Pathways & Apoptosis PDF

# Pathways ## Signaling Pathways ### Pisk Pathway - Pathway initiated when a growth factor (like EGFR) binds to a tyrosine kinase (RTK) on the cell surface. - Cause receptor to autophosphorylate, creating binding sites for Pisk - Pi3k is then activated & catalyzes the conversion of PIP2 into PIP3. -...

# Pathways ## Signaling Pathways ### Pisk Pathway - Pathway initiated when a growth factor (like EGFR) binds to a tyrosine kinase (RTK) on the cell surface. - Cause receptor to autophosphorylate, creating binding sites for Pisk - Pi3k is then activated & 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 & activates Foxo which helps with cell cycle progression. - Foxo inhibits apoptosis. #### Drugs that work on the Pisk pathway: - Idelalisib - Copanlisib - Duvelisib ### Ras Pathway - Pathway initiated when growth factor binds to an RTK on the cell surface causing dimerization & autophosphorylation of the receptor. - Once Ras is activated, it - Activates the small GTPase Ras - Shifts from an inactive GDP-bound state to an active GTP-bound state - Binds to & activates Raf - Activates MEK - Activates 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 in the Raf pathway: - Vemurafenib - Trametinib - Dabrafenib - Sorafenib ## Mutations in Ras + Raf are common in cancers. - Lead to uncontrolled cell proliferation. - If Ras is mutated, drugs administered cannot be given to the patient - Mutated Ras makes cancer cells behave differently, which can complicate treatment. # Apoptosis ## Intrinsic Pathway - Internal stimuli signal cell that conditions are unfavourable for survival. - Signals activate pro-apoptotic members of Bcl-2 family protein (BAX & BAK). - These proteins insert into mitochondria, causing its permeabilization, allowing release of cytochrome c & other apoptotic factors into the cytoplasm. - Cytochrome c & Apaf-1 bind, form Apoptosome. - Apoptosome recruits & activates caspase-9. - Once caspase-9 is activated, it cleaves & activates caspase-3 & caspase-7. - These caspases degrade cellular proteins & other structures, leading to controlled cell death. ### What drives apoptosis? - Mitochondrial damage - Cytochrome c release - Apoptosome formation ## 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 & Procaspase 8 to the intracellular death domain of receptors, to form DISC complex. - Components assemble & Procaspase-8 is cleaved to its active form, caspase-8 - Activated caspase-8 can directly activate downstream executioner caspases & activates the protein Bid. - Caspase-8 cleaves & activates caspase-3. - Caspase-3 degrades cellular proteins, dismantle cell structure & ultimately lead to apoptosis. ### What drives apoptosis? - Receptor activation - DISC formation - Caspase cascade # Immunotherapy - Cancer treatment that leverages the body's immune system to identify, target & destry cancer cells. ## Types of Immunotherapy ### Checkpoint Inhibitors - Drugs that block checkpoint proteins, allowing immune cells to detect & kill 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 & 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. Immunotherapy works by enhancing T-cells ability to detect & destroy cancer cells. 2. PD-1/PD-L1 & CTLA-4 inhibitors block proteins that act as "off switches" on T-cells. 3. CAR T-cell therapy helps the immune system develop a memory response, providing long-term protection against cancer reoccurrence. # Side Effects - Autoimmune disease - Fatigue, fever & 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 & immune cells. ## In cancer: - When PD-L1 on tumor cells binds to PD-1 on T-cells, it essentially sends a "stop" signal to T-cells. - Preventing them from attacking the tumor. - As a result, this allows cancer cells to escape immune detection & 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 antibody - Binding of mAbs to PD-1/PD-L1 disrupts the PD-1/PD-L1 interaction, which prevents T-cells from becoming inactive. - As a result, T-cells can recognize & destry cancer cells, enhancing the body's anti-tumor 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 & tumor cells & can stimulate the immune system to kill cancer cells. - This happens because the antibody acts as a bridge, which helps immune cells recognize & 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 cancer's ability to evade the immune system & 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 - DNA methylation - Methyl groups are added to DNA, often silencing genes. - Abnormal hypermethylation in cancer can turn off tumor suppressor genes. #### Drugs - Azacitidine: reactivating silenced genes - Decitabine: used for treating certain blood cancers - Histone modification - Histone acetylation: acetyl groups attached to histone, 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 - Vorinustat: counteract deacetylation, allowing gene expression in cancer cells, esp. certain lymphomas. - Romidepsin: counteract deacetylation, allowing gene expression in cancer cells, esp. certain lymphomas.