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3rd Year Biomed > Cancer Bio (Garrett Lecture 1 - Drug discovery) > Flashcards

Cancer Bio (Garrett Lecture 1 - Drug discovery) Flashcards

1
Q

What are some features of normal cell vs cancer cells?

A

Normal cells:

  • Reproduce exactly
  • Undergo contact inhibition
  • Stick together in correct place
  • Become specialized or mature
  • Undergo apoptosis if too damaged

Cancer cells:

  • Don’t reproduce themselves exactly
  • Don’t obey contact inhibition
  • Don’t stick together, don’t always remain localised
  • Don’t specialize
  • Don’t always undergo apoptosis
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2
Q

What in the definition of neoplasia?

A

New growth of cells

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3
Q

What is the definition of a tumour?

A

Swelling of a part of the body, usually caused by abnormal cell growth

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4
Q

What are the 2 types of tumour?

A

Benign

Malignant - malignant neoplasm termed cancer

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5
Q

Define benign and malignant neoplasms by these criteria: Size, borders, differentiation, growth rate, dividing cells, necrosis, invasion, metastasis

A

Benign:

  • Small
  • Well defined borders
  • Resembles tissue of origin
  • Slow growth
  • Dividing cells rare
  • No necrosis
  • No invasion
  • No metastasis

Malignant:

  • Large
  • Ill defined borders
  • Variable differentiation
  • Rapid growth
  • Dividing cells common
  • Necrosis
  • Invasion
  • Metastasis
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6
Q

What is a carcinoma? Give an example

A

A cancer derived from epithelial cells

e.g skin, bowel

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7
Q

What is a sarcoma? Give an example

A

Cancers derived from connective tissue

e.g Liposarcoma, derived from adipose tissue

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8
Q

What is a mesothelioma?

A

Cancers derived from mesothelioma cells

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9
Q

What are the mesothelioma cells? What structures do they form?

A

Cells that cover outer surface of most internal organs

  • Form lining called mesothelium
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10
Q

Mesotheliomas are commonly associated with exposure to what?

A

Asbestos

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11
Q

What is a melanoma?

A

Cancers derived from melanocytes in skin

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12
Q

What are leukaemias?

A

Cancers of blood forming cells, involving bone marrow

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13
Q

What are lymphomas?

A

Cancers of the lymphatic system

Derived from cells of lymphoid tissue i.e lymph nodes, glands and lymph organs (e.g. spleen, thymus)

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14
Q

What are the 3 steps in ‘The patients journey’ with cancer?

A

Detection
Diagnosis
Treatment

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15
Q

What are the 2 main types of cancer drugs (systemic therapy)?

A

1) Cytotoxic drugs
2) Molecular targeted drugs
- small molecules
- biologicals e.g. antibiotics

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16
Q

How were Nitrogen mustard drugs first identified?

A
  • 1919, Krumbharr published that mustard gas caused significant decrease in white blood cell count
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17
Q

What did Gilman and Goodman do in the 1940’s?

A

Tested nitrgoen mustards as a treatment for blood cancers e.g hogkins lymphoma

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18
Q

What are the characteristics of modern nitrogen mustard drugs? Give some examples

A
  • Operate by interfering with synthesis, structure and function of DNA or mechanisms of cell division leading to DNA damage
  • Have small therapeutic window due to normal cell toxicity
  • Have side effects

Chlorambucil - CLL, NHL
Melphalan - Ovarian, breast

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19
Q

What are molecular targeted cancer drugs? How do they work?

A
  • Identify genes that are altered in cancer and produce a deregulated protein that is directly responsible for the initiation/progression of cancer
  • Develop drugs that bind and block protein activity
  • More effective and less toxic to normal cells
20
Q

How can patients be selected for molecular targeted drugs?

A

Diagnostic test:

- Identify patients with gene alteration

21
Q

Give 2 examples of novel small molecule drugs acting on molecular targets

A

1) Imatinib
- used in CML
- Inhibits BCR-ABL fusion protein
- encoded by Philadelphia chromosome

2) Vemurafenib/PLX4032
- Targets BRAF V600E protein
- Found mutated in approx 50% of melanomas and 8% of solid tumours

22
Q

How can BCR-ABL and BRAF V600E mutations be diagnosed?

A

BCR-ABL:
- FISH or PCR for detection of BCR-ABL gene

BRAF V600E:
- PCR based analysis

23
Q

What is the main problem with molecular targeted drugs?

A

Drug resistance

24
Q

What makes a good cancer drug target?

