Lecture 5 - 2023 Molecularly Targeted Therapies PDF

Hormonal Therapy of Cancer Treatment that adds, blocks or removes hormones. Androgens and estrogens have been implicated in the development of breast cancer, prostate cancer, and endometrial cancer Hormonal agonists and antagonists are NON-cytotoxic drugs effects of endocrine therapy ar...

Hormonal Therapy of Cancer Treatment that adds, blocks or removes hormones. Androgens and estrogens have been implicated in the development of breast cancer, prostate cancer, and endometrial cancer Hormonal agonists and antagonists are NON-cytotoxic drugs effects of endocrine therapy are mediated through estrogen receptors and progesterone receptors the level of receptor expression is likely to influence the outcome of therapy – ~ 70% of patients with primary breast cancer have ER+ tumours 1 2  Tamoxifen Competitive inhibitor of estradiol binding to the ER in breast tissue Treatment of choice in women with ER+ and PR+ breast cancer Prodrug decreases disease recurrence and mortality rates by as much as 50% Metabolized in liver by CYP2D6 to and 30% respectively active metabolite high inter-individual variability in prophylactic treatment for those at expression of this P450 enzyme high risk of developing breast cancer 3 Tamoxifen – Side Effects Hot flashes - can result in patient non-compliance increased risk of endometrial cancer (partial agonist on estrogen receptors in this tissue) increased risk for thromboembolic events as well as clinical depression. Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat both hot flashes and depression – however, many SSRI have anti-CYP2D6 activity which could lead to a decrease in tamoxifen efficacy 4  Raloxifen Non-steroidal Selective Estrogen Receptor Modifier (SERM) Anti-estrogenic (antagonist) actions on the uterus and breast – Only ER+ breast disease is reduced Estrogenic (agonist) actions on bone – treatment and prevention of osteoporosis in post-menopausal women 5 Anastrozole 2nd line hormonal therapy for breast cancer Dehydroepiandrosterone a selective aromatase inhibitor aromatase Estrone Androstenedione Estradiol Estradiol 6  Hormonal Therapy of Prostate Cancer Dihydrotesterone (DHT) modulates prostate growth DHT binds to cytoplasmic androgen receptors. – The steroid receptor complex undergoes activation and transport to the nucleus where they bind to HRE in the promoters of hormone regulated genes Prostate cancer depends on DHT “androgen-sensitive” prostate cancer occurs in 80% of patients 7 Androgen Withdrawal Therapies Decrease androgen production – Bilateral orechidectomy (castration) – Medical castration using GnRH (LHRH) agonists- leuprolide. block the secretion of LH by the pituitary gland and thereby inhibit the synthesis of testosterone by the testis (due to receptor desensitization) – GnRH antagonists (Degarelix) – Androgen synthesis inhibitors (Abiraterone) Androgen receptor antagonism 8  9 Abiraterone inhibits CYP17A1 which is expressed in testicular, adrenal, and prostatic tumor tissues. CYP17 catalyzes two sequential reactions: 1. the conversion of pregnenolone and progesterone to their 17-α- hydroxy derivatives by its 17 α- hydroxylase activity 2. the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively used in castration-resistant prostate cancer 10  OH Flutamide Non-steroidal antiandrogen 2-OH flutamide blocks binding of androgens at the AR Adverse effects – Diarrhea, nausea and vomiting – Liver function abnormalities Flutamide usually administered with Leuprolide (attenuates initial testosterone ‘flare’ with leuprolide) 11 Enzalutamide (MDV3100) Approved in 2012 for the treatment of castration-resistant prostate cancer (US) Androgen receptor antagonist prevents binding of AR to DNA and AR to coactivator proteins 12  Molecularly-Targeted Therapeutics A new generation of cancer drugs designed to interfere with a specific molecular target, typically a protein, believed to have a critical role in tumour growth or progression Receptor Tyrosine Kinase Inhibitors Glycolysis Inhibitors Proteosome Inhibitors Angiogenesis Inhibitors Apoptosis Modulators Receptor Tyrosine Kinases (RTK) 14 EGF Receptor Activation Enhances Proliferative Capabilities of Cancer Cells Self-sufficiency in growth signals Insensitivity to anti-growth signals Evasion from apoptosis Limitless replication potential Sustained angiogenesis Tissue invasion and metastasis 15 RTK Inhibition 1. Block ligand binding to receptor 2. Block receptor dimerization 