Block C Lecture 3 - Targeted Cancer Therapies Flashcards
What are driver mutations?
Genetic alterations that directly contribute to the initiation and progression of cancer by providing a growth advantage to the cells in which they occur
(Slide 3)
What is targeted cancer therapy?
A therapy which attempts to take advantage of a genetic change which malignant cells have. It involves drugs being targeted at pathways, processes and physiology which are uniquely disrupted in cancer cells such as a protein which is present or more abundant in cancer cell when compared to normal cells
(Slide 4)
What is the main advantage of targeted cancer therapies over classical chemotherapy?
Reduced collateral damage to normal tissues / cells
(Slide 4)
What is personalised cancer therapy?
Use of molecular analysis to achieve the optimum medical outcomes in the management of a patients disease or disease pre-disposition
(Slide 5)
What does the term “disease pre-disposition” mean?
Synonymous with genetic susceptibility it describes an increased likelihood of developing a disease, which can be due to genetics or other factors.
(Slide 5)
Why do patients often tolerate targeted therapies better than classical chemotherapy, and what does this do?
They tolerate targeted therapies better due to less toxicity arising from less collateral damage to normal cells, resulting in a better quality of life during treatment
(Slide 6)
What are the 2 mean categories of targeted therapy?
Small-molecule compounds and monoclonal antibodies
(Slide 8)
What kind of targets are small-molecule compounds used for and why?
Small-molecule compounds are usually developed for intra-cellular targets as agents enter cells relatively easily.
Monoclonal antibodies are usually used for extracellular targets as they are relatively large and generally cannot enter cells
(Slide 7)
What is the generic naming formula?
Name = prefix (variable) + substem(s) + stem
(Slide 8)
What are 2 examples of steam which can be used in targeted drug naming and what do these correspond to?
-mab: means drug is a monoclonal antibody
-ib: means drug is a small molecule with inhibitory properties
(Slide 8)
What are 3 examples of substems which can be used in naming monoclonal antibodies, which refer to the antibodies target?
-ci(r)-: means target is the circulatory system
-li(m)-:means target is the immune system
-t(u)-:means target is a tumour
(Slide 8)
What are 3 examples of substems which can be used in naming monoclonal antibodies, which refer to the antibodies source?
-ximab: means source is chimeric human-mouse
-zumab: means source is a humanized moused
-mumab: means source is fully human
Note: These all include a steam as well (mab)
(Slide 8)
What are chimeric human-mice and humanized mice?
A chimeric human-mouse is a broad term that refers to an organism (or tissue) that contains both mouse and human cells or tissues, usually from different developmental origins.
A humanized mouse is a mouse that has been genetically modified to incorporate human elements, such as human genes, tissues, or cells.
(Slide 8)
What are 4 examples of substems which small molecules can have which give information about what kind of protein they are?
-tinib: means small molecule is a tyrosine kinase inhibitor
-zomib: means small molecule is a proteasome inhibitor
ciclib: means cell molecule is a cyclin-dependent kinase inhibitor
parib: means small molecule is a poly ADP-ribose polymerase inhibitor
Note: These all also include a stem as well (-ib)
(Slide 8)
How are antibodies developed?
By injecting animals (usually mice) with purified target proteins causing the animal to make many different types of antibodies against the target
(Slide 9)
What properties are antibodies tested for?
The ability to bind best to the target protein WITHOUT binding to non target proteins
(Slide 9)
What must happen to antibodies before they are used in human?
They are humanised by replacing the mouse antibody molecule with the corresponding portions of human antibodies
(Slide 9)
How does HER2 contribute to some breast cancers?
It becomes overexpressed and promotes aggressive tumour behaviour
(Slide 11)
What does the HER2 receptor normally act as?
A co-receptor in the HER family
(Slide 11)
What is a co-receptor?
A molecule that assists a primary receptor in mediating a cellular response. It typically works together with the primary receptor to facilitate signalling, cellular entry, or other biological functions.
(Slide 11)
What is the ligand for the HER2 receptor?
It has no known ligand and instead dimerises with other HER receptors, especially HER3
(Slide 11)
What 2 oncogenic pathways is the HER2/HER3 heterodimer particular potent in activating?
The PI3K/AKT pathway - responsible for promoting cell survival and proliferation
The RAS/MAPK pathway - responsible for driving cell growth and division
(Slide 11)
What are 3 examples of HER2 targeted monoclonal antibodies which are used in breast cancer treatment, and what kind of drug are these?
Trastuzumab (Herceptin) - a monoclonal antibody
Pertuzumab (Perjeta) - a monoclonal antibody
Ado-trastuzumab emtansine (T-DM1) - an antibody-drug conjugate (ADC)
(Slide 12)
What is the mechanism of action of trastuzumab?
It blocks downstream signalling pathways and activates immune cell responses through antibody-dependent cellular cytotoxicity (ADCC), recruiting immune cells which destroy HER2-overexpressing cancer cells
(Slide 12)
What is the mechanism of action of pertuzumab?
