IHOP Exam 1.docx

Intro Breast Cancer Prostate Cancer Colon Cancer Hodgkins: Mortality drops by ~70% because of cytotoxic chemotherapy Chronic Myeloid Leukemia: Mortality drops by ~60% because of targeted chemotherapy Acute Lymphoblastic Leukemia: Cure rate 10%-90% because of clinical trial Chemotherapy Cytotoxic (...

Intro Breast Cancer Prostate Cancer Colon Cancer Hodgkins: Mortality drops by ~70% because of cytotoxic chemotherapy Chronic Myeloid Leukemia: Mortality drops by ~60% because of targeted chemotherapy Acute Lymphoblastic Leukemia: Cure rate 10%-90% because of clinical trial Chemotherapy Cytotoxic (kills cells) Indiscriminate killing Predictable toxicity Myelosuppression Alopecia Nausea and vomiting Secondary Cancers Surprising toxicity Targeted therapy More cytostatic (prevents from growing) Preferential blockade of vital cell processes On-target toxicity (predictable) Off-target toxicity (unpredictable) Screening Pro: Cervical and colon cancer have predictable pre-cancerous lesions that occur first Con: Overdiagnosing everyone with elevated PSA that probably would have never caused any significant harm Cancer Pathophysiology Cell Cycle (cytotoxic drugs work on this); “cell-cycle specific”: works in a specific phase of cell cycle; “cell-cycle non-specific”: works no matter where the cell is in the cycle G1 phase: Preparation for DNA replication This phase is analogous to getting ready/packing for a trip. The cell is getting ready to make a new copy of cells – need to make sure there are enough nucleotides, ATP, energy, etc. G1 – S Interphase/Checkpoint Rb (retinoblastoma) – this gene is important in regulating cell cycle progression; when ACTIVE it PREVENTS cell cycle from progressing. children who inherited inactivation of Rb are routinely diagnosed with cancer behind the eye. If 2 bad copies of Rb, they will have cancer much earlier and in both eyes If Rb gene does NOT work properly, the cell will progress to the S-phase when it should not; cell cycle checkpoint of G1-S interphase is inactivated. There is no “check” on whether or not the cell should move on to the S-phase. This increases the chances that a “bad” or oncogenic mutation will occur during DNA synthesis (S-phase). It increases the chances that the cell will become cancerous (mutation during proliferation), BUT it does not mean the cell will definitely become cancerous. Several prominent mutations need to occur for a cell to become malignant. When ready to move into S-phase, CDK is phosphorylated and INACTIVATES Rb. This allows cell cycle to progress S phase: Synthesis & DNA Replication p53 protein Tp53 a tumor suppression gene More errors higher levels of p53 programmed cell death (don’t want to go on to G2 phase) S – G2 Interphase What if the cell isn’t ready? What if there are errors in DNA copying? DNA Repair Enzymes Base excision repair (repairs single strand breaks) PARP Mismatch Repair (MMR) MSH2 MLH1 Double Strand Breaks (deficiencies in these genes higher likelihood of developing cancer) BRCA1 BRCA2 G2: Preparation of Mitotic Spindles Microtubules serve as physical infrastructure necessary to separate cells M: Mitosis & Cell Division G0: Quiescence “resting phase” Protooncogene – encodes for proteins that make cells grow & divide Oncogenes – mutation to protooncogene (always on or increased activity) make cell GO This makes the cell go through the cell cycle to synthesize, replicate, and divide EGFR (HER1), HER2 (ERBb2, Neu, EGFR2), CyclinD1, K-ras, N-ras, H-ras, Braf, Myc, Myb, Fos, FGF3, Ret, Src Tumor Suppressor Genes Brake Pedal TP53, Rb, APC, PTEN, BRCA1/BRCA2, NF1/NF2, VHL Oncogenic Viruses HTLV-1 (T-cell leukemia), EBV (lymphoma), HPV (cervical cancer), HBV/HCV, HHV-8, HIV Hijacks cells own machinery by modifying genome. Anytime you change genes, there is a chance that the change will cause an activation of an oncogene or inactivation of a tumor suppression gene Hallmarks of Cancer Sustained Proliferative signaling – too many pro-growth signals (aka too much gas pedal) Mutated growth factor receptors are always on (usually controlled by tyrosine kinases) Increased cell proliferation Upregulation/Stimulation of growth factors Autocrine (cell itself is stimulating growth factor) Paracrine (from nearby cells widespread inflammation) More cells proliferate more chance for mutation Ex. Constitutive activation of EGFR If a cell developed a mutation to RAF that resulted in RAF loss of function cell would STOP proliferating; RAF is part of the signaling cascade, so if RAF stopped working, the signaling would also stop. With no signal, the cell would stop proliferating. What may happen next would be an alternative pathway that bypasses RAF and activates MEK or ERK to maintain necessary signaling (detour – not the ideal or quickest, but sometimes necessary). “Bypassing” a pathway is a key mediator of resistance to drugs that block cell signaling. Evading growth suppressors – for every growth signal, there is a corresponding signal to prevent growth tumor suppressors PTEN inhibits PI3K/AKT/mTOR pathway If mutated, increased activation of pathway, because cell evaded growth suppressor Rb disruption – this is found at the interphase between G1 and S phases (checkpoint that stops from moving on to the next phase) increased chance of mutation during cell proliferation Tp53 inactivation – this is found at the S and G2 interphase; a tumor suppression gene 50% of human cancers have mutation/inactivation of tp53 Avoiding differentiation There are certain mutations (ex. c-myc oncogene) that prevents cells from becoming the type of cell they are meant to be (hair, skin, etc.) Resisting cell death – more cancers in body more dysregulated growth more cancer cells start to become more and more different b/c of mutations more likely to be resistant to drug therapy because they are all different (can’t have one drug to kill them all if each cancer cell has a different genome) Recall: if during the G1 phase, cell is not ready to move on to S phase, Rb prevents it from moving into the next cycle. If you prevent cell cycle progression long enough, the cell should undergo programmed cell death (apoptosis). Tp53 does the same thing! Programmed cell death serves as protective function against potentially dangerous cellular abnormalities Ex. oncogene over-signaling Ex. DNA damage during proliferation – if you get so much DNA damage, the cell SHOULD die, but some DNA damage lead to mutations. If cell