Cardio-Oncology

Question 1

background

Answer 1

CVD = global leading cause of death
cancer = 2nd cause

Question 2

What is cardio-oncology? (4)

Answer 2

New field in cardiology = seeks to:
- Reduce morbidity & mortality, while improving quality of life
- Cancer survival increasing due to potent and targeted therapies
But…
- Treatments are potentially cardiotoxic
- Cardiotoxicity adversely affects prognosis in cancer patients

Question 3

Cardiotoxicity: cancer or heart targeting

Answer 3

Cancer therapies seek to:
- Promote cell death
e.g., via ROS/oxidative stress
- Halt cell proliferation
- Stop metastasis

Mutant vs WT proteins

On-target vs off-target effects

Question 4

Cardiotoxicity: general pathways (5)

Answer 4

Hypertrophy: ERK1/2 vs CaMKII
Proliferation: ERK1/2 vs AKT
Antioxidants: All MAPKs
Cytoprotection: ERK1/2 vs AKT
Apoptosis: NKs vs RIPKs

Question 5

Cardio-oncology: why is it a problem? (3)

Answer 5

Cancer drugs associated with adverse events
Cardiotoxicity varies with treatment type
 Doxorubicin = 3–26%
 Trastuzumab = 2–28%
 Sunitinib = 2.7–11%

Question 6

Cardiac complications & phasing (5)

Answer 6

normal heart + vessels - asym
cellular injury
Maladaptive changes - symp
Cardiomyopathy - severe/refectory HF
Heart Failure - cardiac death

Question 7

Cardiac complications (7)

Answer 7

1. HF: systolic & diastolic
2. Arterial & pulmonary hypertension
3. CAD/Ischemia
4. Valvular disease
5. Pericardial disease
6. Arrythmias
7. Peripheral vascular disease

Question 8

Current cancer treatment arena (3)

Answer 8

Anthracyclines
HER-2-targeted therapies
Tyrosine Kinase inhibitors

Question 9

Anthracyclines (4)

Answer 9

Most effective anti-cancer treatments

Antibiotics isolated from Streptomyces bacterium

2 mechanisms = inhibit proliferation & promote ROS-linked cell death:
1. Cause DNA intercalation/damage
2. Topoisomerase-IIb inhibition

Question 10

Doxorubicin: discovery & usage (4)

Answer 10

1950s: Farmitalie sought anticancer agents from soil microbes

1960s: successful lymphoma trials

A first-line therapy: Breast, bladder, ovarian, sarcomas, blood (leukemias/lymphoma)…

1967: first signs of cardiac toxicity

Question 11

Doxorubicin = dilated cardiomyopathy (2)

Answer 11

Early- vs late-onset > Arrhythmias, myocarditis, coronary syndromes

18-48% with >550mg/m2 > reversible!

Question 12

Radiotherapy (3)

Answer 12

Difficult to estimate risk

Breast cancer patients increased risk = sig. delay in complication onset

Mechanisms = fibrosis & ischemia

Question 13

Targeted therapies: Immunotherapies or check-point inhibitors (3)

Answer 13

Antibodies
Highly selective
I.V./expensive

Immune cell modulators (e.g., Anti-CTLA4)

Can target mutant receptors

Question 14

Case study 1: The HER2 story (3)

Answer 14

HER2/ERBB2 = cytoprotection signalling

Activating mutations in breast & stomach cancer

1992: Trastuzumab in clinical trials

Question 15

The cardiac cytoprotection pathways

Question 16

Trastuzumab & cardiac complications (2)

Answer 16

endothelial dysfunction
Congestive Heart Failure

Question 17

Mutant receptor/protein kinase inhibitors (3)

Answer 17

56 new anticancer drugs in 2015-2020

Ten classes based on anti-tumour targets

PTK inhibitors = >50%

Question 18

Case study 2: The RAF kinase story (3)

Answer 18

BRAF> cytoprotection signalling via ERK1/2

V600* Activating mutations in melanoma

Vemurafenib (2010) vs dabrafenib (2014) for mutant BRAF tumours

Question 19

RAF kinase & cardiac adaptation

Question 20

RAF targeting & cardiac complications

Question 21

The RAF Paradox (3)

Answer 21

RAF paradox = on-target effects

Washout = enhanced growth

Acquired mutations in MEK

Question 22

Onco-cardiology: 2 sides to every story

Question 23

BRAF inhibitors to treat hypertension