Molecularly targeted therapies

Hormonal Therapy of Cancer

• Treatment involves adding, blocking, or removing hormones.
• Androgens and estrogens are implicated in breast, prostate, and endometrial cancer development.
• Hormonal agonists and antagonists are non-cytotoxic drugs.
• Endocrine therapy's effects are mediated through estrogen and progesterone receptors.
• Receptor expression levels influence therapy outcomes.
• 70% of primary breast cancer patients have ER+ tumors.

Targeting Estrogen Receptor (ER) Action in Breast Cancer

• Aromatase inhibitors block estrogen production.
• Anti-estrogens (e.g., tamoxifen, fulvestrant) block ER binding to estrogen.
• Cancer cell growth stimulation is reduced when ER binding is blocked.
• Coactivator molecules help estrogen bind to ER.
• Small molecule inhibitors can also block ER.

Tamoxifen - Side Effects

• Hot flashes can cause patient non-compliance.
• Increased risk of endometrial cancer (partial estrogen agonist).
• Increased risk of thromboembolic events.
• Increased risk of clinical depression.
• Selective serotonin reuptake inhibitors (SSRIs) treat hot flashes and depression.
• Some SSRIs decrease tamoxifen efficacy due to CYP2D6 inhibition.
• Tamoxifen is a prodrug metabolized by CYP2D6 to its active metabolite.
• There is high inter-individual variability in CYP2D6 enzyme expression.

Raloxifen

• Non-steroidal selective estrogen receptor modifier (SERM).
• Anti-estrogenic actions on the uterus and breast.
• Only ER+ breast cancer disease is reduced.
• Estrogenic actions on bone.
• Treatment and prevention of osteoporosis in post-menopausal women.

Anastrozole

• Second-line hormonal therapy for breast cancer.
• Selective aromatase inhibitor.
• Inhibits conversion of androstenedione to estrone and estradiol.

Hormonal Therapy of Prostate Cancer

• Dihydrotestosterone (DHT) modulates prostate growth.
• DHT binds to cytoplasmic androgen receptors.
• Prostate cancer depends on DHT.
• Androgen-sensitive prostate cancer occurs in 80% of patients.

Androgen Withdrawal Therapies

• Decrease androgen production (e.g., bilateral orchiectomy, medical castration using GnRH agonists).
• GnRH agonists block LH secretion, inhibiting testosterone synthesis.
• GnRH antagonists (e.g., degarelix) block GnRH receptors.
• Androgen synthesis inhibitors (e.g., abiraterone) block androgen synthesis.
• Androgen receptor antagonism (e.g., flutamide, bicalutamide) blocks androgen binding.

GnRH Antagonist versus Agonist

• Antagonists offer faster onset of action compared to agonists.
• Agonists initially lead to elevated LH and testosterone before suppression,

Abiraterone

• Inhibits CYP17A1, crucial for androgen synthesis, in testicular, adrenal, and prostatic tumors.
• CYP17 catalyzes pregnenolone and progesterone to 17-α-hydroxy derivatives (e.g., DHEA).
• Secondary role in conversion to androstenedione and testosterone.
• Used in castration-resistant prostate cancer.

Flutamide

• Non-steroidal antiandrogen.
• 2-OH flutamide blocks androgen binding to the androgen receptor (AR).
• Adverse effects include diarrhea, nausea, vomiting, and liver function abnormalities.
• Often administered with Leuprolide to attenuate initial testosterone "flare" with leuprolide.

Enzalutamide (MDV3100)

• Approved for castration-resistant prostate cancer.
• Androgen receptor antagonist, preventing AR binding to DNA and AR coactivator proteins.

Molecularly-Targeted Therapeutics

• New cancer drugs target specific molecular targets (e.g., proteins) critical in tumor growth.
• Receptor tyrosine kinase (RTK) inhibitors, glycolysis inhibitors, proteosome inhibitors, and angiogenesis inhibitors are examples.
• RTKs (e.g., EGFR, ERBB2, ERBB3, ERBB4) are associated with various cancers.

EGF Receptor Activation Enhances Proliferative Capabilities of Cancer Cells

• Cells become self-sufficient in growth signals, insensitive to anti-growth signals, evade apoptosis, have limitless replication potential, and exhibit sustained angiogenesis; and tissue invasion and metastasis.

RTK Inhibition

• Block ligand binding to receptors.
• Block receptor dimerization.
• Induce receptor endocytosis and degradation via ubiquitination.
• Block tyrosine kinase activity.

ErbB2/HER2 Receptors in Cancer

• Amplification of the HER2 gene is a consistent genetic alteration in breast tumors.
• HER2 belongs to the EGFR family of receptor tyrosine kinases.
• HER2 receptor overexpression is associated with poor prognosis.
• HER2 is a target for anti-cancer therapeutics (e.g, Herceptin).

Herceptin

• Binds to the extracellular domain of the HER2 receptor.
• Disrupts receptor dimerization, signaling.
• Arrests cells in the G1 phase.
• Suppresses angiogenesis.
• Most effective with chemotherapy.

Problems with Antibody Approach for Cancer Treatment

• Dose-limiting systemic toxicities (e.g., in mice lacking EGFR).
• Skin rashes, diarrhea, high molecular weight, slow distribution, incomplete distribution.
• Need for intravenous administration.
• Immune response elicitation.

Imatinib

• Targets BCR-ABL tyrosine kinase, crucial in chronic myeloid leukemia (CML).
• BCR-ABL is a constitutively active kinase caused by chromosomal translocation (Philadelphia chromosome).
• Imatinib competitively binds to the kinase site, inhibiting its activity.
• Imatinib use to prevent tumor cell proliferation.
• Resistance to imatinib can occur from BCR-ABL overexpression or mutations.

Gefitinib (Iressa)

• EGFR tyrosine kinase inhibitor.
• Effective in patients with non-small cell lung cancer.
• Use cases restricted to patients who have already had treatment success in the past, due to evidence of limited treatment success.

Erlotinib (Tarceva)

• EGFR inhibitor approved for non-small cell lung cancer.

Lapatinib

• Dual EGFR/ErbB inhibitor

Tyrosine Kinase Inhibitors (TKIs) versus Monoclonal Antibodies (mAbs)

• TKIs are orally administered, mAbs require IV.
• TKIs have low molecular weight, faster distribution.
• TKIs cross-react with other kinases; mAbs are specific.
• TKIs lack immune responses; mAbs can elicit an immune response.
• TKIs and mAbs have different clinical response profiles.

Angiogenesis Inhibitors

• Monoclonal antibodies (e.g., bevacizumab) inhibit vascular endothelial growth factor-A (VEGF-A) and its receptor, blocking angiogenesis (nutrient, oxygen supply to tumors).

Proteosome Inhibitors

• Proteosome inhibitors (e.g., bortezomib) block proteasome activity.
• Proteosome degrades unwanted or damaged proteins and blocks cells from restarting DNA replication process.
• Inhibitor use in some treatments for various cancers.

This lesson explores hormonal cancer treatments involving the manipulation of hormones. It focuses on targeting estrogen receptors (ER) in breast cancer using aromatase inhibitors and anti-estrogens like tamoxifen and fulvestrant and inhibiting cancer cell growth. The lesson also addresses the side effects of tamoxifen.