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PDA 3 > Directed Therapies of Cancer > Flashcards

Directed Therapies of Cancer Flashcards

1
Q

What is the difference between chemotherapy and directed therapy?

A

chemotherapy is usually cytotoxic and kills normal and cancer cells, whereas directed therapy is usually cytostatic and normal cells survive therapy

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2
Q

How do directed therapies generally work?

A
  • target a protein on tumor cells not found in normal cells
  • target a protein that is mutated in cancer cells
  • target overexpression of protein in cancer cells
  • target DNA changes that are not found in normal cells
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2
Q

What are the uses of genetic/molecular/protein alterations in precision medicine?

A
  • biomarkers for early diagnosis/screening of cancer
  • biomarkers for monitoring response to treatment
  • biomarkers for prognosis and to guide therapy
  • biomarkers to identify those at risk for cancer (lifestyle changes and genetic counseling)
  • identify targets for drug therapy
  • identify targets for enhancing the delievery for cytotoxic drugs
  • therapy for traditionally non-responsive cancers
  • identify individuals who may benefit from therapies that may only work in a select group of patients
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3
Q

What are the types of target therapies?

A
  • proteasome inhibitors
  • signal transduction inhibitors
  • apoptosis inducers
  • gene expression modulators
  • angiogenesis inhibitors
  • cancer vaccines
  • gene therapy
  • monoclonal antibodies-toxic molecule delivery
  • immunotherapies
  • hormone therapies
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4
Q

What is Multiple Myeloma?

A

cancer of B-cells (plasma cells), monclonal plasma cells (PC) secrete monoclonal Ig infiltrate the bone bone marrow which results in organ dysfunction (CRAB= hyperCalcemia, Renal insufficiency, Anemia, Bone lesions) -> debilitation -> death

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5
Q

What are the target drugs used for Multiple Myeloma?

A
  • PROTEASOME INHIBITORS
  • IMMUNOMODULATING AGENTS
  • HISTONE DEACETYLASE INHIBITORS (DACis)
  • monoclonal antibodies
  • chimeric antigen receptor (CAR) T cells
  • selective inhibitors of nuclear export
  • alkylators
  • glucocorticoids
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6
Q

What is the use of 26S proteasome?

A

a large multi-protease complex that controls degradation of more than 80% of cellular proteins which is crital for cellular protein homeostatis

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7
Q

What drugs are Proteasome inhibitors for multiple myeloma?

A
  • bortezomib (Velcade)
  • ixazomib citrate (Ninlaro)
  • carfizomib (Kyprolis)
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8
Q

What is the mechanism of action of Bortezomib (VELCADE)?

A

inhibits activation of beta5 >beta1 >beta2 subunits of the 20S proteasome core by forming complex with Threonine OH group at active site, reversible inhibitor of chymotypsin-like and caspase-like (less trypsin-like) activity -> inhibits proteolysis -> protein accumulation -> stress -> cell death

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9
Q

What is the mechanism of action of Ixazomib (NINLARO)?

A

dipeptidyl boronic acid-based inhibitor which targets beta5 > beta2, reversibly inhibits the chymotrypsin-like, trypsin-like and caspase-like activities at high concentrations with potencies similar to Bortezomib

may overcome resistance to Bortezomib

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10
Q

What is the mechanism of action of Carfilzomib (KYPROLIS)?

A

tetrapeptide epoxyketone inhibitor, irreversibly inhibits 20S proteasome subunit of 26S proteasome which predominantly inhibit beta5 (more potent than Bortezomib) and more selective for chymotrypsin-like activity than Bortezomib

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11
Q

What is the general mechanism of action of Proteasome inhibitors?

A
  • inhibition of proteasomal degradation = misfolded proteins accumulate in cytosol and ER lumen inducing stress
  • endoplasmic reticulum overload = ER-stress related apoptosis
  • generation of excess oxygen = DNA damage induced cell death
  • NF-kB signaling
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12
Q

How do Proteasome Inhibitors effect NF-kB signaling pathways?

A

the NF-kB pathway is regulated by protein IkB (inhibitor) which blocks nuclear translocation of the p50 (NF-kB1)/p65(RelA) heterodimer, NF-kB induces transcription of cancer causing genes, so Proteasome inhibitors have inhibitory effects on NF-kB activity= modulate transcription

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13
Q

What are the mechanisms of resistance of Proteasome Inhibitors?

A
  • other signaling pathways
  • P-glycoprotein (Pgp)/MDR1/ABCB1
  • mutations in the catalytic beta5 subunit gene (PSMB5)
  • non-standard 20S proteasome composition
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14
Q

What drugs are Immunomodulators for multiple myeloma?

