Exam 1 Flashcards

Question

Why are folate intermediates important for cell proliferation?

Answer 1

Folate is an essential cofactor for many enzymatic reactions. Folate/forms of folate are essential for RNA and protein synthesis as well as purine and pyrimidine base synthesis.

Answer 2

Methotrexate mimics folic acid (aka an antifolate) that binds to DHFR, but can't be reduced, so it inhibits the enzyme. - Activation: No activation needed - MOA: Inhibiting DHFR to stop RNA/protein/purine/pyrimidine synthesis - Resistance: Amplification of DHFR gene or mutation to DHFR to a resistant form of the enzyme, decreased polyglutamation to decrease the availability of methotrexate.

Answer 3

With 5-FU: Leucovorin acts as folate, so when you give leucovorin while the patient is getting 5-FU, it increases the efficacy of 5-FU bc more covalent ternary complexes are formed. (increases 5-FU activity) Methotrexate: Used to "rescue" normal tissues from MTX toxicity. It increases intracellular pools of tetrahydrofolate and reverses the toxic effects of DHFR inhibition. (decreases MTX activity)

Answer 4

Alkylating agents are drugs that generate reactive electrophilic intermediates that react with nucleophilic groups on DNA and proteins. This results in adding an alkyl group to DNA and protein. They are bifunctional due to having two alkylating groups that produce DNA intra and interstrand linkages. This cross-linking inhibits DNA replication & transcription (not cell cycle specific)

Answer 5

DNA is the main target. The major mechanism usually involves alkylation of purine bases in DNA. *Guanine N7 is most common site of alkylation these crosslinkers can non-specifically prevent replication or transcription and can act specifically to cause mispairing and DNA fragmentation

Answer 6

Alkylating agents - Cross-linking can cause intrastrand linking between two bases on the same strand and interstrand linking of two separate strands. - Mustards used for therapy have nitrogens that can form 2 covalent bonds - These react with many nucleophiles. Thiols are very reactive, also amines, cysteine and lysine residues, and glutathione (can "quench" activity). - Toxicity to cancer cells results from DNA alkylation and cross-linking. - Non cell cycle specific Platinum agents - These are covalent crosslinkers, but they don't have alkyl groups to alkylate with. These are platinum complexes that can bind in two spots, causing the crosslinking (especially with thiols). - In cells, the aquo form of these platinums are favors. The aquo form reacts primarily with Guanine N-7 and Adenine N-7. - Most commonly causes intrastrand, then the cell doesn't know what to do

Answer 7

Alkylating agents: - Cyclophosphamide - requires hydroxylation by hepatic CYP450, then this hydroxylated metabolite must be converted to PM in the tumor (PM can do the cross-linking; this also produces acrolein) *more modest side effect, but also causes hemorrhagic cystitis (acrolein is toxic to bladder mucosa) - Ifosfamide - similar to cyclophosphamide

Answer 8

Cisplatin - non-enzymatically converted to aquo form in cell, then primarily produces intrastrand cross-links. - cell cycle non-specific, but a little more disruptive in G1, since it messes with transcription - Side effects: dose-limiting nephrotoxicity (unique), N/V, peripheral neuropathy, ototoxicity, minimal bone marrow toxicity (this is good for combo products)

Answer 9

- Increased expression of DNA repair enzymes - Increase intracellular concentration of non-protein thiols, especially glutathione. This detoxifies the drugs. The reactive thiols intercept the reactive intermediates of alkylating agents - Increased expression of cellular glutathione S-transferase (GST), which speeds up the reaction with thiols

Answer 10

- Bone marrow and gut mucosa are especially sensitive due to rapidly proliferating cells (myelosuppresion, N/V) - Monoadducts are mutagenic and carcinogenic, meaning there are incidences of second malignancies...... meaning it causes cancer

Answer 11

Mesna contains a charged sulfonate group, so it doesn't penetrate cells. It ends up accumulating in the urine. This is good for patients on cyclophosphamide, since one of the byproducts of cyclophosphamide's acitvation is acrolein, which causes hemorrhagic cystitis (in bladder). Mesna has a free thiol that reacts and inactivates acrolein metabolites in the urine, thus blocking hemorrhagic cystitis.

