Lecture 20: Targeted cancer therapies

Question 1

Definition of cancer

Answer 1

A disease of populations of cells, which live, divide, invade and spread w/o regard to normal limits
vs. Normally cell growth, death and location are tightly regulated throughout the body

Question 2

Normal vs cancerous colonic epithelium

Answer 2

1. Normal:
   a) amount of cell birth and cell deaths are closely matched –> causing same net number of cells
   b) cells born in bottom of the crypts of colonic mucosa via mitosis –> cells remain situated on BM and then move towards ends of crypts –> programmed cell death –> sloughed off into lumen
2. Cancer:
   a) mismatch b/w amount of cell births and deaths –> net increased accumulation of cells
   b) cells dont remain in BM crypts –> spread into colonic bowel wall, through BM and into the CT and muscle

Question 3

Molecular Basis of cancer

Answer 3

At a molecular level: Abnormalities in DNA are caused by cancer via Exogenous carcinogens, DNA replication errors and inherited abnormalities

• exogenous carcinogens are external chemicals (e.g. tobacco from cig smoke) which causes damage to the bronchial epithelial cells in the lung, which causes lung cancer
• DNA replication errors occur during mitosis
• Inherited errors lead to an unfair predisposition to a condition

Question 4

Cancer genes

Answer 4

1. Oncogenes (activated): abnormalities in DNA which lead to an increased activity of the encoded protein
2. Tumour Supressor genes (inactivated): genetic abnormalities which inactivate the protein product, changing its function –> suppresses the expression of the gene and amount of protein produced

Question 5

Cancer biomolecules

Answer 5

Proteins which have been overactivated

Cancer biomolecules may be suitable molecular targets for drug therapies

Question 6

Example of cancerous development at the molecular level

Answer 6

Mutation inactivates tumour supressor genes –> cells proliferate –> mutation inactivates DNA repair gene –> mutation of protooncogene creates an oncogene –> mutation inactivates several more tumour surpressor genes –> cancer
Overall: cancer formation requires a prior accumulation of multiple mutations in several key genes.

Question 7

What are the 6 common phenotypic characteristics acquired by cancer cells?

Answer 7

1. Evading apoptosis
2. Self sufficiency in growth signals (dont require external growth signals to stimulate mitosis)
3. Insensitivity to anti-growth signals (mitosis isnt controlled in a normal manner)
4. Tissue invasion and metastasis
5. Limitless replication potential (can keep dividing forever, normal cells cant do this)
6. Sustained angiogenesis (BV development so cancer cells can obtain nutrients and spread to other parts of body)

Question 8

Pathophysiological basis of cancer in organs and tissues

Answer 8

1. Growth and invasion of primary tumours
2. Metastasis and distant effects of wide-spread disease
3. Systemic effects of paraneoplastic syndrome (lump in testical, breast development and positive pregnancy test)

Question 9

Chemotherapy targeting mitotic cycling cells

Answer 9

chemo targets cycling cells w/o discriminating b/w normal cells and cancer cells

Question 10

How is selective toxicity achieved through chemotherapy?

Answer 10

There are higher number of cycling cells present in tumours in comparison to normal tissues
- most normal tissues have low numbers of cells undergoing mitosis (bone, fat, nervous system)

Question 11

Reasons for adverse effects of chemotherapy

Answer 11

Inhibition of proliferation of normal cells

e. g. alopecia (hair loss via death of hair follicles which normally rapidly proliferate)
e. g. blood cytopenias ( RBC, WBC and platelet loss via death of bone marrow cells which normally rapidly proliferate too)

Question 12

Antimicrobial drugs

Answer 12

e.g. paclitaxel
Inhibit the mitotic spindle in the M phase specifically
(mitotic spindle is the scaffolding produced during mitosis which allows chromosomes to separate out prior to cytokinesis, allowing cells to split into two

Question 13

Antimetabolites

Answer 13

e.g. methotrexate

Inhibit DNA synthesis in the S phase specifically

Question 14

What are the stages of the cell cycle?

Answer 14

1. G1 phase: forms normal complement of DNA
2. S phase: cells actively synthesise their DNA
3. G2 phase: Double complement of chromosomes formed
4. Mitotic spindle forms + separates. forms 2x daughter cells

Question 15

What are the components of Personalised Cancer Medicine?

Answer 15

1. Genetic Testing
   a. sample of tumour
   b. histopathological assessment
   c. smaple subjected to sequencing/mutation detection analysis to identify the genetic drivers of the cancer for that individual
2. Targeted drug therapy

Question 16

Targeted Cancer Therapy

Answer 16

drug treatments that inhibit oncoproteins, which drive tumour development and progression
- it is a recent form of cancer therapy. May be more effective and safer, in comparison to Chemo. IT also allows for the individualization of therapy based on genetic testing.