doesn’t die, it keeps growing with more mutations Cancerous cells develop ways of resisting apoptotic signals Ex. overexpression of Bcl-2 blood cancer/leukemia/lymphoma resisting cell death There are proteins in cell that serve as mediators of apoptosis mediators bind to proteins to then instigate apoptotic signaling/programmed cell death Bcl-2 binds to the messenger proteins that cause apoptosis and prevent them from carrying the message If you can’t cause apoptosis, cancer cell doesn’t die. We have drugs that can bind to Bcl-2 and prevent Bcl-2 from blocking those signals Inducing angiogenesis (angio = blood; genesis = production production of new blood vessels) – as cancer cells grow, it needs more blood to get nutrients in (oxygen, glucose, nucleotides, proteins) and also needs a way to get a waste out from the cell Vascular endothelial growth factor (VEGF) that is upregulated in many cancer cells and it causes growth of new blood vessels The larger the tumor, the more important angiogenesis becomes in the maintenance of the tumor Some tumors get so big and grow so fast that they can’t keep up with creating blood vessels and start to die from inside out (why you can find necrotic tissue inside large tumors) Enabling replicative immortality – normal cells possess a limited number of times you can go through the cell cycle (there is a cap called a telomere at the end of the DNA strand. Everytime the cell replicates, the telomere gets shorter, like a MDI!) Telomerase adds back the telomere which gives cells a limitless number of copies made of themselves They become resistant to apoptosis Telomerase activity is common in cancer cells, but not in healthy cells It is advantageous that normal cells do not typically have telomerase activity because the lack of telomerase limits or caps the total number of times a cell can proliferate. If a cell proliferates or replicates enough times, it is likely a bad or oncogenic mutation will happen. This is a built in safety feature of cells. The older a cell is and the more times it is replicated, the shorter its telomers. Once they are too short, the cell undergoes apoptosis. Cancer cells use telomerase to keep telomers long to allow for infinite replication and proliferation likely leading to even more genomic instability Activating invasion & metastasis – tumor genetic changes allow cancer cells to invade surrounding tissue Ex. ductal carcinoma in situ (DCIS) – cancer cells that have not yet had genetic change that allows them to invade tissue next door There has to be a certain set of genetic mutations that happen before it can invade local tissue Even more genetic changes later to invade far away tissue (metastasis) Local invasion: breast cancer that spreads from breast to axillary lymph node under the arm Metastatic invasion: breast cancer invades bone in hip, brain, liver etc. There are certain mutations in the breast cancer that allows it to go to bone vs brain (similar, yet different, genetic changes allow cancer cells to colonize distant tissues) Emerging hallmarks Evading immune destruction – CANCER CAN AVOID IMMUNE DESTRUCTION We have drugs that target this avoidance of immune destruction T cells in body can see non-self cells – MHC1 holds peptide up (if not self, immune system will kill; such as protein/peptide fragments from viruses, gene products that are not supposed to be there because of mutations PD-L1 expression prevents T-cell activation upon a tumor cell. Immune system is not able to recognize that the non-self cell is non-self (think invisible cloak) There are drugs that target this! Deregulating cellular energetics – cancer cells have their own diet and because they are constantly growing and dividing, they require more energy needs Ex. upregulation of glucose transporter (GLUT1) that gets more glucose into cells; we use this to monitor cancer therapy in PET scans Enabling characteristics Genomic instability – inability to repair DNA Cancer cells more likely to develop and keep genetic mutations Lots of overlap here in terms of mutations occurring in cancer cells Tumor-promoting inflammation – inflammation results in increased supply of bioactive factors Ex. chronic GERD and Barrett’s esophagus Ex. HBV chronic inflammation b/c of inflammation, have growth factors coming to locale; more growth factors, more gas pedal cell signaling, increasing chance for oncogenic mutation Latest Hallmarks Unlocking phenotype plasticity – leopard can change its pattern Normal differentiation: precursor cell will differentiate to cell its supposed to be (epithelial precursor cell to columnar epithelial cell) Dedifferentiation go backwards ex adult to teenager (grow more, more likely to be oncogenic) Blocked Differentiation never grow up, stay as teenager more likely to become cancer (ex APL) Transdifferentiation changing of the spots ex. Barret’s esophagus (squamous columnar cells) Explains why breast cancer starts to grow in bone despite no disease in breast (phenotypic plasticity type of cell growing somewhere it shouldn’t be) Nonmutational epigenetic reprogramming – hallmark characteristics may develop without mutational changes Not actually changing the code, changing the carbon groups around the code which can turn genes on/off. Ex. hypoxic conditions result in impaired cellular function that may promote tumorigenesis Polymorphic microbiomes – Microbiome can be cancer protective or cancer promoting Bacteria in gut naturally prone to breaking down alcohol (irritating to GI) cancer protective Bacteria produce toxins which increase risk of cancer; ex. butyrate (oncogenic metabolite) Direct inflammation Senescent cells G0 phase (not growing) Senescence is thought to be a protective mechanism, but it appears some cells can be only temporarily senescent These cells go into G0 because telomeres are shortening/should not be replicating; but they can go back and forth into cell cycle and can be a key factor in drug resistance Key Points: Inactivation of Rb’s function potentially leads to cancer because there would be an increased chance of mutations during cell proliferation. TP53 Evading growth suppressors Tumor suppressor gene commonly mutated or inactive Constitutive activation of EGFR Sustained proliferative signaling PD-L1 expression Avoid immune system destruction Bcl-2 over expression Resisting programmed cell death VEGF upregulation inducing angiogenesis HPV affects cell cycle progression of infected cells DNA