MPP lecture 7.pdf

Learning Objectives: 1.Compare and contrast the general mechanisms of action and adverse effects of signal target antineoplastic therapies vs traditional antineoplastic therapies Traditional antineoplastic therapies - are broad-spectrum, affecting both cancerous and normal rapidly dividing...

Learning Objectives: 1.Compare and contrast the general mechanisms of action and adverse effects of signal target antineoplastic therapies vs traditional antineoplastic therapies Traditional antineoplastic therapies - are broad-spectrum, affecting both cancerous and normal rapidly dividing cells, leading to widespread side effects. - Goal: - Stop rapid dividing of cancer cells, Tumors are most sensitive to chemotherapy when growing rapidly - “Mitotoxicity Hypothesis” - Metabolically active cells are susceptible to drugs that interfere with cell growth and division - Mechanism: - These therapies, such as chemotherapy, target rapidly dividing cells indiscriminately. They work by interfering with cell division (mitosis) or damaging DNA, thereby inhibiting cancer cell proliferation. - Examples: - Alkylating agents, antimetabolites, topoisomerase inhibitors, and microtubule inhibitors. - Selectivity: - Non-specific, affecting both cancerous and healthy rapidly dividing cells (e.g., bone marrow, hair follicles, gastrointestinal tract lining). - Mechanism of Adverse Effects: - highly toxic side effects result from damage to healthy, rapidly dividing cells throughout the body. Signal Target antineoplastic therapies - are more precise, targeting specific cancer-related pathways, which generally results in fewer and more manageable side effects, though some are unique to the molecular targets involved. - Mechanism: - These therapies specifically target molecular pathways crucial to cancer cell growth, survival, or proliferation. They often target proteins, receptors, or specific mutations present in cancer cells. - Examples:  - Tyrosine kinase inhibitors (TKIs), monoclonal antibodies (mAbs), and immune checkpoint inhibitors. - Selectivity: - Highly specific to molecular targets, leading to more precise cancer cell targeting while sparing most normal cells. - Mechanism of Adverse Effects: - While more selective, these therapies can affect normal tissues that share the targeted molecular pathways or lead to off-target effects due to similarities in protein families. 2.Describe the mechanism(s) of action of EGF receptor antagonists EGFR Antagonists “Get Every Cell Targeted” - Getfitinib - Erlotinib - Cetuximab - Trastuzumab 1. Gefitinib: Type: Tyrosine kinase inhibitor (TKI) Mechanism: Acts as a reversible inhibitor of EGFR kinase activity, Blocks the ATP-binding site of EGFR, preventing activation of signaling pathways that drive cancer cell growth. Inhibition reduces cancer cell proliferation and survival, particularly in tumors with activating EGFR mutations. 2. Erlotinib: Type: Tyrosine kinase inhibitor (TKI) Mechanism: Inhibits the tyrosine kinase domain of EGFR, halting cell proliferation signals. Significant survival benefit. 3. Cetuximab (anti-ErbB1: Type: Monoclonal antibody (mAb) targeting EGFR family Mechanism: Antibody Binds to the extracellular domain of EGFR, specifically isoform ERbB1, blocking ligand binding and receptor activation, plus engaging the immune system. 4. Trastuzumab (anti-ErbB2):  Type: Monoclonal antibody (mAb) targeting EGFR family Mechanism: Antibody Binds to the extracellular domain of EGFR, specifically isoform ERbB2, blocking its signaling and reducing cancer recurrence by 50% Gefitinib and Erlotinib: inhibit EGFR by blocking the intracellular tyrosine kinase domain, preventing downstream signaling. Cetuximab: antibody that binds extracellular EGFR (ErbB1) with high specificity, blocking ligand binding and receptor activation Trastuzumab: antibody directed against extracellular EGFR (ErbB2), blocking its signaling and inducing immune-mediated cell destruction. 3.Define the mechanism(s) of action of BCR-ABL inhibitors BCR-ABL inhibitors "I Don't Need BCR-ABL" - Imatinib - Dasatinib - Nilotinib Mechanisms of Action for BCR-ABL Inhibitors 1. Imatinib: ○ Type: Tyrosine Kinase Inhibitor (TKI) ○ Key Mechanism: Binds to the ATP-binding site of the BCR-ABL fusion protein, inhibiting its tyrosine kinase activity. This prevents the activation of downstream signaling pathways that promote cell proliferation and survival in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). 2. Dasatinib: ○ Type: Dual SRC-ABL Inhibitor ( 2nd Class of Tyrosine Kinase Inhibitor (TKI)) ○ Key Mechanism: Inhibits BCR-ABL tyrosine kinase activity by binding to both the active and inactive conformations of the BCR-ABL protein. This  broad-spectrum inhibition helps overcome some resistance mechanisms to imatinib and is effective against various BCR-ABL mutations. 