3.8. why cancer therapy fails

Question 1

what is the primary pattern of resistance to therapy?

Answer 1

The tumour does not respond to treatment right from the start

Question 2

what is the secondary pattern of resistance to therapy?

Answer 2

• May develop during therapy where some response is followed by a failure to improve further
• Metastasis may arise which is not responsive to therapy which appeared to be successful against the parent tumour

Question 3

describe surgical failure

Answer 3

The surgery did not remove all the cancer cells or implanted cells at the surgical site which then regrow to form a RECURRENCE at the same site.

Question 4

what is important in radiation and conventional chemotherapy?

Answer 4

APOPTOSIS (and senescence)

*Inactivation of P53 is a major barrier to successful therapy

Question 5

what are two manners in which correct concentrations of drug are NOT delivered to the cancer cell?

Answer 5

1. Poor tolerance and side effects leading to reductionin drug doses
2. Pharmacogenomics –ineffective conversion of the pro-drug by variants of CYP450

Question 6

name two sanctuary sites

Answer 6

1. blood-brain barrier

2. the testes (are a sanctuary site for lymphomas and lymphoblastic leukaemias)

Question 7

how does tumour vasculature lead to cancer therapy failure?

Answer 7

poor drug delivery –> areas of poor perfusion and hypoxia & raised interstitial pressure

Question 8

what are the effects of non-cancer cells and the microenvironment on the delivery of the correct amount of drug to the cancer cell?

Answer 8

1. other cells within the tumour metabolise the drug
2. Survival signals from non-tumour cells e.g. from activated macrophages stimulated by cell death following radiation and chemotherapy

Question 9

describe multidrug transporters as a cause of multidrug resistance

Answer 9

Major mechanism of resistance to manydifferent drugs (especially hydrophobic molecules) at the same time:
•Known as P-glycoprotein (P-gp) or the multidrug transporter
•Gene (MDR1) is widely expressed in many human cancers
•May be expressed de novo or only later on in the course of the disease

Question 10

what are some problems which may develop with the drug targets themselves?

Answer 10

1. increased concentrations of the drug target
2. mutations of the drug target
3. redundancy of drug target pathways
4. development of downstream mutations
5. loss of monoclonal antibody targets by deletion or mutation

Question 11

What characteristics of stem cells make them very hard to kill?

Answer 11

1. Infrequent division

2. Expression of MDR1

Question 12

explain the issue with dormancy of metastatic cells

Answer 12

Some metastases only start to grow long after chemotherapy for the primary tumour has been completed.
These metastases are said to be dormant.
Dormant cells are not dividing:
•Not affected by conventional chemotherapy
•May not be using the targeted signalling pathways

Question 13

list general strategies for effective therapy

Answer 13

1. Combined or multiple therapy –unlikely that a tumour will be resistant or develop resistance to several different types of therapy at the same time. If a cell develops resistance to one component then it will probably still be sensitive to the others.
2. Molecular testing for known/common patterns e.g. analysis of KRAS mutations before treating lung cancer with EGFR inhibitors
3. Pharmacogenomic analysis to determine presence of variants in drug metabolism e.g. tamoxifen in breast cancer needs to be activated by CYP450

Question 14

what is a good general strategies to aim for effective therapy

Answer 14

1. Make the diagnosis as early as possible
2. Remove the tumour surgically before metastasis has occurred
3. Get it right first time
4. Monitor and make changes as necessary