replication occurs in the S phase Separation of copied chromosomes occur in the M phase HBV can cause cancer because it causes chronic inflammation HIV is implicated in causing cancer due to immunosuppression Telomerase promotes cancer development because it allows cells to divide an unlimited number of times, increasing the odds of the cell acquiring an oncogenic mutation. DNA cross-linking agent: Alkylating Agents Prototype: Mechlorethamine; Nitrogen Mustards: Melphalan, Chlorambucil, Cyclophosphamide (Cytoxan), Ifosfamide (Ifex), Busulfan; Nitrosoureas: Carmustine, Lomustine; Thiotepa MOA: Adds something to DNA molecule to cause a distortion in DNA strand to the point that RNA can no longer read the strand and use it for replication. Covalent bond forms on one side of DNA helix. Can’t unwind so stops DNA synthesis/replication. End result is cross-linking of DNA (create a bridge within strand or cross strands to impair DNA synthesis/kill a cell). This can lead to: Base excision Miscoding (possibility for mutations) DNA strand breakage DNA adducts (additions to DNA strand) NOT cell specific – healthy cells will also be compromised in addition to tumor cells Highly electrophilic compounds Nucleophilic groups on DNA attack the electrophilic drug to form COVALENT bonds Cells that are rapidly dividing are more susceptible to cytotoxic chemo Nitrogen mustards (cytotoxic chemo agents similar to mustard gas): Chlorambucil, Melphalan, Cyclophosphamide (Cytoxan), Ifosfamide (Ifex), Busulfan Self-activates: Starts with loss of chlorine atom forms intramolecular bond nitrogen becomes electron deficient/positively charged (iminium ion) Form cyclic aminium ions (aziridinium rings) by intramolecular displacement of the chloride by the amine nitrogen Aziridinium group alkylates DNA once attacked by nucleophilic center on guanine base Reactivity (to reduce toxicity) Remember: electron donating = activating; electron withdrawing = deactivating Aliphatic nitrogen substituent Electron donating promotes self-activation contributing to intramolecular nucleophilic attack As soon as aziridinium ion forms it will react with DNA Lower stability in aqueous environment Aromatic nitrogen substituent – REDUCES reactivity Stabilize lone pair of electrons and SLOW intramolecular nucleophilic attack Permits PO admin Selectivity (to reduce toxicity) – Increase by: Incorporation of amino acids Also helps improve stability because of electron withdrawing groups Incorporation of phosphorous containing functional groups Tumor cells have higher concentration of phosphoramidase, so drug would activate more in tumors vs healthy cells Specificity Modifications to moieties off the nitrogen mustard to increase cellular uptake and increase specificity for cancer cells (-N(C2Cl)2) Melphalan: Historically used for multiple myeloma Contains a substituent that looks like phenylalanine which improves cellular transport; may improve selectivity for cells that are doing more protein synthesis Aromatic substituents: Deactivating group slows the intramolecular nucleophilic attack Chlorambucil, busulfan: Lower seizure threshold Aromatic substituents: Deactivating group slows the intramolecular nucleophilic attack Cyclophosphamide (Cytoxan) – requires metabolic activation (CYP450 Oxidation) therefore lower GI toxicity Toxic metabolites: Acrolein: bladder, kidney, and nerve toxicity Chloroacetaldehyde (2nd toxic metabolite) – 10% of dose is converted to this: neurotoxic and nephrotoxic Active Form: Phosphamide Mustard (produced along with acrolein) Ionized/charged species: activation has to happen inside the target cell otherwise it wouldn’t be able to cross the cell membrane Ifosfamide (Ifex): slower activation due to steric protection by Cl More water soluble than cyclophosphamide Metabolic activation proceeds more slowly due to steric hinderance (CYP 3A4) 60% of dose generates chloracetaldehyde; reaction can occur in the renal tubule Nitrosoureas (Lomustine, Carmustine) – activated using Cl leaving group which generates highly electrophilic species that DNA will attack Very lipophilic, Cross BBB Unstable compounds that decompose in the aqueous environment of the cell into 2 active compounds Intracellular decomposition results in dual MOA DNA alkylation (guanine & cytosine) AA reactivity (lysine) Toxicities associated with cell damage & cell death Carmustine alkylates DNA bases and carbamoates lysine (protein) Packaged as single lyophilized (freeze-dried) dose due to aqueous instability Using 10% ethanol in the preparation of carmustine helps solubilize the drug and reduce its interaction with water Due to low melting point, carmustine should be STORED IN A REFRIGERATOR Lomustine More stable to intramolecular attack because it does not have a chlorine leaving group off the vulnerable nitrogen can be given PO because it doesn’t self-activate Toxicities (of Alkylating Agents) Traditional Myelosuppression – suppression of bone marrow (bone marrow makes RBC, WBC, and platelets; so we are suppression the production/function of bone marrow) Happens 2-3 weeks later No effects on mature WBC already in blood or RBC already in circulation WBC have DNA (RBC do not b/c no nucleus). Cytotoxic chemo preferentially kills rapidly dividing cells; drugs work by preventing and destroying DNA synthesis Nausea/vomiting (body knows it is getting toxins so tries to get rid of it) Mucositis – inflammation of mucosal lining (mouth all the way to anus) Mucosal lining is constantly sloughing off and reinforcements are coming through daily See it more in the mouth Happens a few weeks later Alopecia Unique toxicities (as a class) Secondary leukemias Gonadal toxicity (infertility) Cyclophosphamide & Ifosfamide Hemorrhagic Cystitis because of Acrolein, a toxic metabolite Acrolein is also associated with kidney toxicity and nerve damage Mesna (sulfuric compound given before cyclophosphamide dose) Chemoprotectant that inactivates acrolein Prevents cyclophosphamide/ifosfamide-induced hemorrhagic cystitis Myelosuppressive (decrease production of WBC leads to immunocompromised) and immunosuppressive (impairs T cell function) Ifosfamide produces isophosphoramide mustard: active metabolite which affects DNA adducts chloro-acetaldehyde: neurotoxic metabolite Toxicity Management Cyclophosphamide (Cytoxan) – all patients encouraged to drink 2-3L of fluids the day of an infusion (similar for PO daily dosing) ***REMEMBER: hemorrhagic cystitis Mesna is