Lecture 17- Rational Treatment of Cancer 1

Question 1

Rational cancer strategies

Answer 1

• Induce differentiation
• Discourage proliferative signaling
• Promote pro-apoptotic signaling
• Discourage anti–apoptotic signaling
• Exploit checkpoint vulnerability
• Identify the RELEVANT population for specific strategy- removal of those non -relevant helps the statistics and is just logical

Question 2

What is the issue with increased specificity of cancer treatments ?

Answer 2

number gets smaller more specific issue for funding

Number of patient recruited for study for specific mutation may be limited

Question 3

What is the most popular cancer treatment at the moment and how does it work ??

Answer 3

– chemotherapy and surgery historically

Cancer cell s- check point deficiency allows chemotherapy to treat cancer specifically

Question 4

Clinical intervention –

Number of cases

Answer 4

Falling for stomach, uterus, colonal rectum due to combo of ensuring food quality understood/stored and cervical and colorectal screening
Breast cancer – increase in detection so increase in number but mortality reasonably the same

Question 5

Improvement in detection technology means ?

Answer 5

Significant improvement in detection technology means increased detection
Breast/prostate cancer

Question 6

• Indolent tumours:

Answer 6

low invasive, metastatic potential

Question 7

• Aggressive tumours

Answer 7

high metastatic potential

Question 8

• Tumours of intermediate grade:

Answer 8

treatable , resectable

Question 9

Criteria to asses treatment of BC – metastatic or indolent

Answer 9

• Patient age
• Tumour size
• Number of axilliary lymph nodes
• Histology
• Pathological grade
• Receptor status- Growth receptors eg oestrgogen receptors can be treated with antagonist

Question 10

What ratio of people go on to show life threatening disease ?

Answer 10

1 in 5

80 % of people with BC and PC probably don’t be needed to be treated but we don’t know who they are

Question 11

Stratify cancers:

Answer 11

classify into subgroups of properties and prognosis

Question 12

How do you stratify cancers ?

Answer 12

Gene expression arrays – microrarray looking at mRNA
Looking at upregulation and down regulation
Shows patterns
Can set a threshold
Plot those above and below- look at survival rate

Question 13

Myeloma- Blood Cancer

Answer 13

Phenotype the same for benign and aggressive

Question 14

Microarray analysis for myeloma -

Answer 14

– looking at low expression and high expression
Number of different way different changes in gene expression in different kinds of myeloma
Different myelomas different prognosis
- Targeted specific therapy –e.g target signalling pathway with drugs

Question 15

Common microscopic appearance of myelomas - can be 3 subgroups

Answer 15

• Primary mediatsinal B-Cell lymphomas
• Germinal Centre B -Cell - Like Lymphomas
• Activated B- Cell - Like Lymphomas

Question 16

PML gene

Answer 16

marker for PML bodies

Question 17

What does PML stand for?

Answer 17

Pro- myelotic leukaemia

Question 18

How do you distinguish between types of myeloma ?

Answer 18

Can distinguish types of myeloma by gene expression profiling

Question 19

Differentiation can be exploited to kill cancer cells

Answer 19

• Repurpose or kill cancer cells e.g myelomas/leukaemia’s
  As tumour cell populations evolve to greater degrees of malignancy
  they usually lose increasing numbers of differentiation markers

Question 20

Differentiation can be exploited to kill cancer cells - Example

Answer 20

Acute Pro- myelotic Leukaemia
- Normally Promyelocytes got to neutrphils by Transcriptional repressor switched off by RA
In APL- repression removed

Question 21

Chromosomal instability -Example

Answer 21

RA receptor gene is translocated at a fusion break point and generate fusion between RA receptor and PML gene

Question 22

Solutions/ Treatments of PML

Answer 22

Use a derivative of RA -All trans retinoic acid does the same thing
Or arsenic trioxide (traditional remedy specific and effective for this disease

Question 23

How does Arsenic trioxide work ?/

Answer 23

Recruits a specific ubiquitin ligase
(RNF4) to destroy RAR
When added -
GFP labelled PMLs –fusion gene product disappear normal wt remains
Wt PML and PMLRARA
- not cytotoxic because it isnt affecting the wT gene

Question 24

Exploiting Vulnerability arising from checkpoint abandonment -
Experiment

Answer 24

• inflict DNA Damage/ Replication stress
• Labelled with chlorodeoxiuridine and
  Flurodeoxuridine

Question 25

Normal check point response after inflicting DNA Damage-

Answer 25

Cell Cycle Delay
Induced DNA damage Response
- Normal mitosis
- part of check point response is to block places going to do DNA replication in the future
Inhibition of a check point stop initiation now and in future

Question 26

Cancer cell response after inflicting DNA damage

Answer 26

• Poor check point response
  No cell cycle Delay
  No induce DNA damage response
• Mitotic Catastrophe
  Cancer Cell -
  All replication forks don’t start at the same time, they fire at different times
  Fires replication origins anyway and attempts mitosis
  Attempting – going through s phase and G2 with no replicated DNA – will attempt mitosis and have mitotic catastrophe

Question 27

By knowing what checkpoints are damaged in the cancer cell

Answer 27

we can identify what DNA damage needs to be inflicted

Question 28

Example of exploiting vulnerability arising from check point abandonment

Answer 28

Hepatoma cells (lack G2 checkpoint)
-Treated with doxorubicin
 (DNA damaging drug normally induces 
G2 arrest and normal cell repair)
( stained with DAPI only) 
Don’t have a G2 check point - they will incur DNA Damage and carry on doing mitosis ( no cell cycle arrest) 
Selective 
 - fragmented nuclei which isnt viable