L33 - Targeted Therapies


  1. Cancer treatment usually combines multiple modalities -surgery, radiotherapy, chemotherapy, targeted therapies
  2. While traditional chemotherapies target proliferating cells, targeted therapies target specific mutant or over expressed proteins in cancer cell they spare normal proteins and cells
  3. Thus they spare normal proteins and cells
  4. Traditional and targeted therapies are used in specific combinations for improved results
  5. Know specific examples of cancer therapies
  6. Understand problems associated with these therapies

Targeted Therapies - Example of Leukaemia

  1. Treatments targeting oncogene driven signalling pathways
  2. Drugs targeting immunotherapies

Patterns of Oncogenic Mutations (Slide 6)

  1. Tumour sequencing reveals driver and passenger mutations

Ras/Raf/MAPK & PI3K/Akt signalling pathways are often affected - signal for growth & survival


  1. Specific tumours have different mutations driving growth, e.g. K-Ras in pancreatic cancer

Evolution of Cancer Treatments

Resistance & Targeted Therapies

Survival with Chemotherapy


while traditional chemotherapy has severe side effects… survival rates have ↑↑ in many cancers, especially paediatric cancers, leukaemia and lymphoma
e.g. paediatric ALL & Hodgkin’s lymphoma

2. Leukaemia in Adults

  • Different cytogenics, presentation and treatment to child leukaema

AML - Acute Myeloid Leukaemia

  • Aggressive; 5 y SR = 10% (1980) => 25%
  • Heterogeneous disease -
    subgroups: CBF translocations,
    mutations in FLT3, NPM1, CEBPα

CML - Chronic Lymphocytic Leukaemia

  1. Indolent Disorder: 5y SR > 70%

  2. Treatment - combnation of; Chemo, immuno and targeted therapy


  3. FCR =

    Fludarabine+Cyclophosphamide+Rituximab

CML - Chronic Myeloid Leukaemia

  1. ~350 annual incidence
  2. Homogeneous Disease → Chr 9q & Chr 22q reciprocal translocation → Philadelphia Chr

Targeted Therapies

  1. Inhibit oncogene-driven cancer
    signalling pathways
  2. Inhibitors → target specific
    proteins via 2 mechanisms:
    • Antibodies - humanised proteins, extracellular (-abs)
    • Small molecule inhibitors - membrane permeable → target the kinase domain (-ibs)
  3. Both pathways switch off proliferation, survival and migration signalling

Targeting Kinases

Many oncogenic mutations occur in at least one of the following pathways involving kinases

  1. Ras/Raf/MAPK pathway
  2. PI3K/Akt pathway
  3. JAK/STAT pathway
    All of these pathways are onco-genic and signal survival, proliferation, migration

Kinase - Mechanism of Action

  1. Relies upon ATP to bind to the cleft between (N-ter minor lobe) and (C-ter major lobe) and activate enzyme
  2. Kinases uses PO4 to phosphorylate AA residues
  3. Small molecule inhibitors sits in the cleft between two lobes and inactivates enzyme

Small Molecul Inhibitors

Intrinsic Resistance

  1. Incorrect, or absent target - mutant protein not present
    • Overcome by genotyping tumour first
  2. Resistant mutation already present

Acquired Resistance

  1. Developed during the course of treatment
  2. Oncogenic bypass - activate a different kinase
  3. Gene amplification ↑ BCR-Abl Ex

Strategies to Prevent Resistance - Targeted Therapy Combination


Combine targeted therapies with one or
more traditional chemotherapy drugs


  1. Target RTKs and downstream transduction pathways
    • limits ability to evolve resistance against all drugs smultaneously
  2. Difficult because not all cancers are the same. Relies upon the advent of personalised medicine

Recap from Cancer Pathogenesis

  1. Only minority of cancers are familial
  2. Majority of common cancers are induced by external genotoxic factors
  3. Whilst some cancer rates are constant (e.g. Rb), most cancer ates very greatly (ext. genotoxic. f.)
    • Melanoma
    • Stomach

Gain of Function Mutations

These occur at sites of oncogenes within DNA

  • RTKs

Loss of Function Mutations

These occur in tumour suppressor genes

  • p53, Rb

Slash

Originally surgical - excision or debulking

Burn

Radiotherapy - ~100 years old

Poison

Chemotherapy drugs - developed in the 1940-60s

Biological therapies

B/M
transplants

1

Targeted Therapies

Anticancer drugs interfere with DNA synthesis &/or function*

  1. Damage DNA - alkylating agents, platinum drugs (X-links)
  2. Impair DNA synthesis - 5FU, methotrexate (folate)
  3. Inhibit transcription - topoisomerase inhibitors
  4. Disrupt mitosis - taxanes, vinca alkaloids (MTs)