reserved for higher doses >750mg/m2/cycle Stem cell conditioning regimens hyperCVAD regimen Mesna considered for special conditions such a renal dysfunction Ifosfamide (Ifex) – IV hydration ***REMEMBER: hemorrhagic cystitis (acrolein damages the urothelial lining of the bladder) ALL patients receive Mesna Monitor for neurotoxicity Risk factors: Renal dysfunction Hypoalbuminemia Aprepitant interaction Mesna chemoprotectant used to prevent ifosfamide-induced hemorrhagic cystitis Mitigates acrolein-induced toxicity by mimicking glutathione DNA cross-linking agent: Organoplatinum complexes Cisplatin, Carboplatin, Oxaliplatin Contain an electron deficient metal atom that acts as a magnet for electron-rich DNA nucleophiles Pt(II) and Pt(IV) complexes with a net charge of zero (II) and (IV) indicates how many bonds can form to DNA strand (4 & 6 ligands) Chlorine and oxygen act as electron donors to the platinum atom Loss of chlorine exposes electron deficient metal and makes compound open to nucleophilic attack Bifunctional (like nitrogen mustards) Intra-strand cross-linking typically involves adjacent guanine residues Works the same way as alkylating agents (2 potential Cl- leaving groups) Cisplatin MOA: Cl leaving groups creates a highly reactive intermediary compound Positively charged intermediate that is highly reactive (more than carboplatin and oxaliplatin) Electrophilic reactive intermediate binds to the nucleophilic N7 site of purine bases Forms a DNA adduct Compound can bind to other DNA sites causing DNA crosslinks End result: DNA damage and cell death, especially rapidly dividing cells Like a wrench: one side binds to one part of DNA strand while the other binds to a different part resulting cisplatin-DNA complex prevents DNA replication, resulting in cell death Toxicity Nausea and vomiting (highly emetogenic) Nephrotoxicity (acute and chronic/late effect): highly reactive intermediate binds to proteins and other cellular moieties including those in the kidney; Cisplatin is eliminated via the kidneys, so high concentrations accumulate Hypokalemia Hypomagnesemia Ototoxicity Neuropathy Gonadal toxicity (risk of infertility) Nephrotoxicity Prevention Since activity is dependent on the Cl- as leaving group, saturating the environment with Cls can offer protection Patients should receive IV fluids (1L) with normal saline (0.9% NaCl) pre- and post-cisplatin SLOW infusions (1mg/min) produce lower renal cisplatin concentrations Using D5W instead of normal saline would be most nephrotoxic Carboplatin More bone marrow suppression than cisplatin: especially thrombocytopenia Slower activation than cisplatin because ester hydrolysis must first occur Little to no of other toxicities seen with cisplatin NO IV fluids necessary Dosing based on Calvert equation Dose (mg) = AUC * (GFR + 25) AUC = total drug exposure want 5-6mg/unit time Caveats: eGFR should be capped at 125mL/min Think of 125mL/min as the kidney’s physiology max rate Carefully weigh benefit of treatment with risk of toxicity Obese: using actual body weight for GFR estimate may overestimate GFR and result in excess toxicity Low baseline SCr (<0.8 mg/dL): using actual SCr for GFR estimate may overestimate GFR. May result in excess toxicity Oxaliplatin Slower activation than cisplatin because ester hydrolysis must first occur Similar to carboplatin with regards to toxicity More myelosuppression than cisplatin Moderately emetogenic Unique peripheral neuropathy Acute: exacerbated by cold counsel patients to avoid drinking cold beverage or touching cool objects for ~1 week after treatment Chronic: similar to cisplatin (dose-dependent) Key Points Oxaliplatin: causes peripheral neuropathy that is exacerbated by cold temperatures, including cold beverages Mesna chemoprotectant used to prevent ifosfamide-induced hemorrhagic cystitis Alkylating agents form covalent bonds with DNA base pairs leading to DNA cross-links, which impairs DNA synthesis Ifosfamide-induced hemorrhagic cystitis caused by toxic metabolite (acrolein) which damages the urothelial lining of the bladder Cisplatin AE: hypomagnesemia, hypokalemia, severe nausea Cyclophosphamide (Cytoxan) Hemorrhagic cystitis cyclophosphamide Ifosfamide (Ifex) Shared toxicity of all alkylating agents: secondary leukemias Nephrotoxic Cisplatin Antimetabolites (cell-cycle specific (S phase) agent) Pyrimidine antimetabolites: 5FU, Capecitabine; Purine antimetabolites: 6MP, 6-Thioguanine; Anti-folates: Methotrexate, Pemetrexed (Alimta); Nucleoside anti-neoplastics: Cytarabine, Gemcitabine, Azactibine, Nelarabine MOA: Block normal metabolic pathways in cells Replace endogenous compound in pathway Inhibit enzyme in pathway – interferes with de novo DNA synthesis by inhibiting nucleotide formation Structures resemble normal metabolites or endogenous compounds Entice the enzyme target to choose them over the endogenous substrate All cause some degree of hallmark toxicities (mucositis, myelosuppression, alopecia, n/v) Pyrimidine antimetabolites: 5-FU, Capecitabine Pyrimidine prodrug converted to deoxyribonucleotide form 5-Fluorouracil (5FU) 5-FU MOA: thymidine monophosphate production (TS) inhibition as IV; RNA false base pair as bolus 5FU more electrophilic than actual uracil so nucleophilic enzyme will go after it first (F substrate instead of H) Compound forms a covalent bond to the enzyme. Issue of selectivity is still a problem Creates a highly electrophilic false substrate for thymidylate synthase Thymidylate synthase is critical in DNA replication DNA synthesis is more upregulated in tumor cells so more affected by 5FU than healthy cells Pharmacogenetic test to predict toxicity to dihydropyrimidine dehydrogenase When given with leucovorin, stronger inhibition of thymidiylate synthetase so INCREASES INHIBITION of thymidylate synthetase Leucovorin increases 5FU activity Most common 5FU regimen FOLFOX: All on day 1, repeat Q2weeks (FOLinic acid, 5-Fu, Oxaliplatin) – 3 unique antineoplastic MOAs! Oxaliplatin (2 hour IV) Leucovorin, aka folinic acid (2 hour IV) 5FU bolus (AE myelosuppression, n/v) 5FU 46-hour continuous infusion (mucositis, diarrhea, hand-foot syndrome) Capecitabine (Xeloda) Oral pro-drug of 5FU mimics infusional 5-FU There is a higher concentration of thymidine phosphorylase (capecitabine is activated by this) in tumor cells than in healthy cells when you give this drug, more 5FU is delivered to cancer cells than healthy cells Enzymatic steps helps to narrow