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Cancer Bio > Cancer Therapies > Flashcards

Cancer Therapies Flashcards

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Biology 101 flashcards
1
Q

Classical treatments for Cancer

A
  1. surgery
  2. Chemotherapy
  3. Radiotherapy: High energy particles or waves
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2
Q

Chemotherapies

A

Cytotoxic agents that block cell proliferation and induce cell death by targeting (ex) mitosis, inducing DNA damage, preventing DNA duplication, or activating immune system

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3
Q

Anti-mitotic chemotherapies

A

Vinca alkaloids: Vincristine/vinblastin

  • inhibit microtubule assembly/polymerization
  • arrest mitosis in metaphase

Taxane: Paclitaxel

  • stabilize microtubules and prevent from disassembling
  • block mitosis progression and trigger apoptosis
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4
Q

Chemotherapies inducing DNA damage

A

Topoisomerase:

  • Regulates DNA supercoiling/unwinding of DNA
  • Topoisomerase 1: ssDNA breaks and repair
  • Topoisomerase 2: dsDNA breaks and repair
  • They cut and pass DNA strands through

DNA intercalating agents can act as topoisomerase inhibitors by preventing religation –> mutagenesis or recombination –> activation of apoptotic program

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5
Q

Chemotherapies inhibiting DNA synthesis

A

Anti-metabolites:

  • purine and pyrimidine analogs create stereo-hinderance in growing DNA chain, block growth
  • 5’ fluorouracil inhibits enzymes necessary to generate thymidine
  • Methotrexate interrupts folate metabolism. Folate is necessary for DNA synthesis and repair
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6
Q

Chemotherapy downsides

A
  • Non-specific: intestinal toxicity, anemia, risk of infections, hair loss, hand-foot syndrome (PPE)
  • Relapse common
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7
Q

resistance

A
  • p53 mutations highly implicated in the development of resistance
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8
Q

BCR-ABL

A
  • Blocking in Chronic myeloid leukemia was the 1st targeted therapy
  • BCR-ABL caused by Philadelphia chromosome
  • Activates MYC, Raf, AKT
  • Gleevec prevents ATP from binding to BCR-ABL
  • Patients relapse, due to mutations which change shape of ATP binding pocket, other inhibitors lead to stabilization.
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9
Q

B-cell receptor signaling dependencies

A

B- Cell lymphomas
Chronic Lymphocytic Leukemia

Bruton’s Tyrosine Kinase is an important downstream mediators of B-Cell receptor signaling. Ibrutinib is an irreversible BTK inhibitor, but resistance appears after 1-2 years through C481S mutation in BTK

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10
Q

Common genomic lessions in melanoma progression

A
  • NRAS
  • BRAF
  • CDKN2A
  • PTEN
  • AKT
  • TP53
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11
Q

Vemurafenib

A
  • Inhibits BRAF (V600E, 90% of BRAF mut in melanoma)

- Resistance acquired by expressing a different splicing variant

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12
Q

Identification of mechanisms of resistance

A
  • library sequencing of mutated protein
  • sequencing resistant patients
  • generating resistant cells, using high doses of the drug
  • Genetic screen to predict resistance to therapy
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13
Q

CRISPR Genetic Screens

A
  • Cas9 induces dsDNA breaks
  • Cas9 induces DNA repair by NHEJ or HDR, but host repair organisms either generate small indels, or integrate homologous donor DNA
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14
Q

PI3K-AKT-mTOR as a target

A
  • PI3K inhibitor idelasilib inhibits a specific isoform PI3Kδ
  • mTOR: mammalian target of rapamycin, there are mTORC1 inhibitors and mTORC1/2 dual inhibitors, rapamycin is the original inhibitor
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15
Q

Cell cycle can be inhibited by specific inhibitors of CDK4/6, for example

A

resistance occurs through mutation of inhibitor binding domain, or upregulation of other cyclins.

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16
Q

Nutlins

A

MDM2 inhibitors, prevent MDM2 from inhibiting p53.