A
  • thalidomide
  • lenalidomide
  • pomalidomide
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15
Q

What is the major warning associated with Immunomodulators for multiple myeloma?

A

pregnancy, tetratogenic and embryo-fetal toxicity

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16
Q

What is the mechanism of action of Immunomodulators used in multiple myeloma?

A

CRBN E3 ubiquitin ligase complex marks proteins with ubiquitin for degradation, binding of Immunomodulators to this complex leads to the degradation of two key proteins, Aiolos (IKZF3) and Ikaros (IKZF1)= degradation of IKZF1/3= multiple myeloma cell death

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17
Q

What are the effects of Thalidomide?

A

degrades IKZF1/3 = toxic to tumor, inhibits pro-inflammatory cytokine production by monocytes (IL-6 inhibition= reduced myeloma cell adhesion to bone marrow, reduced TNF-alpha= reduced vascularization through decreased VEGF), activates and increases number of T cells and NK cells, T-cells increase cytokines (IL-2 and interferon)= enhances immune attack by NK cells on myeloma

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18
Q

What is the use of histones?

A

histones are proteins on chromatin that undergo methylation and acetylation (epigenetic regulation)

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19
Q

What drug is a Histone Deacetylase?

A

Panobinostat (Farydak)

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20
Q

What is the mechanism of action of Panobinostat (FARYDAK)?

A

histone deacetyltransferases (DACs) remove acetyl groups (acetylation of histones results in the opening of chromatin and consequently DNA = increased transcription of genes) -> in multiple myeloma closed conformation is preferred = reduced expression of tumor suppressor genes leading to growth and proliferation of cancer cells, Panobinostat inhibits histone deacetyltransferase (DACi)

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21
Q

What is the function of protein kinase?

A

phosphorylates proteins, enzyme chemically adds terminal phosphate group of ATP to: serine, threonine, and tyrosine= functionally alters target protein by regulating signal pathways

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22
Q

How do kinases regulate signaling pathways?

A
  • activating/amplifying signaling
  • alter location of target
  • regulate interactions with regulatory proteins
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23
Q

What are the mechanisms of kinase activation in cancer?

A
  • point mutation
  • gene amplification
  • fusion of kinase ligand
  • gene fusion
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24
Q

How does BRAF V600E mutant kinase lead to metastatic melanoma?

A

BRAF V600E Mt kinase is constitutively active= MAPK= excessive cell proliferation and survival

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25
Q

What is the mechanism of action of Kinase Inhibitors for BRAF V600E mutation in metastatic melanoma?

A

block activation of MAPK -> G1 cell senescence = apoptosis

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26
Q

What drugs are Kinase Inhibitors for metastatic melanoma?

A
  • Vemurafenib
  • Dabrafenib
  • Trametinib
  • Cobimetinib
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27
Q

What is the molecular target of Vemurafenib?

A

BRAF V600E mutant kinase

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28
Q

What is the molecular target of Dabrafenib?

A

BRAF V600E mutant kinase

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29
Q

What is the molecular target of Trametinib?

A

MEK

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30
Q

What is the molecular target of Cobimetinib?

A

MEK

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31
Q

What is the role of non-receptor tyrosine kinase (NRTK) BCR-ABL signaling in cancer?

A

several pathways activated= increased cell proliferation, increased tumor survival, increased cell motility

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32
Q

What is the mechanism of action of Imatinib (GLEEVEC)?

A

inhibit BCR-ABL kinase activity

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33
Q

What drugs are BCR-ABL Tyrosine Kinase Inhibitors?

A
  • Imatinib (Gleevec)
  • Dasatinib
  • Nilotinib
  • Ponatinib
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34
Q

What is T315I in BCR/ALB mutant tyrosine kinase?

A

Thr315Iso (T315I) is the most vicioius mutant and accounts for 15% of relapse cases in chronic myloid leukemia (CML), cofers resistance to most approved tyrosine kinase (except Ponatinib)

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35
Q

What is the target for Ponatinib?

A

BCR-ALB including T3151I mutant kinase

36
Q

What is the role of VEGFR (tyrosine kinase receptor) signaling in cancer?

A

VEGF = protein growth factor, ligand binding= dimerization of RTK= autophosphorylation of RTK= signaling= INCREASED ANGIOGENESIS and LYMPANGIOGENESIS IN TUMORS

vascular edothelial growth factor (VEGF)

37
Q

What drugs are VEGF/VEGFR inhibitors?

A
  • Axitinib
  • Sunitinib
  • Sorafenib
38
Q

What is the mechanism of action of VEGF/VEGFR?