effect to tumors MOA: RNA false base pair Toxicity (different admin schedules have different toxicities) Bolus 5FU Myelosuppression (more DNA false base pair produced) Supportive care: CBC, temperature monitoring Nausea/vomiting Supportive care: avoid sun exposure Capecitabine (PO BID x2 weeks/1 week off) & Continuous infusion 5FU Mucositis Supportive Care: Cryotherapy (ice chips) – vasoconstriction so less drug delivery Diarrhea Supportive Care: PRN anti-diarrheal Hand-foot syndrome (esp Capecitabine) Supportive Care: Emollients (10% urea) Avoid sun exposure Pharmacogenetic Considerations Dihydropyrimidine dehydrogenase (DPD) is the rate limiting step in 5-FU metabolism Pt with DPD deficiency likely to experience life-threatening toxicity Neutropenia Mucositis Diarrhea Neurotoxicity Uridine triacetate (Vistogard) – competes with FUTP for RNA incorporation Used to rescue patients with DPD deficiency or accidental overdose Lonsurf (trifluridine/tipiracil) Trifluridine – thymidine false base pair Tipiracil inhibits thymidine phosphorylase prevents intracellular breakdown of trifluridine triphosphate Approved for advanced colorectal cancers Unique: hemolytic uremic syndrome/thrombotic thrompcytopenia purpura Purine antimetabolites (tend to be used for lymphocytic malignancies): 6-Mercaptopurine (6MP), 6-Thioguanine, Fludarabine 6-Mercaptopurine, 6-Thioguanine Currently marketed agents are both 6-thio analogs of endogenous purine bases Prodrugs that must be converted to ribonucleotide Have to undergo activation to a full nucleotide MOA: Inhibit DNA synthesis & sometimes affect RNA synthesis Interfere with biosynthesis of purines May disrupt DNA synthesis by being incorporated into DNA structure Act as RNA & DNA false base pairs to inhibit purine synthesis Lymphocytes do not have salvage pathway entirely dependent on de novo pathway Purine analogs are much more effective at killing lymphocytes than other types of cells AE: Low levels of B&T cells PO agents used in maint tx of acute lymphocytic leukemia Primary metabolic route: thiopurine methyltransferase (TPMT) TPMT testing required before initiation Homozygous TPMT deficiency requires at least 90% dose reduction Xanthine oxidase metabolizes 6-MP/6-TG Allopurinol, febuxostat drug interaction: increased 6MP/TG toxicity Allopurinol increases myelosuppression of 6MP by slowing metabolism (50% dose reduction needed) Some patients have altered metabolism of 6MP that creates more hepatoxic metabolites ADDING allopurinol decreases hepatotoxicity, but requires 6MP dose reduction to minimize severe myelosuppression Fludarabine Inhibits DNA polymerase & ribonucleotide reductase Unique toxicity Profound lymphopenia (good for lymphocytic cancers) Opportunistic infections: PCP, VZV/HSV Prophylaxis required PCP: TMP/SMX DS MWF, inhaled pentamidine, dapsone VZV/HSF: acyclovir, valacyclover Cladribine & Pentostatin Seldom used (hairy cell leukemia) Cladribine: DNA false base pair inhibiting DNA synthesis Pentostatin: inhibits adenosine deaminase Enzyme critical to purine base metabolism Similar to fludarabine in effect Profound lymphopenia Opportunistic infection prophylaxis indicated Antifolates: Methotrexate (MTX) MOA: Hijack utilization of folic acid in cell (inhibit a key enzyme in the folate pathway) Structurally designed to compete with 7,8-dihydrofolate for the dihydrofolate reductase (DHFR enzyme) – key enzyme in the folate pathway inhibiting this results in feedback inhibition for purine & pyrimidine biosynthesis Effects of inhibiting tetrahydrofolate production Impaired DNA & RNA synthesis Decreased production of cellular proteins (due to decreased production of methionine & serine) C4NH2 substituent is key to activity of MTX Folic acid is functional, MTX is an inhibitor MTX binds to DHFR through an ionic interaction with Asp27 on the enzyme Highly hydrophilic will go where water goes Accumulation may occur in fluid reservoirs (pleural effusions, ascites) Renally eliminated (filtration & secretion) Drug interactions Urine alkalinization promotes excretion MTX is functionally acidic increasing urine pH will increase water solubility and urinary excretion Toxicities Myelosupression MUCOSITIS Most often seen with weekly, low-dose MTX in autoimmune disorders (often in setting of too much drug such as in reduced renal clearance) LFT elevations (usually transient) Acute renal failure MTX can precipitate in the acidic environment of the kidneys causing damage Hydration & alklalinization of urine can minimize/prevent this Pulmonary (chronic/cumulative in nature) High Dose MTX > 1gm/m2 LETHAL without leucovorin rescue Leucovorin = reduced folic acid rescues healthy cells without rescuing cancer cells NECESSARY FOR HIGH DOSE MTX Dose is adjusted by MTX levels 10mg/m2 IV/PO Q6 hrs initially Rescue theory The folate transport mechanism is broken in a malignant cell. High dose MTX enters cell via passive diffusion so Leucovorin cannot enter (cancer cells develop a mutation that prevents the pump from working) The folate transport mechanism works fine in healthy cells so Leucovorin is able to enter the cell & rescue it from MTX Leucovorin uses cancer cell mutation against it Overcomes resistance and the need for active transport into tumor cells Maintain urine pH >7 and UOP >100 mL/hr must have good urine output Alkalinization of urine requires IV fluids containing NaHCO3- beginning before drug administration Avoid drugs that may delay clearance, thus increasing potential for toxicity Probenecid, sulfamethoxazole, PCN, NSAIDS (or other nephrotoxic drugs) PPIs; H2Ras are safe Without proper supportive care kidney failure, death Glucarpidase (Voraxaze) Antidote for MTX toxicity/overdose Enzyme that hydrolyzes MTX Indication: delayed clearance of MTX following high-dose admin due to renal impairment Pemetrexed (Alimta) Anti-folate that inhibits multiple enzymes in the folate pathway (DHFR, TS, GARFT, AICARFT) REQUIRES pre-medication Folic acid 400mcg to 1000mcg daily Vit B12 1000 mcg IM q 9 weeks Folic acid & B12 supplement reduce myelotoxicity Dexamethasone 4mg PO BID x3 days beginning the day before treatment Dexamethasone reduces cutaneous reactions (ex. desquamation) Prevent skin reaction/cutaneous reactions Nucleoside anti-neoplastics: Cytarabine, Gemcitabine, Azactibine, Nelarabine Complex, multi-faceted mechanisms: DNA polymerase inhibition DNA chain elongation inhibition DNA methyltransferase inhibition All have a base (purine