It prevents HER2 from dimerising with other HER family receptors, blocking downstream signalling and enhancing the antibody-dependent cellular cytotoxicity (ADCC) response, recruiting immune cells to kill HER2-overexpressing cancer cells
(Slide 12)
What is Ado-trastuzumab emtansine?
A combination of trastuzumab with emtansine (DM1)
(Slide 12)
What is the mechanism of action of Ado-trastuzumab emtansine?
Emtansine (DM1) is a cytotoxic agent (also a spindle poison) which inhibits microtubule formation, which delivers targeted chemotherapy directly to HER2-positive tumour cells, leading to cell cycle arrest and apoptosis, while the trastuzumab component maintains a HER2 blockage by inhibiting downstream pathways
(Slide 12)
When is trastuzumab used?
In early and metastatic (spread) breast cancer
(Slide 12)
What can pertuzumab be used in combination with and why?
Trastuzumab - as it complements it by targeting HER2 receptor dimerization, enhancing trastuzumab’s effect
(Slide 12)
What are 2 examples of HER2 targeted tyrosine kinase inhibitors which are used to treat breast cancer?
Neratinib
Lapatinub
(Slide 13)
What is the mechanism of action of neratinib?
It is an irreversible inhibitor of the HER family which blocks downstream signalling cascades, which prevents tumour cell proliferation and survival
(Slide 13)
What is neratinib used for?
As an extended adjuvant (helps increase efficiency or potency of a drug) post-trastuzumab
(Slide 13)
What is the mechanism of action of lapatinib?
It blocks HER2 and EGFR activity, blocking intracellular signalling and preventing tumour cells from surviving and proliferating
(Slide 13)
How do tyrosine kinases work?
When ATP binds to a specific region of the receptor, phosphorylation of tyrosine residues on the receptor and effector proteins occur, and the receptor removes a phosphate group for ATP (turning it into ADP) and transfers it to the receptor / effector protein
(Slide 14)
What is the mechanism of action of a tyrosine kinase inhibitor (such as EGFR-TKI) (TKI)?
They impair the ability of tyrosine kinases to bind and utilise ATP by binding to the ATP binding site, reducing the receptor’s activity
(Slide 14)
What are 3 examples of endocrine therapies for hormone receptor positive breast cancer (luminal A and B?
Selective Oestrogen Receptor Modulators (SERMs)
Aromatase Inhibitors (AIs)
Selective Oestrogen Receptor Degraders (SERDs)
(Slide 15)
What is an example of a Selective Oestrogen Receptor Modulator (SERM), a Aromatase Inhibitor (AI) and a selective oestrogen receptor degrader (SERD)?
Selective Oestrogen Receptor Modulator (SERM): Tamoxifen
Aromatase Inhibitor (AI): Letrozole, Anastrozole, Exemestane
Selective Oestrogen Receptor Degraders (SERDs): Fulvestrant
(Slide 15)
What is the mechanism of action of Selective Oestrogen Receptor Modulators (SERM)?
They block oestrogen receptors in the breast tissue, which blocks activating of the ER pathway, which results in the inhibition of cancer cell growth and prevention of tumour progression
(Slide 16)
What is the mechanism of action of aromatase inhibitors?
They reduce oestrogen production by inhibiting the aromatase enzyme, which is responsible for converting androgens into oestrogens, reducing activation of the ER pathway, inhibiting cancer cell growth and tumour progression
(Slide 15)
What women are aromatase inhibitors primarily used in?
Postmenopausal women
(Slide 15)
What is the mechanism of action of Selective Oestrogen Receptor Degraders (SERDs)?
They degrade and inactive oestrogen receptors, reducing the activation of the ER pathway, resulting in the inhibition of cancer cell growth and tumour progression
(Slide 15)
When are Selective Oestrogen Receptor Degraders (SERDs) used?
In advanced or metastatic ER-positive breast cancer
(Slide 15)
What do co-regulators do?
They determine if a gene is activated or repressed
(Slide 16)
What happens when the oestrogen receptor (ER) is activated?
It changes conformation when oestrogen binds, which recruits co-activators to the oestrogen response element ERE on DNA
(Slide 16)
How can SRC-3 (AIB1) drive tumour growth?
In breast cancer cells, high levels of SRC-3 can lead to excessive ER signalling, which can drive tumour growth
(Slide 16)
How do SERMs inhibit oestrogen receptors?
They bind to them and change their shape, which increases recruitment of co-repressors which inhibit transcription and tumour growth
(Slide 16)
How can SERMs act as ER agonists or antagonists?
They can activate or block oestrogen signalling based on the tissue type
(Slide 17)
What 3 things decide if SERMs act as an agonist or antagonist?
- Tissues expressing different levels of ERα and ERβ
- Tissue specific co-activators or co-repressors
- Gene expression patterns in each tissue
(Slide 17)
How do SERDs deactivate and degrade ERs?