17
Q

Players in immunotherapy

A
  • B cells
  • T cells
  • NK cells
  • Macrophages
  • Dendritic Cells
18
Q

B cells

A
  • Upon double signal (Helper T cell signal + BCR activation) become plasma cell and release Antibodies
  • Activated B cells proliferate and undergo affinity selection, and class switching.
  • Dormant B cells reside in dark zone of Be cell follicle.
19
Q

Lymphoma

A

B or T cell proliferation in the lymphoid organs

20
Q

Leukemia

A

High levels of undifferentiated B and T cells circulating in the blood

21
Q

NK Cells

A

Kills cells with different or missing MHC Class I. Includes: transplanted cells, cells under viral infection, transformed cells

22
Q

Macrophages

A

APC of the innate immune system

23
Q

Dendritic cells

A

APC, mediator of innate and adaptive immune responses

24
Q

MHC I antigen presentation pathway

A

Endogenous antigen is processed by proteasome, imported to Endoplasmic reticulum where it binding to MHC Class I, which is exported to cell surface.

All cells have MHC I

25
Q

MHC II antigen presentation pathway

A

Exogenous antige and endogenous antigen are broken down in endocytic route. Meet MHC II in endoplasmic reticulum (?) and are exported to the membrane

26
Q

Advantages of the adaptive immune system

A

Stronger reaction to specific threats. Has long term memory.

27
Q

Mediators of the innate immune system

A
  1. Macrophages: Pathogen uptake and elimination
  2. Inflammatory cytokines: Inflammatory reaction and shock
  3. Interferons: Attack on virus, autoimmunity.

PAMPs activate TLR, which lead Dendritic cells to potentiate T cells through antigen presentation and cytokine release., as well as activate innate immune system through release of inflammatory cytokines (2) and interferons (3).

28
Q

Adaptive immune response through helper T cells:

A

MHC I activation: secrete INF-γ, stimulate killer T (CD8+) directly.

MHC II activation: secrete IL-4, which activates B cells, leads to antibody production, leads to opsonization, activation of NK cells through FC receptor

29
Q

Rituximab

A

An anti-CD20 antibody for B-cell lymphoma.

  • Activates NK cells through Fc receptors, leading to tumor killing.
  • Activates complement
  • Induces apoptosis directly (through grouping of surface CD20?)
30
Q

Immune tolerance

A
  • T-reg cells protect the body from auto-immune disease, release IL10/TGF-β, and inhibit T-cell activation
  • Autoimmunity occurs when T-reg activity is decreased.
  • Self tolerance occurs largely through recognition of MHC complexes, tumors cannot be transplanted into allogeneic host.
31
Q

Tumor microenvironment

A
  • Also composed of immune infiltrate and cancer-associated fibroblasts
32
Q

Immune desert tumors

A
  • Tumors that don’t present antigens
  • Characterized by high mutation rates or high chromosomal changes.
  • May hide antigen presentation by suppressing or mutating MHC I (β2m subunit), mimic function of T regs by releasing inhibitory cytokines (IL-10, TGFβ)
  • Copy number changes are not immunogenic.
  • Strategy: mutate proteins to be recognized as non-self antigen, activate immune response, use immune cells without TGFβ receptor
33
Q

TGFβ

A

Immune cells with TGFβ receptor apoptose upon TGFβ binding

- Strategy for Immune desert: make immune cells without TGFβ receptor

34
Q

Checkpoint inhibitors

A
  • anti-CTLA4
  • anti- PD1
  • anti-PDL1
35
Q

CTLA-4

A

Blocks T cell activation by blocking B7 coactivation

36
Q

PDL-1

A

expressed by tumor cells and DC to prevent killing. Neutralizes T cells.

37
Q

CAR

A

Engineered with synthetic receptor domain (single chain variable fragments), costimulatory domains (CD28) and signaling domain (CD3ζ)

  • T cells are processed ex-vivo with gammaretroviral vector encoding CAR gene.

Cancer Bio (7 decks)

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