therefore inhibits growth of estrogen-dependent tumors; -osteoporotic fractures ⭐️ Bones need estrogen and suppression leads to risk of fractures |
| Aromatase inhibitors are classified as? | -Steroidal (Type I): analogs of androstenedione; bind to same site of aromatase as androstenedione, but bind irreversibly⭐️ because of their conversion to reactive intermediates by aromatase. -Nonsteroidal (Type II): reversible binding to heme group in aromatase⭐ |
| What are our aromatase inhibitors? | -Anastrozole (non-steroidal, potent and selective; effective in some women whose breast tumors have become resistant to tamoxifen) -Letrozole (non-steroidal) -Exemestane (Steroidal) irreversible binder⭐ *all are approved for use in advanced breast cancer |
| Estrogen receptors and estrogen MOA? | -Estrogens are ligands for nuclear receptors. -There are two estrogen receptors: ERa and ERb -Both ERs are estrogen-dependent nuclear transcription factors -Have different tissue distributions and transcriptional regulatory effects |
| Estrogen receptors and estrogen MOA? | Genomic: classic: complex dimerizes (two ERs come together) bind to ERE on DNA. Co-activators and general transcript. machinery are recruited leading to Transcription of target genes--> direct DNA binding by ER to regulate gene transciption Non-classic mode: not bind directly to DNA. interacts with other TF like Fos/Jun (AP1 complex). ER-tethered complex influences gene transc. indirectly through response elements."indirectly" |
| SERMS: Some antiestrogens are mixed ____/_____. They inhibit estrogenic effects in some tissues; promote estrogenic effects in other tissues. Several factors contribute to this phenomenon--> | agonist/antagonists; -Threre are 2 estrogen reecptors -Expression of ERa and ERb is tissue specific -ER interaction with transcription cofactors depend on the structure of the ligand -Transcription cofactors are also tissue-specific *this mixed characterisitc contributes to therapeutic and AE of SERMS |
| SERM figue: why you end up with different responses to different tissues (top is bone tissue and bottom is breast tissue)--> *look for effect on gene expression of Gene 1,2,3 in presence of estrogen or SERM in bone and breast tissue. *see which cofactor plays--> | 1. Bone with estrogen--> binds to receptor, dip, has to dimerize with another estrogen receptor complex--> affects gene trans. --> X bound to Gene 1. Gene 2 expressed with TFy has interacted with estrogen receptor complex. Gene 3 needs both TFx and y to be expressed. *all 3 can be expressed |
| SEMRS are used to produce beneficial estrogenic actions in certain tissues (___, _____, _____) during postmenopasual hormone therapy, but antagonist activity in tissues such as breast and endometrium, where estrogenic actions (i.e. carciongenesis) might be deleterious | bone, brain, liver |
| SERMS that are currently approved in the US are? | -tamoxifen citrate (NOLVADEX, OTHERS) -raloxifene hydrochloride (EVISTA) |
| SERMS: Tamoxifen drug info: MOA? | -ER antagonist in breast; partial agonist in endometrium and bone⭐ -Associated with 4-6X increase in the incidence of endometrial cancer⭐ ; typically given for up to10 years⭐ |
| SERMS: Tamoxifen drug info: Uses? | -Currently approved for use in the treatment and prevention of breast cancer -Palliative treatment of metastatic breast cancer -Adjuvant therapy after lumpectomy |
| SERMS: Raloxifene drug info: MOA? | -ER agonist in bone; antagonist in breast and endometrium⭐ -Does not increase incidence of endometrial cancer (cofactors in the endometrium cannot play with Raloxifene. |
| SERMS: Raloxifene drug info: Uses? | -Prevent osteoporosis in post-menopausal women -⭐ Breast cancer prophylaxis in women with risk factors |
| ANTI-estrogens include a class of meds referred to as? | -Selective Estrogen-Receptor Downregulators (SERDS) or Pure Anti-Estrogens |
| Our 1 agent that is an anti-estrogen that was the first FDA approved SERD is? | Fulvestrant (FASLODEX) |
| what is the difference between SERMS and SERDS? | *Different from SERMs because are pure antagonists in all tissues studied (have no estrogen activity) |