3. Nilotinib: ○ Type: Tyrosine Kinase Inhibitor (TKI) ○ Key Mechanism: Similar to imatinib, nilotinib binds to the ATP-binding site of the BCR-ABL protein but has a higher binding affinity. This results in more effective inhibition of the BCR-ABL tyrosine kinase activity and is useful in cases resistant to imatinib. Imatinib: a potent small molecule TKI inhibitor of ABL kinases in leukemia Dasatinib and Nilotinib: a dual SRC-ABL Inhibitor of BCR-ABL by binding to the ATP site of both active and inactive forms, addressing imatinib resistance. 4.Describe the mechanism(s) of action of Ras, JAK2, mTOR, MAPK, and proteasome inhibitors Ras/MAP Inhibitors - FTI’s - Sorafenib Mechanism: Ras inhibitors target the Ras protein, a key regulator in cell signaling pathways that control cell growth and division. These inhibitors block the activation or function of Ras, preventing it from transmitting growth signals downstream to effector pathways like the MAPK/ERK pathway. This impairs cancer cell proliferation and survival. FTIs: Inhibit RAS farnesylation, preventing Ras from being anchored to the membrane and activated, disrupting Ras/MAPK signaling. Sorafenib: a multi-kinase inhibitor that targets several RAF kinases (e.g., BRAF and CRAF), which are downstream components of the Ras signaling pathway. disrupts the MAPK/ERK signaling cascade, reducing cell proliferation and inducing apoptosis in cancer cells. PI3K Signaling mTOR Inhibitors - Rapamycin - Temsirolimus Mechanisms of Action for PI3K Signaling Inhibitors 1. mTOR Inhibitors: ○ General Mechanism: mTOR inhibitors block the mammalian target of rapamycin (mTOR) pathway, which is a central regulator of cell growth, proliferation, and survival. The mTOR pathway is activated by signaling through the PI3K/AKT pathway and plays a key role in translating growth signals into cellular responses. Rapamycin: - Mechanism: Inhibits mTORC1 by binding to FKBP12, reducing cell proliferation and increasing apoptosis. Temsirolimus: - Mechanism: A rapamycin derivative that also inhibits mTORC1, affecting tumor growth and survival. JAK-STAT Signaling JAK Inhibitors - Jak2 Inhibitors JAK-STAT Signaling Pathway 1. Mechanism: ○ JAK-STAT Pathway: ​Involves JAKs phosphorylating STATs, leading to their dimerization and translocation to the nucleus, which then act as transcription factors to regulate gene expression. JAK2 Inhibitors  - Mechanism: Block JAK2 activity, preventing STAT activation and downstream signaling, thereby reducing cell proliferation and survival in diseases associated with JAK2 dysregulation. Proteasome Inhibitors - Bortezomib Mechanism: Proteasome inhibitors block the activity of the proteasome, a cellular complex responsible for degrading ubiquitinated proteins. By inhibiting the proteasome, these drugs prevent the breakdown of proteins that regulate the cell cycle, apoptosis, and stress responses. This leads to the accumulation of pro-apoptotic factors and the inhibition of anti-apoptotic factors, promoting cancer cell death. Bortezomib: - Inhibits the proteasome, preventing the degradation of regulatory proteins, leading to increased apoptosis, disrupted NF-kB signaling, and cell cycle arrest in cancer cells. 5.Understand the basics of microtubule dynamics for mitosis The ability of microtubules to assemble and disassemble rapidly is important for their physiologic roles Pharmacologic agents can disrupt microtubule function either by: 1. Preventing the assembly of tubulin into microtubules 2. Stabilizing existing microtubules - preventing microtubule disassembly 6.Categorize, compare and contrast the three classes of chemotherapeutic agents and relate the mitotoxicity hypothesis to each class DNA damaging agents - Alkylating agents - Directly modify DNA structure by attaching an alkyl group to DNA ex: Cyclophosphamide, Mechlorethamine - Nitrosoureas (BCNU) target DNA in the same way as other alkylating agents, treat brain tumors crossing BBB - Antitumor antibiotics - Platinum complexes - Cisplatin Act similarly to alkylating agents by targeting nucleophilic centers is the most active drug used to treat testicular cancer - Bleomycin binds DNA and chelates iron causing single- and double-strand DNA breaks Inhibitors of DNA synthesis and integrity - Antimetabolites and folate pathway inhibitors - Topoisomerase inhibitors Inhibitors of Microtubule Function - Vinca Alkaloids - Inhibitors of Microtubule Polymerization: VincaAlkaloids Bind to β-tubulin on a portion of the molecule - Taxanes - Taxanes promote microtubule polymerization and inhibit depolymerization - Bind to β-tubulin on a portion of the molecule 7.Explain the mechanism(s) of action of alkylating agents, platinum compounds, and microtubule inhibitors 8.Predict the most appropriate chemotherapy given a clinical scenario Oncogenic mutation of ras is one of the most common events in malignancy (30% of cancers)