Question 17

Components of Target Cancer Therapy

Answer 17

1. Small molecular drugs: block specific enzymes or growth factor receptors (or intracellular signal transduction enzymes). e.g. imatinib and getfitinib
2. Monoclonal Antibodies: bind to growth factors or their receptors
   e. g. trastuzumab (human epidermal growth factor receptor 2 binding monoclonal antibodies),
   e. g. bevacizumab (vascular endothelial growth factor binding monoclonal antibodies)

Question 18

Chronic Myeloid/Myelogenous Leukemia

Answer 18

200 new cases/year
Characteristic chromosomal translocation –> forming the Philadelphia chromosome
Leads to an accumulation of myeloid leukemia cells in blood and bone marrow (eventual replacement by these cells and accumulation in high numbers in peripheral circulation)
Treatment previously consisted of chemotherapy and immunotherapy, but no consists of targeted therapy

Question 19

Philadelphia chromosome of CML

Answer 19

t(9;22) translocation
- metaphase spread leads to C9 having extra chromosomal material, and C22 being abnormally short.
abnormal (fusion) protein (bcr-abl) and self-sufficiency of growth signals (bcr-abl gene and hence protein drives the abnormal development of this leukemia)

Question 20

Imatinib (gleveec) Clinical Indications and Tyrosine Kinase Activation

Answer 20

Clinical indications: Chronic Myeloid Leukemia + Gastrointestinal Stromal Tumours
Tyrosine Kinase Activation: CML: chromosomal translocation/unique protein (bcr-abl). GIST: point mutation activating c-kit

Question 21

Imatinib chemical action

Answer 21

Small MW inhibitor of bcr-abl and c-kit tyrosine kinases
Binds to ATP-binding site –> inhibiting tyrosine kinase activity
(p.s. tyrosine kinases are enzymes which transfer phosphate groups from ATP to itself or another protein. It is a signalling event)

Question 22

Imatinib adverse effect profile

Answer 22

Generally well tolerated, as it is specific and doesnt inhibit the activity of other tyrosine kinases.
Except in GIST, c-kit gene has a point mutation which constitutively activates its kit-protein product –> molecular driver of this cancer

Question 23

Mechanism of action of imatinib

Answer 23

Overall: Gleevec inhibits Bcr-Abl fusion tyrosine kinase

1. Gleevec inhibits ATP binding site on Abl kinase –> blocks the phosphorylation of tyrosine residues on the substrate protein
2. Cannot transfer phosphate onto its substrate
3. Prevents activation of signal transduction pathways which would normally induce CML leukemia transformation process

Question 24

Selectivity of Gleevac

Answer 24

Not entirely selective for Bcr-Abl tyrosine kinase

• inhibits the receptor tyrosine kinases for PDGF Platalet Derived Growth Factor
• inhibits stem cell factor c-kit

Question 25

CML treatment with Imatinib vs other options

Answer 25

Vastly superior survival compared to those who were treated prior to imatinib being available
Imatinib treatment leads to about the same survival rate as normal population
Success story for target cancer therapy

Question 26

Clinical example of using genetic testing to direct patients to specific targeted therapies

Answer 26

** table

Question 27

Immune Check point modulation

Question 28

Case presentation of a person with Lung Cancer

Answer 28

History: two months worsening breathless ness (1 tumour) and lower back pain (boney mets)
Left Pleural effusion
Investigations: CXR, pleural aspiration (drain fluid from left pleural cavity w. needle. x-ray after to ensure no pneumothorax), lymph-node biopsy
Treatment:
1. Lung cancer treatment
2. Resistance to treatment via brain mets (drugs dont penetrate brain well, therefore is a common site of resisitance/treatment failure)
3. New liver EGFR mutation
4. Responded to 3rd lot of treatment

Question 29

Lung Cancer treatment

Answer 29

Gefitinib - an EGFR tyrosine kinase inhibitor, drug treatment
Improvement: shrinkage of primary lung lesion and decreased nodularity of pleural cavity
Side effects: Skin rash and Diarrohea, due to EGFR receptor expression in skin and gut

Question 30

Summary:

Answer 30

Targeted therapies inhibit oncoprotein drivers, of cancer development and progression
Individualisation of therapy by genetic testing to detect somatic mutations, to direct patients to specific targeted therapies
Adverse effects are often related to the pharmacological mechanism