Pathways PDF

# Pathways ## Signaling Pathways ### 1. PI3K Pathway * **Pathway initiated** when a growth factor (like EGFR) binds to a receptor tyrosine kinase (RTK) on the cell surface, creating binding sites for PI3K. * **PI3K** is then activated and catalyzes the conversion of PIP2 into PIP3. * **PIP3** act...

# Pathways ## Signaling Pathways ### 1. PI3K Pathway * **Pathway initiated** when a growth factor (like EGFR) binds to a receptor tyrosine kinase (RTK) on the cell surface, creating binding sites for PI3K. * **PI3K** is then activated and catalyzes the conversion of PIP2 into PIP3. * **PIP3** acts as a secondary messenger, recruits proteins like Akt (PKB) to the cell membrane. * **Akt** inactivates BAD which inhibits apoptosis; activates mTOR which stimulates protein synthesis (cell growth); inactivates GSK-3B, which stimulates cell proliferation and activates Foxo which helps with cell cycle progression and inhibits apoptosis. #### Drugs that work on the PI3K pathway - Idelalisib - Copanlisib - Duvelisib ### 2. Ras Pathway * **Pathway initiated** when growth factor binds to an RTK on the cell surface causing dimerization and autophosphorylation of the receptor. * **Once Ras** is activated, it recruits adapter proteins, which in turn activates the RTK. * **Ras then** switches from an inactive GDP-bound state to an active GTP-bound state. * **Activated Ras** binds to and activates Raf. * **Raf then** phosphorylates and activates MEK, which in turn phosphorylates ERK. * **Once ERK** is activated, it leads to transcription of genes in the nucleus that drive cell cycle progression, differentiation, survival, and growth. #### Drugs that work on the Raf pathway - Vemurafenib - Trametinib - Dabrafenib - Sorafenib ## Mutations in Ras and Raf are common in cancers, leading to uncontrolled cell proliferation. * If Ras is mutated, drugs administered to the patient cannot be given as mutated Ras makes cancer cells behave differently, which can complicate treatment. # Apoptosis ## 1. Intrinsic Pathway * **Internal stimuli** signal cells that conditions are unfavorable for survival. * **Signals activate** pro-apoptotic members of Bcl-2 family protein (BAX and BAK). * **These proteins insert** into mitochondria, causing its permeabilization allowing release of cytochrome c and other apoptotic factors into the cytoplasm. * **Cytochrome c and Apaf-1 bind** and form Apoptosome. * **Apoptosome recruits and activates** caspase-9. * **Once caspase-9 is activated, it cleaves and activates** caspase-3 and caspase-7. * **These caspases degrade cellular proteins and other structures** leading to controlled cell death. #### What drives apoptosis? - Mitochondrial damage - Cytochrome C release - Apoptosome formation ## 2. Extrinsic Pathway * **Extracellular death ligands bind to specific death receptors** on the cell surface * **Ligand binding causes receptor trimerization leading to the recruitment of FADD and procaspase-8 to the intracellular death domain of receptors** * **Components assemble** to form DISC complex. * **Procaspase-8 is cleaved to its active form, caspase-8**. * **Activated caspase-8 can directly activate downstream executioner caspases, or intersect the intrinsic pathway by cleaving and activating the protein Bid.** * **Caspase-8 cleaves and activates** caspase-3. * **Caspase-3 degrades cellular proteins, dismantling structure and ultimately leads to apoptosis** #### What drives apoptosis? - Receptor activation - DISC formation - Caspase Cascade # Immunotherapy * Cancer treatment that leverages the body's immune system to identify, target and destroy cancer cells. ## Types of Immunotherapy ### Checkpoint Inhibitors * Drugs that block checkpoint proteins, allowing immune cells to attack cancer cells. * **CTLA-4 Inhibitors:** * Ipilimumab targets CTLA-4, a checkpoint protein on T-cells. * **PD-1/PD-L1 Inhibitors:** * Pembrolizumab targets PD-1/PD-L1 pathway, preventing cancer cells from “turning off" T-cells. * Nivolumab targets PD-1/PD-L1 pathway, preventing cancer cells from “turning off" T-cells. ### CAR T-cell Therapy * A patient's T-cells are removed, modified to better recognize and attack cancer cells. * **Engineered to target specific proteins** on cancer cells. * **Used for certain types of blood cancers:** * Leukemia * Lymphoma * Gives the immune system more specific tools to fight certain cancers. ### Cancer Vaccines * **Stimulate the immune system to attack cancer cells.