or pyrimidine) & sugar moiety Cytarabine (SQ, Intrathecal, continuous infusion: 100-200mg/m2/day) MOA: S-phase-specific inhibits DNA polymerase Phosphorylated into active component Cytarabine triphopsphate, aracytidine triphosphate Used for leukemias/lymphomas Toxicities Hallmark: mucositis, myelosuppression, alopecia, n/v Rare: cytarabine syndrome (diffuse rash and nonspecific symptoms corticosteroids may be helpful) High Dose Ara-C (HiDAC) Generally considered 1000-3000 mg/m2 Higher dose overcomes cytarabine resistance Higher dose forces CNS penetration Unique toxicities Cerebellar dysfunction requires monitoring during treatment Chemical conjunctivitis/keratitis Prophylaxis with corticosteroid eye drops: from start of tx to 48 hrs after end of tx Gemcitabine (Gemzar) MOA: S-phase specific inhibit DNA polymerase Requires phosphorylation Wide spectrum of activity Leukemia, lymphoma, solid tumors Dosing: 1000-1250 mg/m2 IV Cycles vary by indication and patient Days 1 & 8 of a 21 day cycle Days 1, 8, & 15 of a 28 day cycle Admin over 30 minutes longer admin times = more toxicity Toxicities Hallmark: mucositis, myelosuppression, alopecia, n/v Especially thrombocytopenia (low platelet) Key Points MTX MOA inhibits a key enzyme in the folate pathway MTX AE mucositis Supportive care for high dose MTX (>1gm/m2) Urinary alkalization Leucovorin rescue Sustained UOP >100mL/hr High dose MTX w/o proper supportive care death, kidney failure Pt with delayed clearance following high-dose MTX treatment Voraxaze Pharmacogenetic test to predict toxicity to 5FU Dihydropyrimidine dehydrogenase 6-mercaptopurine thiopurine methyltransferase (TPMT) Leucovorin with 5FU increase 5FU activity MTX rescue healthy cells from MTX toxicity Gemcitabine Gemzar Pemetrexed Alimta Supportive care meds required to be given: vit b12, folic acid, dexamethasone Capecitabine Xeloda Cytarabine cell-cycle specific: S phase AE of high-dose cytarabine (>1000 mg/m2) Chemical conjunctivitis/keratitis Cerebellar dysfunction AE of hand-foot syndrome capecitabine More pronounced AE with purine analogs low levels of B & T cells MOA of 5FU Incorporation into RNA as a false base pair, inhibition of thymidine monophosphate production Accidental 5-FU overdose Uridine Triacetate (Vistogard) Greater myelosuppression: 5-FU 500mg/m2 IV bolus weekly x6 weeks of an 8 week cycle Mitosis Inhibitors Taxanes: Docetaxel, Paclitaxel (Taxol), nab-paclitaxel (Abraxane); Vinca alkaloids: Vincristine > vinorelbine > vinblastine All microtubule inhibitors cause peripheral neuropathy Microtubule Function: Cytoskeletal support Chromosomal separation during M-phase Assembly Disassembly Concentrated in CNS: movement & axonal transport involvement Taxanes: Docetaxel (Taxotere), Paclitaxel (Taxol), Cabazitaxel, nab-paclitaxel (Abraxane) MOA: bind to tubulin, promote microtubule assembly Prevent disassembly (M-phase specific) Compounds come from natural product sources 15-membered taxane ring fused to an oxetane ring and esterified side chains stability issues! Ongoing challenges with water solubility Some drugs are conjugated with albumin to help with solubility & stability Paclitaxel (Taxol) “paclitaxel paralyzes” Unique toxicities Hypersensitivity reactions (diluent) Cremophor diluent – a castor oil derivative Premedication required: dexamethasone, diphenhydramine, H2RA Peripheral neuropathy – any drug that inhibits microtubules will cause peripheral neuropathy Administration Special “Taxol” tubing required DHEP-free; in-line (0.22 micron) filter Infusion rate is dose-dependent (1 vs 3 vs 24 hours) Vesicant precautions (tissue necrosis if leaves blood) Nab-paclitaxel (Abraxane) Nab formulation has greater solubility No Cremophor vehicle required no hypersensitivity concern no premedication Faster infusion possible (30 minutes) NOT interchangeable with conventional paclitaxel Dosing NOT equivalent Greater delivery to tumor cells, especially pancreatic cancer cells Docetaxel (Taxotere) Unique toxicities Hypersensitivity reactions (less than paclitaxel) Edema Requires premedication: dexamethasone (edema is an odd manifestation of peripheral neuropathy) Peripheral neuropathy (less severe than pacli) Greater myelosuppression than pacli Vinca alkaloids: Vincristine (Oncovin), Vinorelbine, Vinblastine MOA: Inhibits microtubule elongation by binding to alpha- and beta- tubulin Bind to tubulin, prevent microtubule assembly (M-phase specific) Unique Toxicities FATAL if given intrathecal Mandatory aux label upon dispensing Best practice dispense in mini-bag vs syringe Peripheral neuropathy (all agents) Constipation (a form of autonomic neuropathy) Vincristine dose capped at 2mg/dose Bone marrow suppression (myelosuppression) VinorelBine VinBlastine NOT Vincristine – makes it attractice for multi-agent chemo regimens 2 main ring systems: Velbanamine – chiral systems cannot be modified Vindoline – most opportunity for modifying SAR Ixabepilone Epithilone B analog Binds to Beta tubulin subunit Promotes, then paralyzes microtubule function Contains Cremophor (same premed as Pacli) Premedication required: dexamethasone, diphenhydramine, H2RA Eribulin Halichonrin B analog Inhibits microtubule spindle formation and thus polymerization Key Points By law, requires an auxiliary label upon dispensing with the warning “FATAL if given intrathecal” vinorelbine Dexamethasone required before docetaxel to prevent edema Gemcitabine S-phase Requires DHEP-free rubing w/ 0.22 micron in line filter for admin Taxol Vincristine Oncovin Unique toxicity of paclitaxel hypersensitivity reactions Pre-meds to safely administer conventional paclitaxel dexamethasone, diphenhydramine, famotidine Taxotere Docetaxel Vincristine works on M-phase Prevent microtubule assembly Leucovorin rescue is needed with: MTX 6grams IV over 4 hours Cisplatin NOT cell cycle specific Paclitaxel Taxol MOA: prevents microtubule disassembly Topoisomerase I Inhibitors Irinotecan (Camptosar), Topotecan (Hycamtin) MOA: cleaves one DNA strand and inhibits resealing Camptothecin analogs Irinotecan (Camptosar, CPT-11) IV ONLY SN-38 active metabolite Liposomal formulation now available Toxicity Early diarrhea (during infusion) Cholinergic “storm” (SLUD – salivation, lacrimation, urination, defacation) Tx: atropine 0.25 to 1mg IV – an anticholinergic may also be used as prophy Late diarrhea (~12-24 hours after infusion) Loperamide 4mg initially, then 2mg Q2 until no loose stools x12 hours MAY exceed OTC max