Answer 12

Topoisomerases reduce localized supercoiling that occurs during transcription and translation. They also provide access to double stranded DNA by enzymes that are needed for replication, etc. Type I Topoisomerase - Cuts one strand of double stranded DNA, relaxes the remaining strand, then puts it back together. Type II Topoisomerase - Catalyzes double-stranded DNA breaks, which relieves torsional strain and untangles DNA. It can undo catenated DNA (chain-linked)

Answer 13

Topoisomerase I inhibitor - Binds to topo I and the DNA, which locks topo I onto the sites at the breaks in ssDNA. This stops DNA replication. These inhibitors can also insert themselves into the DNA, called intercollating, (due to polycyclic aromatic motif) so they act as a physical barrier preventing replication. - Ex. camptothecin (not used), topotecan, irinotecan (prodrug) Topoisomerase II inhibitor - Only inhibitors that produce double stranded DNA breaks are considered cancer chemotherapies. This type of inhibitor intercalates DNA, causes DNA damage due to free radicals, most importantly inhibits topo II - Ex. Doxorubicin ("the red devil"), daunorubicin, epirubicin, idarubicin, liposomal doxorubicin

Answer 14

Irinotecan is a prodrug that is converted to its active metabolite SN-38 by carboxylesterases. SN-38 is metabolized by UGT1A1. Around 10% of the population has polymorphisms that result in low expression of UGT1A1, meaning the active SN-38 would not be metabolized as fast. This leads to increased toxicity of irinotecan in this population.

Answer 15

Topo I inhibitors - resistance occurs from pgp overexpression, MRP overexpression, glutathione S-transferase overexpression, or topoisomerase downregulation/mutation to prevent the inhibitor from binding. Topo II inhibitors - all same as topo I inhibitors, but also if there is increased DNA damage repair. Etoposide is not impacted by glutathione S-transferase overexpression.

Answer 16

Topo I induced cleavage - cells in S phase are most sensitive (synthesis) Topo II - - Doxorubicin: non-cell cycle dependent, but activity tends to be greater in G2/M phase - Etoposide: G2 block-cell cycle specific. Only inhibits religation of topo II (does not intercalate).

Answer 17

Topo I inhibitors - polycyclic aromatic motif (used for intercalation) Topo II inhibitors - planar polycyclic ring linked to amino sugar

Answer 18

Anthracyclines - Doxorubicin, Dauomycin, Epirubicin, Idarubicin Due to free radial damage, Topo II inhibitors cause cardiotoxicity. This is because heart tissue has low levels of enzymes that neutralize free radicals. Dexrazoxane - EDTA (metal chelating agent) analog. Enters the cell and binds to iron, so it blocks iron-oxygen induced toxicities. Since the cardiotoxicity of doxorubicin is believed to be caused by iron-catalyzed free radical formation, this helps detoxify the damage. There is no evidence of this interfering with the antitumor effect.

Answer 19

Bleomycin - cytotoxic agent with 2 essential parts - bis(thiazole) intercalates into DNA with its charged side chain - imidazole coordinates iron oxygen species to generate DNA free radicals. - the radical intermediate leads to DNA ss and ds breaks Has greatest effect on cells in G2 and M phases of cell cycle Toxicity - Pulmonary toxicity (pulmonary inflammation -> fibrosis), minimal myelosuppression, also see a rash. - This is due to bleomycin usually being inactivated by bleomycin aminohydrolase, but there's not very much of that in the skin and lungs.

Answer 20

Microtubules are an essential part of the mitotic spindle. They move chromosomal material into daughter cells during mitosis. *Microtubules are somewhat unstable. As they grow larger, they fall apart. - Chromosomes need to be lined up & kinetochores need to be attached to spindle microtubules, or else the cell won't continue through mitosis. (if not -> cell death)

Answer 21

Vinca alkaloids - (destabilizers) prevent microtubule assembly (at + end) by binding to tubulin, leading to no attachment of microtubules to mitotic spindle and then mitotic arrest - Ex. vincristine, erubulin Taxanes - (stabilizers) prevent microtubule disassembly. These bind to tubulin to promote microtubule assembly & block depolymerization, which leads to mitotic arrest. - Ex. paclitaxel, docetaxel, cabazitaxel - pgp is a big problem (but not for cabazitaxel) Epothilones - (stabilizers) binds to tubulin and promotes tubulin polymerization & microtubule stabilization - Ex. ixabepilone - poor pgp substrate, so it's NOT cross-resistant with taxanes! - same toxicity as taxanes