| MOA of anti-estrogens according to Smith? | -Steroidal anti-estrogen -Binds to ER with affinity > 100 times that of tamoxifen -Inhibits ER dimerization, increases ER degradation therefore reducing number of ERs in cells; suppresses expression of estrogen-dependent genes |
| Anti-estrogens are hypothesized to have an improved ____ profile, faster onset, and longer duration of action than _______ | safety; SERMS |
| SERMS figure in breast with estrogen around, which genes cna be expressed? | Gene 2, why? Transcription cofactor Y is the only one present. different distribution of cofactors and X and Y are both in Bone but Y is only present in breast therefore only Gene 2 is expressed. *estrogen is a FULL agonist in bone since both transcription factors are present. |
| SERM figure: SERM binds to estrogen receptor (different shape) so which cofactor cannot help because of the shape of the SERM? | Y (cannot bind becaue it needs the lignad to be curved and therefore Y cannot bind. X can bind--> moves to nucleus---> only gene 1 is expressed, why? bc cofactor y cant bind to the SERM. |
| Anti-estrogens have efficacy against _____-______ breast cancer | tamoxifen-resistant *clinical trials not showing fulvestrant has more effective anti-estrogen activity than tamoxifen in metastatic breast cancer |
| MOA of Anti-androgens? | -Competitively inhibit binding of endogenous androgens to androgen receptor (which are nuclear receptors) -Do not decrease LH production; therefore, testosterone levels are normal or increased -Have complete androgen blockade (CAB) when given with GnRH agonists -Are either steroidal or nonsteroidal; non-steroidal ones used more commonly |
| What are our first generation Anti-Androgen Receptor Antagonists? | -Bicalutamide -Flutamide -Nilutamide |
| What are our 2nd generation Anti-Androgen Receptor Antagonists? | -Enzalutamide -Apalutamide -Darolutamide |
| Drug information for Bicalutamide (one of our anti-androgens)? | -Nonsteroidal -Orally once daily⭐ -The t1/2 increased in severe hepatic insufficiency⭐ (*dose adjust) -Reduced toxicity and improved tolerability compared to others -Recommended to reduce tumor flare when GnRH agonist is needed⭐ |
| Drug information for Flutamide (one of our anti-androgens)? | -Nonsteroidal -Orally three times per day -Metabolized to active metabolite⭐ , hydroxyflutamide -Common side effects: diarrhea, breast tenderness, and nipple tenderness⭐ ; -Rare reports of fatal hepatotoxicity |
| Drug information for Nilutamide (one of our anti-androgens)? | -Nonsteroidal -Orally once daily -Common side effects: mild nausea, alcohol intolerance⭐ , decreased ocular adaptation to darkness⭐ -Risk of interstitial pneumonitis⭐ |
| Drug information for Enzalutamide (one of our anti-androgens)? | -Nonsteroidal -Orally once daily -Greater affinity for AR compared to first generation meds =Additional mechanism of action: induces cell apoptosis⭐ -CYP2C8 metabolizes it to active metabolite N-desmethyl enzalutamide -⭐ Side effects are fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension. Fractures, falls, and cognitive impairment |
| Drug information for Apalutamide (one of our anti-androgens)? | -Nonsteroidal -Once a day; bioavailability ~100%⭐ -⭐ Strong inducer of CYP3A4 and CYP2C19; weak inducer of CYP2C9. -Similar side effects as enzalutamide; also can increase the QT interval and seizures ⭐️ |
| Drug information for Darolutamide (one of our anti-androgens)? | -Nonsteroidal -Orally twice daily ⭐️; should be given with food -Does not induce CYPs -⭐ Common side effects: fatigue, pain in extremities, and rash. -Significant adverse reactions: ischemic heart disease, heart failure, urinary retention, pneumonia, and hematuria -Does not penetrate the blood-brain barrier, therefore seizure not common ⭐️ |
| Inavolisib is a PI3K inhibitor. MOA? | -inhibitor of phosphatidylinositol 3-kinase (PI3K) which decreases cell proliferation and induces apoptosis ⭐️ -PI3Ks are heterodimers composed of regulatory (p85) and catalytic (p110 which does the kinase work) subunits⭐️ -There are four PI3K isoforms (α, β, δ, and γ) -PI3Kα is the most commonly associated with solid tumors because of PIK3CA genetic variants ⭐️ -Results in variant p110α catalytic subunit of PI3Kα ⭐️ |