dose (16mg/day), but 48-hr limit Hallmark: myelosuppression, n/v, alopecia, mucositis Predictors of Effect PK: Metabolized by CYP3A4 into two inactive metabolites Carboxylesterase turns it into SN38 (primary active agent) SN38 does most of the effect (good and bad) Inactivated by UGT1A1 a glucuronidase enzyme into SN38G Beta-glucoronidase (intestinal) produced by bacteria in gut and will de-glucoronidate SN38G back into SN38 in the lumen of the GI tract reactivated SN38 can cause diarrhea, & can be reabsorbed and cause more myelosuppression Both forms Eliminated fecally (via bile into GI tract) Elevated tbili greater irinotecan toxicity (needs dose reduction) Ex. hepatic dysfunction, Gilbert’s syndrome UGT inducers decreased toxicity/effect Smoking (smokers breakdown SN38G very well, but will also decrease effect) Carbamazepine, phenobarbital, phenytoin (increase UGT activity) Normal dose; 125mg/m2 IV Q2weeks Inducer dose: 340mg/m2 IV Q2weeks Pharmacogenetic UGT1A1*28 deficiency Pre-testing not routine for conventional irinotecan Labeled doses different for liposomal irinotecan Usual 75mg/m2 50mg/m2 if homozygous for UGT1A1 allele Supportive Care Plan for diarrhea to occur Low dose atropine prn early diarrhea/cholinergic storm High dose loperamide (above OTC 16mg/day max) Educate on importance of staying hydrated Pharmacist order review Tbili Drug interactions Pharmacogenetic evaluation Topotecan (Hycamtin) IV & PO availability Topoisomerase II Inhibitors Etoposide (Toposar), Etoposide phosphate (Topophos), Teniposide MOA: Double DNA strand breaks, but religation is inhibited S/G2 phase arrest Epipodophyllotoxins Significant myelosuppression, some n/v and mucositis Derived from natural toxins of American Mayapple Etoposide (Toposar, VP-16) – IV & PO Unique toxicity: secondary leukemia MLL gene mutations Happen a 2-3 years later Etoposide phosphate (Topophos) Increased solubility Allows for faster infusion Hypotension is rate-limiting for IV rate of admin (30-60 mins) Teniposide Anthracyclines Drug class is some of the most important at treating leukemias Toxicity Hallmark: n/v, myelosuppression, mucositis, alopecia Cardiotoxicity Decreased left ventricular ejection fraction (LVEF) Class effect Risk increases with cumulative exposure of Doxorubicin Cumulative dose monitoring (mg/m2) Lifetime max exposure (cumulative lifetime dose >400mg/m2) Standard dose = 50mg/m2 8 standard doses to reach lifetime max exposure Vesicant Causes tissue necrosis with extravasation Red-colored urine/tears following admin Doxo and Dauno Bolus vs infusion Likely more myelosuppression & cardiotoxicity with bolus Secondary leukemias (MLL gene mutation) Doxorubicin (Adriamycin) – The Red Devil MOAs Cell Cycle specific Topoisomerase II inhibition (predominant MOA) The most important contributor to cytotoxicity Covalently binds to Topoisomerase II & DNA prevents religation Cell Cycle Non-specific DNA intercalation Insertion of a drug (or something else) in between DNA base pairs results in single & double strand DNA breaks Free radical production Mediated by enzymes and Fe-complexes Reactive intermediates are then capable of damaging intracellular proteins and metabolites that can covalently bind to DNA Historically believed to be a driving mechanism of the class’ cardiotoxicity VESICANT properties! Liposomal Doxorubicin (Doxil) Liposomal formulation leads to lower Cmax, but longer exposure Different toxicity profile from conventional doxorubicin Less n/v, myelosuppression, cardiotoxicity More dermatologic toxicity (mucositis) Hand-foot syndrome can be dose limiting Mitoxantrone (just 3 rings) Same MOAs, but less free radical production than anthracyclines Toxicity profile vs anthracyclines Less cardiotoxicity Less severe vesicant properties Dexrazoxane (anti-dote for doxorubicin) Failed topoisomerase II inhibitor as chemo also has chelating properties to prevent Fe-mediated free radical production (did not treat cancer, but caused myelosuppression) Zinecard approved to limit cardiotoxicity of doxorubicin Consider in patients with 300mg/m2 lifetime exposure Also appears to decrease effectiveness of doxorubicin Totect Approved to treat anthracycline extravasation Remember to remove ice before administration (initial treatment is ice slows down free radical cascade and decreases blood flow to area) When ready to give dose, take ice off for at least 15 minutes to allow for more blood flow drug will work as free radical scavenger Monitoring LVEF assessment @ baseline ECHO (EF %) or MUGA (radioactive scan that will give exact number of ejection fraction) Signs/Sx of extravasation Tx with ice dexrazoxane CBC Typically antineoplastic nadir (lowest point): 10-14 days after dose LFTs Dose reductions for t. bili >1.2 (normal = 1) per package insert If bili is elevated, ability of body to eliminated drugs will be lower so more toxicity Miscellaneous Agents Bleomycin – hallmark drug for Hodgkins and Testicular Cancer Antitumor antibiotic MOA: Inhibits DNA synthesis by creating single & double strand breaks Free radical production after binding to metal Broken down by bleomycin hydrolase Unique toxicity PULMONARY FIBROSIS, pneumonitis PFT monitoring (before tx) DLCO (look for this on report) Cumulative lifetime exposure tracking highest risk after 400 units lifetime exposure NO myelosuppression Idiosyncratic reactions test dose required in some cases Change in skin tone (gray/blue) Procarabzine Alkylating agent Slightly higher rate of secondary leukemias than some alkylating agents PO dosage form Monoamine Oxidase Inhibitor (MAO-I) Patient education on high tyramine-containing food and drink (aged sausages, cheese, wine, beer, etc) Drug interaction considerations serotonin syndrome (fever, muscle changes, hypertension) Forgotten Alkylators Dacarabazine (DTIC) Pro-drug Hepatic activation to MTIC (an alkylating agent) HIGHLY EMETOGENIC Temozolomide (Temodar) Pro-drug serum hydrolysis to MTIC PO agent 100% bioavailability BBB penetration CNS malignancy use (brain tumors) Low dose QD for 6 weeks white count will go down to 3 or 2 severe lymphopenia (decrease in B & T cells PJP/PCP) Then higher dose for 5 days Long-term use (6 weeks) Lymphopenia PCP prophy required Hydroxyurea Antimetabolite inhibits ribonucleotide diphosphate reductase Blocks conversion of ribonucleotides deoxyribonucleotides (myelosuppression) G1/S phase arrest As an antineoplastic, used mainly to reduce WBC in leukemia patients