Answer 22

Myelosuppression (sensory neuropathy is also common but it's reversible)

Answer 23

vinca alkaloids - peripheral neuropathy (microtubules are critical to nerve cell axon function) - vincristine: neurotoxicity - vinblastine and vinorelbine have less severe neurotoxicity - eribulin: lower rate of neurotoxicity

Answer 24

Synthetic glucocorticoids (ex. dexamethasone, prednisone, methylprednisolone) are used as palliative care to reduce inflammation and manage pain during chemotherapy. In lymphoid cancer, they have anti-cancer effects due to inducing cell death and cell cycle arrest, so they are commonly used in combo chemotherapies.

Answer 25

- Hormone-dependent cancers are disease specific (ex. breast vs prostate vs endometrial) - Primarily, we are targeting estradiol (breast, endometrial) and dihydrotestosterone (prostate) - The hormones are produced in the adrenal, ovary, testis, and adipocytes - These hormone receptors are cytosolic hormone-dependent transcription factors. They bind to their ligand, then they translocate to the nucleus, then they bind to DNA promoters and promote transcription. - The pituitary gland secretes LH and FSH that turns into testosterone or estrogen. This is regulated by negative feedback inhibition.

Answer 26

Breast cancer - - Estrogen receptors (ER) and progesterone receptors (PR) are measurable in tumors. If the tumor is well differentiated, it will likely have more ER. Poorly differentiated tumors will probs be ER-. ER+ is significantly more likely to respond to therapy. ER+/PR+ has an even better chance. - We also use molecular diagnostics to know what subtype the breast cancer is (there are at least 4 distinct types: Luminal A, Luminal B, HER2+, or triple neg) Prostate cancer - - Gleason scale determines how differentiated the cancer is - PSA (prostate specific antigen) is high (>6.5 ng/mL) in pts with prostate cancer (but if PSA is high, it doesn't automatically mean someone has prostate cancer)

Answer 27

- Prostate cancer is a slowly progressing disease. - Most important risk factor is age (40 years old) - Testosterone is rapidy and irreversibly converted to dihydrotestosterone (DHT) by 5α-reductase in prostate cells. DHT binds to the androgen receptor in prostate cells, and that complex is translocated to the nucleus. - AR binds to all the androgens, so we can't just inhibit the testosterone -> DHT conversion.

Answer 28

SERMs (selective estrogen receptor modulators) - Tamoxifen: prodrug that must be metabolized to 4-OH-TAM by CYP2D6. It is both an agonist and antagonist, depending on where it is in the tissue. - MOA: When tamoxifen binds to the ER, it inhibits both translocation and DNA binding by inhibiting estrogen from binding to the receptor. This blocks estrogen-dependent breast cancer cell proliferation. - Side effects: Due to agonist effects, there's an increased incidence of endometrial cancer (bad) and preservation of bone density in postmenopausal women (good). Due to antagonist effects, it can cause hot flashes/other menopausal symptoms. *tamoxifen is effective in both pre- and postmenopausal women. **ER agonist in uterus and blood; ER antagonist in breast, brain, and bone (partial)

Answer 29

SERDs (selective estrogen receptor down modulators) - Fulvestrant - pure ER antagonist - MOA: binds to ER and inhibits DNA binding, leading to rapid receptor degradation. - Approved to treat ER+ metastatic breast cancer in POSTmenopausal women who have progressed on other antiestrogen therapy. - Injection

Answer 30

Aromatase (aka CYP19) is essential in producing estradiol. It adds aromaticity. Aromatase inhibitors block the synthesis of estrogens, but not androgens or progesterone. The target of aromatase inhibitors is the peripheral adipose tissue. Ex. anastrozole, letrozole

Answer 31

In addition to the ovaries, adipocytes also produce estrogen in postmenopausal women. This is important because we are never going to be able to use a drug to negate the estrogen production of the ovaries, but we could negate the estrogen production of peripheral production if the woman is postmenopausal. For this reason, the primary target of aromatase inhibitors is in the peripheral tissue (adipose tissue), not the ovaries.

