cancer therapy

• options for cancer therapy...

  surgery, radiotherapy, drugs, cell therapies
• why is surgery as an option for cancer treatment not always possible/simple?

  location of the tumour can be an issue (like if it’s near important tissues). So can’t get a nice surgical margin without causing significant impairment to the person.
• turning into a cancer cell = an endogenous process where a cell in your body changes to become a cancer cell through a series of mutations
• What are the expanded hallmarks of cancer?

  Deregulating cellular energetics, Avoiding immune destruction, tumour-promoting inflammation, Genome instability and mutation
• The hallmark of cancers leads to what?

  to uncontrolled growth of tumour cells
• Expanded hallmarks of cancer…

  • can have tumours without them
  • they are more merging and some are more enabling - if these are present it’s easier for cancers to progress
• What are the side effects of cancer therapy?

   Narrow therapeutic index (small difference between the dose that has an effect and the dose that has side effects)

  • Particularly chemotherapy
  • Affects fast-dividing healthy cells e.g. cells in the hair follicle + bone marrow (leading to increase susceptibility to infection + certain areas of the lining of the gut
  • not all chemotherapy affects the hair follicles
  • Unwanted induction of the immune system
  • Immunotherapy
  • Cell therapy
• How does chemotherapy work?

  By preventing tumour growth/blocking the hallmarks

  • cancer drug will pick on what only the tumours do and the rest of the body doesn’t so that you get a therapeutic window
• What is the sole purpose of chemotherapy?

  to slow down cell division (prevent tumour cell division) - target cells that are hyper-proliferating
• What are the 4 chemotherapeutics?

  Alkylating agents

  Antimetabolites

  Mitotic spindle inhibitors

  Topoisomerase inhibitors I and II
• What is the mechanism of action for alkylating agents?

  They cross-link DNA (locks DNA closed covalently), preventing the separation of DNA strands and inhibiting DNA replication and transcription.

  Damage caused by alkylating agents activates cell cycle checkpoints, leading to cell cycle arrest
• Examples of alkylating agents

  • Cyclophosphamide
  • Ifosfamide
  • Chlorambucil
  • Melphalan
• How do antimetabolites work in chemotherapy?

  They compete with natural substrates for binding to enzymes involved in nucleic acid synthesis - they block the incorporation of the natural substances and so inhibit the synthesis of DNA and RNA. They block the formation of metabolites and so stop DNA bases from being made.
• Examples of antimetabolite drugs for chemotherapy

  Fluorouraciil (5-FU)

  Methotrexate

  Capecitabine

  Gemcitabine
• How do mitotic spindle inhibitors work? (mechanism of action)

  They prevent the proper aliment and segregation of chromosomes during cell division 

  Example of mechanisms:

  • target the entry and the beginning formation of the spindle
  • target how the chromatids are getting lined up
  • preventing the exit/splitting
• Examples of mitotic spindle inhibitors

  • Vinblastine
  • Vincristine
  • Docetaxel
  • Paclitaxel
• How do topoisomerase inhibitors work?

  They interfere with the activity of topoisomerase. They work by stabilising the enzyme-DNA complex in its cleaved form or by preventing the resealing of the DNA strands after they have been cut. This interference leads to the accumulation of DNA strand breaks and ultimately induces cell death, particularly in rapidly dividing cells like cancer cells.
• Topoisomerase I Inhibitor

  stabilise the complex formed between topoisomerase I and DNA when the enzyme has cut one strand of the DNA double helix. This stabilisation prevents the resealing of the DNA strand, leading to the formation of permanent single-strand breaks in the DNA.
• Topoisomerase II inhibitor

  these stabilise the complex formed between topoisomerase II and DNA when the enzyme has cut both strands of the DNA double helix. This stabilisation prevents the resealing of the DNA strands, resulting in the formation of double-strand breaks in the DNA
• What is the function of topoisomerase?

  allows the DNA to unwind in specific areas to allow for the copying of genetic material - so genes can be copied during transcription or replication
• Examples of topoisomerase inhibitors

  Irinotecan and topotecan
• Common chemotherapy toxicities...

  • Nausea and vomiting 
  • Mucositis
  • Gastrointestinal side effects – constipation or diarrhoea
  • Bone marrow toxicity
  • Alopecia
  • Skin Toxicity
  • Neuropathy (no feeling in hands or feet)
  • Fatigue
• Acute chemotherapy toxicities...

  • Anaphylaxis
  • Infusion-related / hypersensitivity reactions
  • Extravasation
  • Tumour lysis syndrome
  • Acute cholinergic syndrome
• Less common chemotherapy toxicities...

  • Tinnitus 
  • Renal impairment (transient or permanent)
  • Hepatic impairment (transient or permanent)
  • Cardiotoxicity
  • Electrolyte disturbances
  • Ocular toxicity
  • Secondary malignancies
  • Fertility problems
• GI side effects of chemotherapy...

  • Sore mouth
  • Changes in taste and smell
  • Nausea and vomiting
  • Changes in appetite
  • Mucositis
  • Diarrhoea
  • Constipation
• Cause of nausea and vomiting

  • two pathways that cause nausea and vomiting ion response to chemotherapy:
  • a central pathway - the direct effect off those drugs on the CNS and the brain
  • a peripheral pathway - the effect on the GI tract oof those drugs and that proxy triggers the central response
• Cause of diarrhoea

  • direct cell death
  • things that are doing the absorption and the balance of the water and the electrolytes are killed
  • chronic inflammation
  • imbalance in microbiome
• Cause of mucositis

  • mucositis causes diarrhoea but not all diarrhoea is caused by mucositis
  • occurs when chemotherapy has a profound effect on the lining of the gut
  • breaks down the barrier of the gut - get diarrhoea and malabsorption
  • can heal from this + that why one reason why chemotherapy is given in cycles
• Treatment for mucositis

  • Antibiotics 
  • Pro-biotics
  • Anti-oxidants
  • Mucosal barrier regulators
  • Anti-inflammatories
  • Hormones
  • Pain killers
  • Nutrition replacement
• Target cancer therapy...

  • focussed on very specific biology of cancer
  • take some of the hallmarks and think about drugs that can use to block the hallmarks/pathways
  • some drugs can target multiple hallmarks
• What are the different types/ways of immunotherapy?

  Cellular therapy

  Immunomodulators

  Oncolytic virus therapy

  Monoclonal antibodies

  Cancer treatment vaccines
• cell therapy...

  A) blood

  B) multiplied

  C) isolated

  D) enhanced

  E) living

  F) multiply

  G) recognise

  H) cancer

  
• • blue blob - how often it happens
  • red blob - how often is that side effect severe

  
• Why haven’t we cured cancer yet?

  • Dose limiting side effects of drugs
  • Think about the biology of cancer
  • Mutations
  • Evolution
  • Tumour microenvironment
  • Extrinsic factors
  • Discovery and diagnosis
  • Access to health care
  • Available drugs
  • Health economics