Cytoreduction A temporizing measure Most common use is for sickle cell disease Increases production of fetal hemoglobin Trabectedin Alkylating agent that binds to DNA minor groove Unique toxicity Hepatotoxicity Mitomycin C Alkylating agent Creates guanine-cytosine crosslinks Long nadir (4-8 weeks) Vesicant HUS/TTP Key Points Agent to tx diarrhea following irinotecan that occurs immediately after completion of infusion atropine Days after completion of infusion loperamide Irinotecan topoisomerase I Most to least cardio toxicity: Daunorubicin Mitoxantrone Etoposide Daunorubicin’s vesicant properties free radical production Etoposide inhibition of topoisomerase II Unique toxicity secondary leukemia Test before Epirubicin ECHO Doxorubicin Adriamycin Red-colored urine doxorubicin Predict toxicity from irinotecan UGT1A1 Decrease the risk of cardiomyopathy with doxorubicin Zinecard Agent approved to treat doxorubicin extravasation injury Totect Irinotecan Camptosar Vincristine and Bleomycin are NOT myelosuppressive Targeted Therapy The problem with chemo … kills ALL rapidly dividing cells Nausea/vomiting Myelosuppression Anemia Infection Thrombocytopenia Targeted therapy: focused effect on malignant cells Target: unique extracellular expression (CD20, HER2) Target: upregulated/mutated pathway (EGFR) Unique toxicity profile Usually based on target Target: unique extracellular expression (CD20, HER2) Target: upregulated/mutated pathway (EGFR) Unique toxicity profile Usually based on target Ex. pathways more active inside of a cell targeted epidermal growth factor receptor causes epidermal toxicity (rash, diarrhea: epidermal in nature) Toxicity profiles Chemotherapy narrow but severe Myelosuppression (affects quality of life, can be life threatening) Note this does NOT happen with vincristine and bleomycin Organ-specific Drug-specific Anthracycline Cardiotoxicity Cyclophosphamide and Ifosphamide Hemorrhagic cystitis Cisplatin nephrotoxicity Infertility Nausea Mucositis Alopecia Targeted Agent – wide breadth/greater variety, not as severe or life threatening; side effects are dependent on the target Hemorrhage ILD LFT Impaired wound healing Hypertension Metabolic abnormalities Hypothyroidism QTC prolongation Extreme fatigue (Asthenia) Rash Diarrhea Signal Transduction Intracellular Inhibition Kinase inhibitors – a kinase is an enzyme that adds a phosphate (an on switch). At end of each arrow, a phosphorylation occurs; blocking phosphorylation, blocks signaling Usually tyrosine kinase Bock phosphorylation and downstream signaling Independent of ligand Extracellular Inhibition Monoclonal Antibodies – binds on the outside of the cell (receptor) or circulating ligand in interstitial space in blood Block ligand binding Bind to target (receptor) Bind to ligand Ex. bevacizumab On-Target Toxicities (learn by pathway rather than drug) VEGF Angiogenesis, glomerular fenestration (help prevent protein from spilling in urine); helpful for releasing NO in blood which causes vasodilation IF BLOCKED: bleeding, VTE (if you stop a blood vessel in the middle of production and there is a hole in vessel, body will try to wall it off), proteinuria, HYPERtension (blocking release of NO), impaired wound healing EGFR skin, GI tract, nails Rash, diarrhea, paronychia (inflammation of nail beds) (B)RAF skin Rash, hand-foot skin reaction Lots of off target bc in all cells FGFR kidney Hyperphosphatemia mTOR so many metabolic (hyperglycemia, hyperlipidemia), mucositis, impaired wound healing, immunosuppression (mTOR inhibitors are used to prevent organ rejection) FLT3 bone marrow Myelosuppression PARP DNA single-strand break repair Myelosuppression, secondary malignancies (broken DNA strand break can be carried forward and propagated) HER2 epithelial cells, heart Diarrhea, cardiomyopathy PI3K all cells (metabolic function), B-cells Hyperglycemia, infection Imatinib & CML: Targeted Agent Success Story Philadelphia Chromosome CML (chronic myeloid leukemia) Only ONE single mutation can lead to this bcr-ABL fusion protein; needs ATP for ongoing signal transduction Imatinib binds to ATP binding pocket, so deprives oncogene of ability to phosphorylate Just one switch to eradicate all CML cells Most successful target because of underlying disease state (bc one mutation/simple) Immune System Targeting Not blocking essential cellular pathways Utilizing a unique antigen Present on malignant Absent on benign cells Rituximab CD-20 Present on B-cells & many B-cell malignancies Absent on other cells Spares T-lymphocytes, neutrophils, cells in bone marrow & heart MOA B cell with CD20 (extracellular/transmembrane protein), Rituximab will bind to CD20 and FcR receptor of effector cells (such as CD8+ T cell) will bind to it and can lead to lysis of B cell ADCC: “Antibody-dependent cell-mediated cytotoxicity” Complement can also bind to B cell which will lead to complement cascade which forms membrane attack complex, contents fall out and cell death occurs CDC: “Complement dependent cytotoxicity” Complement binds to macrophages and leads to phagocytosis ADP: antibody-dependent phagocytosis Apoptosis directly binding to CD20 Checkpoint inhibitors Allow immune system to “find” cancer cells Similar to viral infection process: virus infects cells virus inserts its genome into human genome to try to trick cells into making more virus particles in the process, will make viral DNA and viral protein will express on MHC-1 CD8+ T cells will look at that and say not normal peptide, I’m gonna kill the cell! this is also how body fights cancer Evading Immune System Evasion: Immune Checkpoint Inhibitors CTLA-4 is an example of checkpoint system a way of prevent immune system from overreacting and attacking own body PDL1; by blocking brake pedal, T cell can be activated and kill tumor cell Immune checkpoint inhibitors have revolutionized cancer treatments; bc cancer cell is growing rapidly, going through much more cell division and accumulates lots more mutations; some mutations lead to upregulation of PDL1 which is like an invisibility cloak (helps hide from immune system) Summary Targeted agents aim to take advantage of unique biologic differences in cancer cells Abnormal gene protein expression Upregulation of pathways More targeted towards specific pathologic variant that makes cancer cell more susceptible (usually some overlap with specific target and EGFR dependent toxicities) Different toxicity profile from traditional chemotherapy