Answer 32

*these are used in post menopausal women Non-steroidal aromatase inhibitors - letrozole & anastrozole - competitive inhibitors of aromatase activity - toxicity: minimal toxicity. increases extent of bone density loss, causing increased fractures (compared to tamoxifen) Steroidal aromatase inhibitors - exemestane & androstenedione - irreversibly binds to the active and inactivates the enzyme ("suicide inhibitor") - toxicity: hot flashes, occasional peripheral edema and weight gain, increased cholesterol levels (nothing crazy)

Answer 33

**primary indication in PREmenopausal Chronic administration of GnRH analogs downregulates pituitary GnRH receptors and leads to pituitary desensitization. Decreased FSH leads to decreased aromatase and therefore decreased estrogen. At first the acute administration induces a surge of LH and FSH, which can make the tumor grow & increase all steroid hormone levels. But chronic administration with downregulate pituitary GnRH receptors and cause the pituitary to be less sensitive to GnRH, causing a severe loss of estrogen within 3-4 weeks. Long term side effects: hot flashes (+ menopausal symptoms), sexual dysfunction Ex. Leuprolide, Goserelin

Answer 34

yes, in the same way that they are used for breast cancer, GnRH analogs can shut down the ability for the testes to synthesize testosterone. Toxicity: "feminization"; gynecomastia, sexual dysfunction Ex. Leuprolide acetate, goselerin

Answer 35

AR antagonists - - AR binds to androgens and promotes transcription. We want to prevent the ligand-receptor complex from getting to the nucleus. These prevent AR translocation and binding to DNA Ex. enzalutamide, apalutamide, darolutimide *approved for metastatic and non-metastatic prostate cancer 5α-reductase inhibitors - These wouldn't work to fight the cancer, as AR can bind to lots of androgens, not just DHT. CYP17 inhibitors - - CYP17 catalyzes conversion of pregnenolone and progesterone to DHEA and androstenedione. Inhibiting CYP17 shuts down the first 2 steps in androgen synthesis. Ex. abiraterone

Answer 36

Breast cancer - - All patients that initially respond to endocrine therapies will develop resistance. We need to try to predict which pts will respond and what to treat them with next. - Several anti-estrogens are combined with CDK4/6 inhibitors, which helps with resistance since CDK4/6 has nothing to do with estrogen, it'll just kill stuff. Prostate cancer - - Mutations in AR can result in androgen independent activation and prevent binding of AR antagonists. This is called Castration Resistant Prostate Cancer

Answer 37

- Tyrosine - Threonine - Serine No, we can't phosphorylate phenylalaine. Instead, we use it to see if phosphorylating certain AAs actually makes a difference or not

Answer 38

Type I - binds to the active conformation of the kinases (ATP has to be bound first) Type II - bind also to the inactive conformation of the kinase (ATP bound or not, they can bind to both) Type III - allosteric binding outside of the ATP pocket

Answer 39

Gefitinib - type I TKI targeting EGFR Afatinib - covalent inhibitor of all ErbB receptors. starting to favored over competitive binding of gefitinib. Lapatinib - reversible TKI that blocks both HER2 and EGFR signaling Tucatinib - TKI that preferentially binds HER2. Has less side effects than lapatinib, maybe due to specificity for HER2.

Answer 40

Bcr-Abl is achromosomal translocation that is demonstratable in ~95% of chronic myeloid leukemia. It occurs when ABL is translocated to be attached to BCR. Bcr-Abl drives several proliferation pathways and is often hyperactive, which is bad. imatinib - type II inhibitor of Abl tyrosine kinase. Inhibition of the Abl tyrosine kinase results in reduced proliferation and enhanced apoptotic cell death (primarily indicated in treatment of chronic myeloid leukemia). Pts need to be on Abl inhibitors for LIFE ponatinib - BCR-Abl inhibitor. It can inhibit T315I, which usually is resistant to all other BCR-Abl compounds. Again, pts need to be on this for LIFE.