| Inavolisib indication? | -Breast cancer, locally advanced or metastatic, endocrine-resistant, PIK3CA-mutated, HER2-negative, hormone receptor-positive ⭐️ |
| AE of Inavolisib? | -Common: Rash, Hyperglycemia, decreased appetite, Nausea, Stomatitis, ⭐️neutropenia, ⭐️ thrombocytopenia, elevated liver enzymes, fatigue -Serious: Diarrhea, anemia, decreased white blood cell count, UTIs ⭐️ |
| For bone metastasis: review of bone remodeling | *Osteoblast precursor--> Blast build and Clast break down; Blast is activated under influence of PTH or stress on the bone or TGF-b (mechanical sensors activate--> once activated--> precursor will put RANK lignad on its surface and osteoblast presucurs will find a class precursor and blast will bind to RANK receptor and get clast breaking bone--> new clean hole for blast to do their work *cycle of bone remodelling |
| Bisphosphonates: Zoledronic Acid MOA? *for bone metastsis | binds to hydroxyapatite⭐ in bone which inhibits osteoclast-mediated bone resorption *stop bone break down where the clast can't bind to break down bone |
| Zoledronic Acid: PK: | -Low oral bioavailability; food decreases absorption -Have very long-lasting effects; some administered once weekly, once monthly, once yearly |
| AE of Zoledronic Acid? | -Most common: Hypertension, headache, skin rash, gastrointestinal perforations, ulcers, or bleeding; diarrhea, nausea, abdominal pain, urinary tract infection, arthralgia, back pain -Rare but serious: Atypical femur fractures and osteonecrosis of the jaw (ONJ) due to bone turnover suppression |
| Important points about Zoledronic Acid includes? | -To prevent esophageal ulceration, take with lots of water, remain upright for 30 minutes, avoid situations that cause esophageal reflux (activities that increase intra-abdominal pressure) *D/C use after 3-5 years in lower-risk pts |
| RANK ligand inhibitor: Denosumab MOA? *for bone metastsis | -A human monoclonal antibody -MOA: binds to RANKL, blocking RANKL binding to RANK on the surface of osteoclast precursor cells; inhibits osteoclastogenesis |
| AE of Denosumab? | -Peripheral edema, hypertension, fatigue, headache, skin rash, dermatitis, eczema, hypophosphatemia, hypocalcemia, diarrhea, nausea, decreased appetite, vomiting, constipation, anemia, thrombocytopenia, dyspnea, cough, upper respiratory tract infection, asthenia, back pain, arthralgia, limb pain -Rare but serious: Atypical femur fractures and osteonecrosis of the jaw (ONJ) due to bone turnover suppression like with bisphosphonates *CI for pregnant women |
| What is radium Ra 223 dichloride? | -A radioactive agent that emits alpha particles and mimics calcium ⭐️ -11.4 day half life -Complexes with bone hydroxyapatite⭐️ where bone is turning over (like where bone metastases have occurred) -The alpha particles break DNA in adjacent cells ⭐️, killing them -The range of the alpha particles is less than 10 cell diameters, and the damage to surrounding normal tissue is limited -For treating prostate cancer, symptomatic bone metastases |
| Sipuleucel-T is an autologous cellular immunotherapy for prostate cancer. MOA? Administration? | -Induces an immune cell response against prostate acidic phosphatase (PAP), which is expressed in most prostate cancers; ⭐️Administered by Infusion three times at 2-week intervals ⭐️ *get pts own immune cells to respond to PAP--> enzyme that's expressed on surface of most prostate cancer cells. a way og getting the immune ceslls to see the PAP, find it and kill it off |
| Sipuleucel-T. how it works? | -Patient blood cells are isolated and cultured -The cells are exposed to the ⭐️human recombinant protein PAP–GM-CSF ⭐️ -PAP prostate acid phosphatase is selectively expressed on prostatic tissues -GM-CSF is included to enhance the immune response -APCs take up and present PAP as an antigen -Cells are re-infused into the patient to stimulate a T-cell response against PAP -The patient’s T-cells then attacks prostate cancer cells |
| GnRH is produced, finds the anterior pituitary gland and releases ___ and ____. goes to the sex organs to produce our estrogens and androgens | LH and FSH |
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