Cancer Therapies Flashcards
Classical treatments for Cancer
- surgery
- Chemotherapy
- Radiotherapy: High energy particles or waves
Chemotherapies
Cytotoxic agents that block cell proliferation and induce cell death by targeting (ex) mitosis, inducing DNA damage, preventing DNA duplication, or activating immune system
Anti-mitotic chemotherapies
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
Chemotherapies inducing DNA damage
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
Chemotherapies inhibiting DNA synthesis
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
Chemotherapy downsides
- Non-specific: intestinal toxicity, anemia, risk of infections, hair loss, hand-foot syndrome (PPE)
- Relapse common
resistance
- p53 mutations highly implicated in the development of resistance
BCR-ABL
- 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.
B-cell receptor signaling dependencies
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
Common genomic lessions in melanoma progression
- NRAS
- BRAF
- CDKN2A
- PTEN
- AKT
- TP53
Vemurafenib
- Inhibits BRAF (V600E, 90% of BRAF mut in melanoma)
- Resistance acquired by expressing a different splicing variant
Identification of mechanisms of resistance
- library sequencing of mutated protein
- sequencing resistant patients
- generating resistant cells, using high doses of the drug
- Genetic screen to predict resistance to therapy
CRISPR Genetic Screens
- 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
PI3K-AKT-mTOR as a target
- 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
Cell cycle can be inhibited by specific inhibitors of CDK4/6, for example
resistance occurs through mutation of inhibitor binding domain, or upregulation of other cyclins.
Nutlins
MDM2 inhibitors, prevent MDM2 from inhibiting p53.
Players in immunotherapy
- B cells
- T cells
- NK cells
- Macrophages
- Dendritic Cells
B cells
- 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.
Lymphoma
B or T cell proliferation in the lymphoid organs
Leukemia
High levels of undifferentiated B and T cells circulating in the blood
NK Cells
Kills cells with different or missing MHC Class I. Includes: transplanted cells, cells under viral infection, transformed cells
Macrophages
APC of the innate immune system
Dendritic cells
APC, mediator of innate and adaptive immune responses
MHC I antigen presentation pathway
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
MHC II antigen presentation pathway
Exogenous antige and endogenous antigen are broken down in endocytic route. Meet MHC II in endoplasmic reticulum (?) and are exported to the membrane
Advantages of the adaptive immune system
Stronger reaction to specific threats. Has long term memory.
Mediators of the innate immune system
- Macrophages: Pathogen uptake and elimination
- Inflammatory cytokines: Inflammatory reaction and shock
- 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).
Adaptive immune response through helper T cells:
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
Rituximab
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?)
Immune tolerance
- 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.
Tumor microenvironment
- Also composed of immune infiltrate and cancer-associated fibroblasts
Immune desert tumors
- 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
TGFβ
Immune cells with TGFβ receptor apoptose upon TGFβ binding
- Strategy for Immune desert: make immune cells without TGFβ receptor
Checkpoint inhibitors
- anti-CTLA4
- anti- PD1
- anti-PDL1
CTLA-4
Blocks T cell activation by blocking B7 coactivation
PDL-1
expressed by tumor cells and DC to prevent killing. Neutralizes T cells.
CAR
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.