Answer 41

Type II inhibitors (ex. Quizartinib) are specific for ITD mutations. This is good because they will leave the correctly functioning receptors alone. first and second gen FLT3 inhibitors can have lots of side effects. Second gen (crenolanib) is more specific than the first gen (midostaurin) ones though.

Answer 42

BRAF mutations can cause melanoma. Dabrafenib - second generation BRAF-v600 inhibitor. This is good, but also has shown to maybe cause cancer? Also some mutations don't respond to this treatment. Trametinib - Type III inhibitor that inhibits kinase activity of MEK1 and MEK2 (these are downstream of BRAF). This is to be used with dabrafenib

Answer 43

BTK (Bruton's Tyrosine Kinase) is found to be more active in B-cell malignancies. BTK is important for normal B cell activity and B cell tumor growth. Ibrutinib - covalent inhibitor of BTK. We use ibrutinib in mantle cell lymphoma and chronic lymphocytic leukemia Acalabrutinib - second generation covalent BTK inhibitor. It's more potent and selective than ibrutinib, which means less side effects. It's indicated for B-cell lymphoma

Answer 44

mTOR is a serine-threnonine kinase. Inhibiting mTOR inhibits the immune response by blocking IL-2 signaling transduction. Rapamycin analoges are anticancer agents and immunosuppressants. - Sirolimus - Everolimus (only inhibits mTORC1 (not mTORC2) which can lead to feedback activation of Akt (bad) - Temsirolimus - Deforolimus Major problem - RESISTANCE

Answer 45

After a ligand binds to the receptor, the receptor dimerizes, then the kinase domain gets phosphorylated. This starts a chain of phosphorylation that results in proteins getting into the nucleus to cause replication/transcription. We can target kinase activity at the receptor binding site, at the dimerization site, at the kinase phosphorylation site, and at downstream kinases. (ex. EGFR, FLT3, MET, FGFR, PDGFR, RET) (VEGFR also good target)

Answer 46

Kinase inhibitors require biomarkers to guide their application. Mutations can be identified from tumor biopsy. anti-EGFR threrapies - EGFR (EGFR is mutated to be constitutively active, so targeting EGFR is especially effective). Detection of EGFR exon 19 deletions or exon 21 mutations FLT3 inhibitors - mutations in FLT3 lead to increased proliferation and decreased apoptosis MET inhibitors - METex14 mutations can cause hepatocyte growth factor (HGF) to be constitutively active. FGFR - mutations can cause activation in bladder cancer PDGFR - mutations are activated in gastrointestinal stromal tumors RET - mutations can cause activation in NSCLC and thyroid cancer

Answer 47

EGFR inhibitors - associated with a skin rash, but it actually relates to the pt doing better on the med compared to if they didn't get a rash (we don't know why this happens) lapatinib (HER2/EGFR inhibitor) - diarrhea, nausea, vomiting, reversible decrease in cardiac function (CHF symptoms) *tucatinib is more selective for HER2 and has less side effects imatinib (Abl inhibitor) - N/V, fluid retention/edema, neutropenia/thrombocytopenia; none of these are too bad trametinib (MEK1/2 inhibitor) - rash, diarrhea, lymphedema

Answer 48

T790M - this mutation is associated with drug resistance. This will render gefitinib and afatinib (EGFR inhibitors) pretty useless. We can use osimertinib in this case. Osimertinib is a 3rd generation EGFR inhibitor. It works differently, so it's not at risk of having the tumor develop resistance. (our only worry is if the cysteine that the drug binds to starts mutating, it'll render the drug useless. But this hasn't happened yet)

Answer 49

It helps predict recurrence of cancer, which can help prevent overtreatment. But these tests do NOT drive indications for specific therapies.

Answer 50

B-cells: antibody-producing cells. A B-cell is triggered when it encounters its matching antigen. The B-cell engulfs it and presents fragments of the antigen to T-cells. Binding of the T-cell activates the T cell. The T-cell then secretes cytokines that help the B-cell multiply and mature into antibody producing plasma cells. The released antibodies bind to matching antigens, then the antibody-antigen complexes are cleared. Antibodies: Composed of 2 heavy chains and 2 light chains. The top regions are variable domains where antigens bind. The bottom is called the constant domain

Answer 51

First, we inject the antigen into the mouse. The mouse will produce B cells that are specific to that antigen. At this time, we will fuse immortal tumor cells to the antibody-forming cells, creating hybridomas. These hydbridomas replicate to produce more antibodies. Then we can use those monoclonal antibodies and test for efficacy. We need to "humanize" these antibodies before we give them to a human, or else our immune system will recognize these as foreign.