A

1) Target validation - target knockdown blocks cancer proliferation - target is present in cells
2) Drugability of target - is there somewhere for the drug to bind
3) Opportunity for structure-based approach
4) Practicalities of a screen
5) Availability of assays to detect target activity in the cell

6) Diagnostics
- ability to test whether patient has drug target

25
Q

Explain how BRAF matches each criteria as a good drug target

A

1) Therapeutic validation:
BRAF mutated in mutiple cancers and 50% of melanoma
Common mutation = V600E

2) Drugability of target - enzyme kinase, has ATP binding pocket - can design drugs that mimic ATP

3) Opportunity for structure-based approach
- crystal structure observed

4) Practicalities of a screen - RAF protein available for assay

5) Availability of assays to detect target activity in the cell
- ELISA available for detection of pMEK, pERK (BRAF phosphorylates MEK, which in turn phosphorylates ERK)

6) Diagnostics
- Detection of V600E mutation by PCR assay

26
Q

Who make cancer drugs? Give examples

A

1) Pharmaceutical companies
- Roche

2) Biotech companies
- Astex pharmaceuticals

3) Academic/charitable organisations
- Cancer research UK
- The institute of cancer research

27
Q

What type of molecule is BRAF?

A

Serine/threonine protein kinase

28
Q

What is Plexxikon?

A

Structure based drug design company

29
Q

What do protein kinases do?

A

Transfer the terminal phosphate of an ATP onto a substrate

  • Tyrosine kinases transfer to tyrosines
  • Serine/threonine kinases transfer to serine or threonine
30
Q

What was developed in the early 2000s that helped in the development of a BRAF kinase inhibitor?

A
  • Basic scaffold structures that could inhibit kinases

- Contain 2 nitrogens that can hydrogen bond to the ATP binding doman

31
Q

What was the problem with the early structures developed in the early 2000s?

A

None could selectively bind to BRAF or other kinases altered in cancer

32
Q

What was the initial aim of Plexxikon in designing a BRAF inhibitor?

A
  • Aim was to find a chemical scaffold that binds to a kinase pocket in one orientation
33
Q

How did they tackle this aim?

A

Screened 20,000 scaffold-like compounds of a small molecular weight with 5 different kinases

34
Q

What were the initial findings?

A
  • 100 structures showing bound compounds were seen
  • One structure revealed binding of 7-azaindole to ATP binding site of Pim-1, but in multiple orientations
  • Identification of a 3 amino phenyl analouge of 7-azaindole that bound in 1 orientation
35
Q

What did they then do after the discovery of the 3-amino-phenyl analouge of 7-azaindole?

A
  • Built a library of mono and di-substituted analogs of the 7-azaindole core, with substitutions at positions 3,4 and 5
36
Q

What did they find from these substitutions?

A
  • Screening showned a compound with a difluro-phenylsulfonamide motif
  • Bound specifically to oncogenic BRAF and not to wild type or other kinases
37
Q

Further optimisation led to the discovery of what drug?

A

PLX4302 (Vemurafenib)

38
Q

In Late Stage Preclinical Development, what is formulation and toxicology?

A

Formulation:

  • Determining drug delivery
  • Formulate drug as tablets, capsules or injections

Toxicology:

  • Checking to see if there are any long term side effects
    e. g. heart problems, blindness, kidney/liver failure
39
Q

Breifly explain the purpose of phase 1,2 and 3 clinical drug trials

A

Phase 1:

  • Is the treatment safe
  • Any harmful effects
  • Dosages

Phase 2:
- Look at how treatment works

Phase 3:
- Treating new treatment against existing treatments

Completion on phase 3 trials submitted for registration with EMA (europe) or FDA (USA)

40
Q

Who will take part in phase 1 clinical trials? Where will they be?

A
  • Patients who have failed treatment for their particular cancer, willing to volunteer and are fit enough
  • In a specialised Phase 1 Unit (Medicines and Health Products Regulatory Authority (MHRA) approved)
41
Q

When was Vemurafenib approved as a registered drug? What cancers was it approved for?

A
  • August 11th 2011
  • FDA approved
  • Use in patients metastatic melanoma with the BRAF V600E mutation
42
Q

What was the median progression free survival for verurafenib compared to current treatment?

A

5.3 months compared to 1.6 months

43
Q

What was a major problem in some patients treated with vemurafenib?

A

Acquired drug resistance

44
Q

Name some ways that cancer cells can get around BRAF inhibition

A

RAS signalling pathway alterations:

Normally:
RAS –> BRAF –> MEK
–> ERK –> Proliferation and survival

1) ARAF or CRAF elevation
- Work in place of BRAF

2) Upregulation of alternative signalling pathway e.g PI3K

45
Q

What is translational research?

A

Clinical evaluation of a drug and then using this info to change/improve treatment

46
Q

What is a curret technique for overcoming vemurafenib resitance in melanoma patients?

A

Personalised medicine by drug combinations:

  • Taking tumour and assessing resistance mechanisms
  • Designing drug combinations that inhibit resistance mechanisms

e.g patient with upregulated PI3K signalling, giving BRAF and PI3K inhibitors

Sometimes given as a pair from initial treatment
Sometimes BRAF inhibitor used first and second inhibitor introduced later

3rd Year Biomed (44 decks)

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