** * **Includes** treatments like HPV, which prevent cancer related to certain viral infections. ## Mechanism of Action ### 1. Activation of T-cells * Immunotherapies work by enhancing T-cells’ ability to detect and destroy cancer cells. ### 2. Checkpoint Inhibitors * PD-1/PD-L1 and CTLA-4 inhibitors block proteins that act as “off switches” on T-cells, freezing them to attack cancer cells. ### 3. Memory response * Immunotherapies, such as CAR T-cell therapy may help the immune system develop a memory response, providing long-term protection against cancer recurrence. # Side Effects * Autoimmune disease * Fatigue, fever and flu-like symptoms * Organ inflammation # PD-1/PD-L1 Pathway * **PD-1 (Programmed Death -1):** a receptor on T-cells. * PD-L1 (Programmed Death - Ligand 1): a protein on some cancer and immune cells. ## In Cancer: * When PD-L1 on tumor cells binds to PD-1 on T-cells, it essentially sends a “stop” signal on T-cells. * Preventing them from attacking the tumor. * As a result, this allows cancer cells to escape immune detection and destruction. ## Under normal conditions: * PD-1 receptor binds to PD-L1 on cells as a regulator signal, telling T-cells to reduce its activity. * This interaction helps prevent autoimmunity by protecting normal cells from an overactive immune response. # Monoclonal Antibodies (mAbs) * Lab-produced molecules engineered to bind to specific antigens. ## How they work: * mAbs are designed to attach specifically to cancer cell antigens, allowing mAbs to hone in on cancer cells without affecting most normal cells. * Once bound, mAbs can attract immune cells to kill cancer cells. * Some mAbs (like trastuzumab for HER-2 positive breast cancer) block signals that promote cancer cell growth. * Certain mAbs are paired with chemotherapy drugs or radiation to deliver treatment directly to cancer cells. ## Advantages: * Offer targeted treatment, reducing damage to normal cells. * Work well with other treatments (chemotherapy or immunotherapy) * Targeted action leads to fewer side effects compared to traditional therapies. # Bispecific Antibodies * Engineered antibodies that can simultaneously bind 2 different antigens or 2 distinct sites on a single antigen. ## How they work: * They have 2 antigen-binding sites that recognize different targets. * By binding immune cells and tumor cells, they can stimulate the immune system to kill cancer cells. * This happens because the antibody acts as a bridge, which helps immune cells recognize and attack tumor cells. * Some bispecific antigens are designed to target a tumor while also blocking a specific signaling pathway that promotes cancer growth. This dual approach limits cancers’ ability to evade the immune system and grow. ## Advantages: * Target 2 sites simultaneously, helping to reduce unintended effects on healthy cells. * By guiding immune cells to cancer cells, they strengthen the immune response against tumor. * Bispecific antibodies combine cancer targeting with immune activation in a single treatment. * Dual-targeting makes it harder for cancer cells to evade treatment, helping to prevent resistance. # Epigenetics * **Epigenetic changes** = heritable modifications in gene expression without altering the DNA sequence. ## Main mechanisms ### 1. DNA Methylation * Methyl groups are added to DNA, often silencing genes. Abnormal hypermethylation in cancer can turn off tumor suppressor genes. * **Drugs:** - Azacitidine - Decitabine reactivate silenced genes, used for treating certain blood cancers. ### 2. Histone Modification * **Histone acetylation:** Acetyl groups attached to histones, loosening DNA around them, which promotes gene expression. * **Histone deacetylation:** Removal of acetyl group makes DNA wrap tighter which can repress important gene function. * **Drugs:** - Vorinostat - Romidepsin counteract deacetylation, allowing gene expression in cancer cells, especially certain lymphomas