A

inhibit receptor tyrosine kinase autophosphorylation within the cell

39
Q

What is the role of EGFR signaling in non-small cell lung cancer?

A

EGFR contains tyrosine kinase activation domain that is important for multiple signaling pathways leading to: evasion of apoptosis, sustained angiogenesis, resistance to antigrowth factors, invasion of metastasis, self-efficiency in growth signals

40
Q

What drugs are EGFR tyrosine kinase inhibitors in non-small cell lung cancer?

A
  • Erlotinib
  • Afatinib
  • Osimertinib
41
Q

What is the role of ALK-EML4 in non-small cell lung cancer?

A

EML4-ALK= activation of oncogenic signaling through multiple pathways through ALK interacting partners, such as: PI3K/Akt, JAK/STAT, RAS/RAF/MEK/ERK

42
Q

What is the mechanism of action of ALK-EML4 kinase inhibitors for non-small cell lung cancer?

A

inhibits autophosphorylation of ALK= inhibits STAT3 PO4= inhibits proliferation

43
Q

What drugs are ALK–EML4 kinase inhibitors for non-small cell lung cancer?

A
  • Ceritinib
  • Lorlatinib
44
Q

What drugs are cyclin dependent kinase 4/6 (cdk4/6) inhibitors?

A
  • Palbocicib (Ibrance)
  • Ribociclib (Kisqali)
  • Abemaciclib (Verzenio)
  • Trilaciclib (Cosela)
45
Q

What is the mechanism of action of cyclin dependent kinase 4/6 (cdk4/6) inhibitors?

A

cdk4/6 is activated by binding cyclin D1/D2/D3, cdl4/6 is amplified in cancer= complex is needed for G1 -> S phase cell cycle transition (rate-limiting step), cdk4/6 inhibitors inhibit the cyclin D-cdk4/6 complex activity

46
Q

What are the indications for cdk4/6 inhibitors in breast cancer?

A

postmenopausal women with advanced and metastatic breast cancer in hormone receptor positive (HR+) and HER2 negative in combo with other drugs

Palbociclib, Ribociclib, Abemaciclib

47
Q

What is the mechanism of action of Lapatinib (TYKERB)?

A

tyrosine kinase inhibitor that targets HER2 (and EGFR)= inhibits proliferation, increase G1 phase cell cycle arrest, and increase senescence

48
Q

What is the indication of Lapatinib (TYKERB)?

A

reserved for use in addition to Trastuzumab, hormone receptor positive (HR+) and HER2-positive advanced breast cancer

49
Q

What is Chimeric Antigen Receptor T-cell (CAR-T) cell therapy?

A

immunotherapy that relies on adoptive cell transfer (ACT), collect T cells from patient -> re-engineer patients T-cells -> T-cells express synthetic receptor (CAR-T cell) -> expand CAR-T cells -> CAR-T cell infusion is then administered back to the patient

50
Q

What is the structure of CAR-T cell receptor?

A

fusion T-cell, antibody segment that is the extracellular domain for antigen recogonition and co-stimulatory molecule that is activated independently of antigenpresenting cell

51
Q

What is included in 4th generation CAR-T cells that is not seen in previous generations?

A
  • CD28/OX40/4-1BB
  • CD3
  • NFAT
52
Q

What is the mechanism of action of Tisagenlecleucel (KYMRIAH)?

A

CAR-T cell that binds CD19 protein of cancer cells (and normal cells)= cytotoxic

53
Q

What is the indication of Tisagenlecleucel (KYMRIAH)?

A

B-cell acute lymphoblastic leukemia

54
Q

What is the mechanism of action of Axicabtagene ciloleucel (YESCARTA)?

A

CAR-T cells that bind CD-19 protein of cancerous B-cells (and normal cells)= cytotoxic

55
Q

What is the indication of Axicabtagene ciloleucel (YESCARTA)?

A

diffuse large B-cell lymphoma (DLBCL)

56
Q

What is the mechanism of action of Brexucabtagene autoleucel (TECARTUS)?

A

CAR-T cell that binds CD19 protein of cancerous B-cell (and normal cells)= cytotoxic

57
Q

What is the indication Brexucabtagene autoleucel (TECARTUS)?

A

some patients with mantel cell lymphoma (relapsed/refractory)

58
Q

What are the pretreatment options for mAB IV infusion reactions?

A

acetaminophen and antihistamine

59
Q

What is the mechanism of action of Blinatumomab?

A

bispecific T-cell engager (BiTE), combination of 2 Ag binding sites, engages unstimulated T-cell recognition of tumor CD19+ B-cells, results in cell mediated cytotoxicity

60
Q

What is the indication of Blinatumomab?