3. Induce receptor endocytosis and degradation (via ubiquitination 4. Block tyrosine kinase activity 16  ErbB2/HER2 Receptors in Cancer Amplification of the gene encoding HER2 was the first consistent genetic alteration detected in human breast tumors HER2 belongs to the epidermal growth factor (EGFR) family of receptor tyrosine kinases Patients with elevated HER2 have a poor prognosis HER2 receptor a target for anti-cancer therapeutics – MCAB against extracellular domain – Tyrosine kinase inhibitors that inhibit the intracellular enzymatic activity of the receptor 17 Herceptin Binds to the extracellular domain of the HER2 receptor Disruption of receptor dimerization and downstream signaling Arrest cells in G1 phase Herceptin suppresses angiogenesis Most effective when used in combination with chemotherapy Cetuximab stimulates EGFR internalization Panitumumab - fully human monoclonal antibody to EGFR (newer generation of antibody) 18 Problems with Antibody Approach Dose-limiting systemic toxicities Mice lacking EGFR usually die during first postnatal week due to respiratory problems. They also show gastrointestinal phenotypes, thin skin, and hair-follicle defects. Some skin rashes and diarrhea in treated patients High molecular weight, distribute slowly and incompletely Require I.V. Elicit immune response 19 Targeting one specific receptor species may not block heterogeneous receptor combinations Solution: Use tyrosine kinase inhibitors 20 Imatinib: template for rational drug design  Target: BCR-ABL tyrosine kinase  Clinical use: Chronic myeloid leukemia (CML) CML is characterized by a chromosomal translocation called the Philadelphia chromosome The bcr-abl tyrosine kinase activates mediators of the cell cycle regulation Constitutively active 21 Imatinib 22  Resistance to imatinib is multifactorial BCR-ABL overexpression BCR-ABL kinase mutation BCR-ABL independent mechanisms Nilotinib is a second-generation tyrosine kinase inhibitor active against a wide range of imatinib-resistant or-intolerant patients 23 Gefitinib (Iressa) ATP site competitive inhibitor of EGFR tyrosine kinase activity IC50 value of 0.033 μM (EGFR/HER1) and was shown to also effectively inhibit HER1-HER2 heterodimers. approved (by US FDA) in 2003 for patients with non-small cell lung cancer (NSCLC). The response rate in patients taking the drug was approximately 10%. Due to the lack of evidence of benefit of Gefitinib, the FDA issued an alert (06/2005) to health care professionals to use Gefitinib (Iressa) only in patients that had already responded to the treatment in the past. 24  Erlotinib (Tarceva) EGFR inhibitor approved FDA for patients with non-small cell lung cancer (NSCLC) Lapatinib Dual EGFR/ ErbB inhibitor 25 Tyrosine Kinase inhibitors (TKI) versus mAbs TKI are orally administered, mAb require I.V. TKI have low molecular weights and distribute more rapidly and possibly more completely than mAbs. Cross react with other kinases (dual EGFR/ErbB2 inhibitors), mAbs are specific TKI lack immune responses Severe acneic skin rashes (including folliculitis) and diarrhea with TKI TKI do not downregulate Receptors, mAb do TKIs and mAbs exhibit different clinical response profiles 26  Angiogenesis Inhibitors Monoclonal antibodies against vascular endothelial growth factor-A (VEGF-A) and its receptor – inhibits angiogenesis – starves the tumor cell of oxygen/nutrients Avastin (Bevacizumab) - used to treat metastatic colorectal cancer – First clinically available angiogenesis inhibitor in the US (2004) – not a chemotherapeutic agent – administered with standard chemotherapy treatment e.g. 5-FU 27 Angiogenesis Inhibitors 28  Proteosome inhibitors Drugs that block the action of proteasomes Proteasomes degrade unneeded or damaged proteins Prior to degradation protein are first tagged by linkage to ubiquitin Proteasomal degradation of certain proteins are critical for cell cycle regulation 29 Bortezomib B atom binds the catalytic site of the proteasome – High affinity and selectivity Proteasome inhibition may prevent degradation of pro-apoptotic factors – Cell cycle arrest and apoptosis Used in the treatment of relapsed multiple Myelosuppression** myeloma- Peripheral neuropathies – approved June 2008 for use in combination with melphalan and prednisone for newly diagnosed patients Marizomib (NPI-0052) – currently in clinical trials – an irreversible proteasome inhibitor, derived from a marine actinomycete – less myelosuppression and peripheral neuropathy 30