They bind to ERα and induce a conformational change which prevents co-activator recruitment while also targeting ERα for proteasomal degradation, reducing ER levels in the cell
(Slide 18)
How do the levels of ERα in tissues effect the activity of SERDs?
High (such as in the breast) - SERDs block ER signalling, leading to cancer cell death
Moderate (such as in bones) - SERDs produce a minimal effect and don’t cause osteoporosis like aromatase inhibitors
Variable level (such as in the uterus) - SERDs don’t stimulate ER and avoid uterine cancer risk as seen with tamoxifen
Low to none (such as in the brain, liver or muscle) - SERDS produce a minimal effect and preserve normal function
(Slide 18)
Why are aromatase inhibitors not often used in premenopausal women?
As in them, the main source of oestrogen is the ovaries
(Slide 19)
Why are aromatase inhibitors less effective?
Due to the oestrogen negative feedback loop;
Low oestrogen increases Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH), which increase oestrogen
(Slide 19)
What do the ovaries and peripheral tissues do concerning aromatase activity?
The ovaries convert androgens into oestrogen using aromatase
The peripheral tissues convert adrenal androgens into oestrogen
(Slide 19)
What do the adrenal glands do regarding aromatase activity?
They don’t have any aromatase activity, HOWEVER, they can produce androgen precursors, but just can’t convert them into oestrogen
(Slide 19)
What are the 2 different classes of aromatase inhibitors?
Steroidal (type I) and non-steroidal (type II)
(Slide 20)
What are some key differences between steroidal (type I) and non-steroidal (type II) aromatase inhibitors?
Type I structure is androgen-like whereas type II structure is non steroidal (triazole / imidazole)
Type I is an irreversible inhibitor which permanently deactivates aromatase whereas type II is a reversible competitive inhibitor which only temporarily blocks enzyme activity
Type I lasts long than type II due to enzyme degradation
(Slide 20)
What is an example of a steroidal (type I) and and a non-steroidal (type II) aromatase inhibitor?
Steroidal: Exemestane (Aromasin)
Non-steroidal: Letrozole (Femara) or Anastrozole (Arimidex)
(Slide 20)
Why are type II (non-steroidal) aromatase inhibitors used more commonly than type I (steroidal) inhibitors?
Due to their high potency
(Slide 20)
What are 3 side effects of SERMs?
Hot flashes
Venous thromboembolism (blot clot in vein)
Endometrial cancer risk (due to agonist effect)
(Slide 21)
What are 3 side effects of aromatase inhibitors?
Osteoporosis
Joint pain
Hot flashes
(Slide 21)
What are 3 side effects of SERDs?
Injection site reactions
Fatigue
Nausea
(Slide 21)
How are SERMs, aromatase inhibitors and SERDs delivered?
SERMs and aromatase inhibitors are delivered as an oral tablet whereas SERDs are delivered via intramuscular injection
(Slide 21)
What was the original target of EGFR tyrosine kinase inhibitors and how has this evolved through different generations of drugs?
Originally just EGFR mutations, but eventually went to just T790M-specific EGFR mutations and scientists are currently working on an inhibitor which targets C797S mutations
Note: These have also went from reversible to irreversible inhibitors
(Slide 23)
What are gefitinib and erlotinib?
1st generation EGFR tyrosine kinase inhibitors which were approved in the early 2000s and later withdrawn due to a lack of survival benefit but re-approved for first line treatment of EGFR mutant Non-small cell lung cancer (NSCLC) in the early 2010s.
(Slide 24)
What mutation has been attributed to cause resistance to first generation EGFR TKI therapy?
An acquired T790M point mutation
(Slide 27)
Why do common EGFR mutations increase TKI drug affinity whereas the acquired T790M mutation decreases TKI drug affinity?
Erlotinib and gefitinib bind to the ATP binding site of EGFR. Most common EGFR mutations structurally change the ATP-binding pocket, increasing drug affinity as the receptor has weaker ATP binding.
For the T790 mutation, steric hindrance prevents erlotinib and gefitinib from binding effectively with the mutation, as a small threonine amino acid is replaced with a large methionine one. This increases the receptors affinity for ATP, making the receptor prefer ATP over the TKI drugs
(Slide 28)
What is osimertinib?
A third generation EGFR TKI, which was originally approved for use in treating Non-small cell lung cancer (NSCLC) whose disease has progressed on after another EGFR TKI was used but it is now the preferred first-line treatment over first generation (such as gefitinib and erlotinib) and second generation (such as afatinib or dacomitinib) EGFR TKIs for NSCLC
(Slides 29 and 30)
What is the most common resistance mechanism to osimertinib and why?
A C797S mutation, as cysteine 797 (C797) is a key residue where osimertinib covalently binds to EGFR, with the change of cysteine to serine preventing irreversible binding of osimertinib
(Slide 31)
What are 2 common side effects of EGFR TKIs?
Rash and diarrhoea
(Slide 32)