2° Malignancies

  1. DNA damage → particularly 2° myeloid neoplasms, MDS & AML (especially alkylating agents)
  2. Hodgkin’s Lymphoma → treated with radiotherapy and/or chemotherapy
    • 4.6 fold ↑ risk of 2° cancer - usually solid tumours

3

Classical chemotherapy:

  1. Anti-metabolite - Cytarabine/ara-C
  2. Cytotoxic antibiotic - Idarubicin

Targeted therapies,

E.g. FLT3 inhibitors, not yet routine

Traditional Chemotherapy

Fludarabine + Cyclophosphamide

Immunotherapy:

Rituximab (αCD20)

Targeted Therapies

  1. Ibrutinib → Bruton’s TK
  2. Idelalisib → PI3K p110δ

1

Immune Modulation

  • Lealidomide
    • Derivative of Thalidomide

2

Mechanism

Uncontrolled proliferation due to the philadelphia translocation resulting in fusion of BCR-ABL genes

BCR-ABL protein

  1. Unregulated tyrosine kinase activation (100%)
  2. uncontrolled proliferation of myeloid cells
  3. Treatment → targeted therapy

3

4

Antibodies target the EC ligands/receptors

1
2

Small molecule Inhibitors target IC kinase domain

Humanised Anti-body Therapies for solid tumours (E.g. EGFR family)

Oestrogen growth factor receptor (breast cancer)

Trastuzumab (Herceptin)

  1. Partciularly effective at blocking ErbB2/HER2
  2. Expression of this gene is amplified in breast cancer
  3. Tratuzumab - sensitive to EC domain
  4. Believed to induce immune-mediated cell death

4

Imatinib and CML

  1. Imatinib sts in BCR-ABL kinase cleft
  2. Switches off BCR-ABL activation
  3. Reduces proliferation and increases survival Rates

Serine/Threonine Kinase Therapies

B-Raf & Cutaneous Melanoma

Melanoma Responds poorly to Traditional Chemotherapies

50% of Melanoma cancers have associated B-Raf mutation

Gain-of-Function

Ras/Raf/MAPK pathway ↑↑

Hyperproliferation

Targeted Therapy with Vemurafenib

  • Targets mutant B-Raf protein
  • Short lived, yet effective response, ~ 7 months

Limitations

  1. Side effects are generally well tolerated
  2. Acquired Drug Resistance from cancers (selects for resistant cancers in evolutionary pressure)
  3. Effective in homogeneous tumours, limited against hetereogeneous tumours
  4. Extraordinary Costs due to R&D

Side Effects

Generally Less toxic than traditional chemo

Cutaneous Effects - specifically with EGFR inhibitors

acne-like rash - severity of rash indicates (commensurate) better response to treatment

Other Effects

  1. GI - diarrhoea common
  2. Skin/hair depigmentation (c-Kit, PDGFR)
  3. Cardiovascular - VEGFR (Thrombosis & ischaemia
  4. Liver - Hepatitis
  5. Endocrine - hypothyroidism, changes to bone-density and glucose metabolism + dyslipidaemia

Immuno-Therapies

Immune homeostasis - T-cells are either activated/inhibited by a series of co-stimulatory and co-inhbitory pathways


Ensures that immune response is effective yet not destructive of our own tissues


Work best in tumours carrying
high mutational burdens

Inhibition of T-cells

  1. Interaction between PDL1 ligand on an MHC presenting cell and PD1 receptor on T-cell suppresses cytotoxic response
    • PDL1 =/= PD1
  2. Activation of CTLA-4 on T-cell inhibits their activation by CD86 ligand on dendrocytes
    • CD86=/=CTLA-4

  1. Impilimumab

    → ipilimumab blocks CTLA-4 checkpoint → enabling T cell priming

Inhibits the inhibitory response

  1. Nivolumab

    cancer cells express PD-1L → stops activated T cell cytotoxicity. Nivolumab blocks PD-1 → release of T cell activity

1

2

In combination survival rates of advanced melanoma exceed 50% (52%)