Answer 52

trastuzumab - humanized, specific for HER2. This induces ADCC and incudes receptor internalization & degradation, which reduces the amount of HER2 on the surface. Binds to domain 4 of HER2. - SE: flu-like symptoms, risk of cardiomyopathy/CHF (increased in combo with adriamycin), hypersensitivity reactions pertuzumab - humanized, specific for HER2. This inhibits dimerization of HER2. Used in combo with trastuzumab!! Binds to domain 2 of HER2. cetuximab - chimeric antibodies that binds specifically to the extracellular domain of the EGF receptor (competitively inhibits binding of TGF-alpha and EGF) - SE: severe infusion reaction!! rash, muscle weakness, fever panitumumab - human antibody that specifically binds to extracellular domain of EGFR (competitively inhibits binding of TGF-alpha and EGF) - SE: way better. skin rash and diarrhea

Answer 53

bevacizumab - humanized antibody that is specific for VEGF (vascular endothelial growth factor). It binds to VEGF and blocks its interaction with endothelial receptors. It inhibits solid tumor growth. But there is NO EVIDENCE of efficacy as a single agent. It's used in combination with 5-FU - ramucirumab binds to the VEGF receptor, biut bevacizumab binds the ligand.

Answer 54

CD20 - transmembrane protein that regulates an early step in activation of B cell cell cycle initiation and differentiation. - rituximab - fully human antibody that is specific for CD 20. - also ofatumumab CD38 - multifunctional transmembrane protein that is highly expressed on plasma B cells that makes antibodies - daratumumab - human antibody that targets CD38

Answer 55

when several antibodies bind to a receptor on the surface of a cell, it can lead to these two things: 1. complement-dependent cytotoxicity (CDC) - process where the cell is killed by making a pore for the cell contents to leak out 2. antibody-dependent cellular cytotoxicity (ADCC) - "tag" cells to be killed by NK cells This two-tiered effect may be why blocking antibodies have unique effects over kinase inhibitors.

Answer 56

monoclonal antibodies - antibodies bind to their target receptors and then cause the receptor to be downregulated, initiates CDC (pore), and does ADCC (cytokines). They can also bind to ligand to prevent the activation of pathways (ex. VEGF). ADC (antibody drug conjugates) - these are combo products that combine antibodies with a drug. This allows for dual action. Bi-specific antibodies - These bind simultaneously to multiple proteins to improve T cell interaction.

Answer 57

Immune checkpoint therapies: CTLA-4 and PD1 (on T cells) act as brakes/checkpoints on the immune system. We can block these interactions by using antibodies, which reactivates T-cells. Tumor vaccines-CAR T-cells: APCs are collected from the patient through leukapheresis. The APCs are activated outside the body andt hen reinfused into that individual patient. The goal is to stimulate a patient's own immune system to attack the cancer.

Answer 58

Ipilimumab - human antibody with a unique mechanism of action. This antibody inhibits CTLA4. By doing this, ipilimumab blocks the "emergency break" by dendritic cells (usually, the APC could present the tumor antigen to T cells, but then an inhibitory signal may be released via CTLA receptor), which in turn encourages T cell proliferation. - Some severe immune mediated adverse reactions (GI tract, dermatits, neuropathy, endocrinopathy)

Answer 59

Pembrolizumab - this binds PD-1 receptor (T cell) and blocks its interaction with PD-L1 and PD-L2 (on tumor cells, macrophages, and dendritic cells). This prevents the inhibitory signaling within T cells, which leads to enhanced tumor cell killing. - (also nivolumab, cemiplimab, ostarlimab, retifanlimab do this) Atezolizumab - binds to PD-L1 receptor to block the interaction with PD-1.