A

refactory acute lymphoblastic leukemia

61
Q

What is the mechanism of action of Cetuximab (ERBITUX)?

A

competitively inhibits EGFR binding= inhibits tumor growth, induces apoptosis, inhibits angiogenesis

62
Q

What is the indication of Cetuximab (ERBITUX)?

A

colorectal cancer

63
Q

What is the mechanism of action of Trastuzumab (HERCEPTIN)?

A

binds HER2 protein on tumor cells that overexpress HER2= inhibit proliferation, inhibits migration, induces antibody dependent cell cytotoxicity

64
Q

What is the indication of Trastuzumab (HERCEPTIN)?

A

HER2+ breast cancer

65
Q

What is the indication of Trastuzumab emtansine?

A

HER2+ breast cancer

66
Q

What is the mechanism of action of Dinutuximab (UNITUXIN)?

A

targets glycolipid disialogangliodis (GD-2) which is overexpressed in neuroblastoma= induces provoking complement-mediated cytotoxicity (CDC) and provoking antibody-dependent cell-mediated cytotoxicity (ADCC)

67
Q

What is the indication of Dinutuximab (UNITUXIN)?

A

high risk neuroblastoma in pediatric patients

68
Q

What is the mechanism of action of Bevacizumab (AVASTIN)?

A

binds VEGF which prevents binding of VEGF-A to receptors on endothelial cells= inhibits vascularization of tumor

69
Q

What is the indication of Bevacizumab (AVASTIN)?

A

colorectal cancer

70
Q

What is the mechanism of action of Ramucirumab (CYRAMZA)?

A

binds VEGFR2 to block receptor binding

71
Q

What is the indication of Ramucirumab (CYRAMZA)?

A

gastric cancer

72
Q

What is the mechanism of action of Brentuximab vedotin (ADETRIS)?

A

targets CD30= bystandard killing effect and inhibit microtubule polymerization

73
Q

What is the indication of Brentuximab vedotin (ADETRIS)?

A

hodgkins lymphoma and systemic anaplastic large cell lymphoma

74
Q

What is the mechanism of action of Daratumumab (DARZALEX)?

A

binds CD38 of multiple myeloma cells= induces cell lysis

75
Q

What is the mechanism of action of Alemtuzumab (LEMTRADA)?

A

binds CD52 which is overexpressed on tumor cells= induces cell death

76
Q

What is the indication of Alemtuzumab (LEMTRADA)?

A

chronic myeloid leukemia

77
Q

What is the notable adverse effect of Alemtuzumab (LEMTRADA)?

A

immunosuppression

78
Q

What drugs bind CD20?

A
  • Rituximab (RITUXAN)
  • Ofatumumab
  • Obinutuzumab
79
Q

What is the goal of immune checkpoint inhibitors?

A

block the immune checkpoints: CTLA-4, PD-1, or PD-L1through T-cell targeted immunomodulators

80
Q

What are the co-inhibitor signals of T-cell regulation?

A
  • PD-L1 and PD-1
  • CTLA-4 and B7-1 (CD80)/B7-2 (CD86)
    co-inhibitory signals act as immune checkpoints= negatively regulate the immune system (modulate T-cell activation)
81
Q

What drugs block the immune checkpoint through CTLA-4 (anti-CTLA-4 mAb)?

A
  • Ipilimumab
  • Tremelimumab
82
Q

What drugs block the immune checkpoint through PD-1 (anti-PD-1 mAb)?

A
  • Pembroluzumab
  • Nivolumab
  • Cemiplimab
83
Q

What drugs block the immune checkpoint through PD-L1 (anti-PD-L1 mAb)?

A
  • Atezolizumab
  • Avelumab
  • Durvalumab
84
Q

What is the role of the immune checkpoint: CTLA-4?

A

potent inhibitor of T cells that is expressed on effector T-cells and regulatory T-cells, binding to B7-1/B7-2 inhibits co-stimulation which dampens immune response to Ag

85
Q

What is the mechanism of action of Ipilimumab (YERVOY)?

A

binds CTLA-4 and blocks binding of B7= augments T-cell activation and T-cell proliferation= amplifies T-cell mediated immune response= enhances anti-tumor immune response

86
Q

What is the mechanism of action of Pembroluzumab (KEYTRUDA)?

A

binds PD-1 receptor= blocks interaction with ligands and activation of T-cell mediated immune responses against tumor cells

87
Q

What is the mechanism of action of Durvalumab (IMFINZI)?

A

targets PD-L1

PDA 3 (6 decks)

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