Answer 60

mouse = -o chimeric (lots of the variable region is from the mouse, constant region is mostly human) = -xi (ex. cetuximab) humanized (made through genetic engineering) = -zu (trastuzumab) fully human = -u (ramucirumab)

Answer 61

trastuzumab emtansine (T-DM1) - Trastuzumab binds to HER2 receptor. Emtansine enters the cell & inhibits microtubule assembly. Emtansine toxicity is significantly reduced due to selective HER2 targeting. - Has some toxicity, but not too bad

Answer 62

BiTE (bispecific T-cell engager) - takes the variable region of CD3 and links it to CD19. CD3 is a part of the T-cell receptor and is on all T cells. CD19 is on the tumor cell. Linking these together increases the interaction between the T cell and cancer cell. Blinatumomab - targets T cells to receptors that are highly expressed on cancers (CD19 highly expressed on B cells and acute lymphoblastic leukemia). The activated T cell will then lyse the tumor cell. Mosunetuzumab - targets CD3 and CD20 on non-Hodgkin lymphomas (B-cell malignancy) Teclistamab - targets CD3 on T cells and BCMA on multiple myeloma cells Taquetamab - targets CD3 on T cells and GPRC5D on multiple myeloma cells

Answer 63

T cells are produced in bone marrow and then go to the thymus for maturation. In the thymus, the T-cell goes through a positive & negative selection. 1. + selection: We need to make sure the T cell recognizes MHC (not the antigen it's presenting). If the T cell does recognize MHC, it lives. 2. - selection: T cells now have hypervariable regions. Here, the T cell will be shown APCs. If the T cell binds too strongly, it'll be killed, since we don't want the T cell to recognize self antigens. This process is good for healthy people, but because our tumor cells are US, we want to overcome this central tolerance. There are a few ways to do this.

Answer 64

1. Naive T cell encounters presented antigen in combo with MHC. 2. If T-cell receptor (TCR) recognizes the antigen, it will become activated. 3. A cytolytic/toxic T cell will kill that cell and proliferate, creating a population of antigen-specific T cells. 4. Once an infection (or tumor) is cleared, the specific T-cell population will die down to a memory population that will be ready for when that antigen comes again.

Answer 65

- More specific to tumor cells and therefore less widespread side effects

Answer 66

- One problem for immunotherapy is that is the response to the antigen is too strong, it can induce a cytokine release syndrome. - Due to the cancers developing ways around therapies, combination therapies are needed to address multiple steps in the immune process - Right now, T-cell therapy is dependent on finding a selective antigen (best success is in B-cell leukemias where CAR is specific for CD19) - Toxicity is a big limiting factor. We need to find a way to turn CAR T-cells off after the tumor has been eliminated to reduce life long toxicity.

Answer 67

Chromatin acetylation of histones can increase the transcription of tumor suppressor genes. (this is good) We have deacetylation inhibitors to increase tumor suppressor activity (romidespin, vorinostat, belinostat, panobinostat) Chromatin methylation by EZH2 is increases (and mutated) in many cancers. This is bad because it mades the gene "switch off." We can inhibit this with EZH2 inhibitors (tazemetostat)

Answer 68

Azacitibine & Decitibine - these inhibit DNA methyltransferases. They incorporate into DNA, then covalently bind to DNMT enzymes, which prevents their function. This requires the cell to be cycling and for DNA synthesis to happen in order to be incorporated. As a result, DNMT inhibitors reactivate tumor suppressor genes.

Answer 69

Proteasome break down misfolded proteins. This is good for healthy cells. But, cancer cells have a lot more misfolded proteins. We want to inhibit the proteasomes so that the cancers have more "bad" proteins. For this reason, we use proteasome inhibitors. Proteasome inhibitors: - bortezomib (carfilzomib, ixazomib): inhibits ubiquitin-proteasome pathway, eventually leading to cell death. thalidomide: binds cereblon to degrade IKZF TFs, which are important in lymphocyte development and regulate cell survival in mutiple myeloma. So this actually increases the degrading.

Answer 70

BCL2 - anti-apopototic protein that inhibits upstream apoptotic proteins. This is why cancer cells can evade apoptosis. Venetoclax - inhibits BCL-2, so it drives cell death via apoptosis. - this was approved to work as a combo product with azacitindine for AML - it's the 1st FDA approved small molecule that inhibits a protein-protein interaction