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Flashcards in Oncology drugs Deck (55)
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1

4 Types of anti-cancer drug therapies

 

  • Chemotherapy (cytotoxics)
  • Targeted therapy: (increasing)
    • Endocrine therapy 
    • Genotype/Molecularly targeted therapy
    • Immunotherapy

2

What are key cancer signalling pathways?

EGFR, HER2 pathway

intracellular signalling pathway

Ras/MAPK pathway

PI3K/AKT/mTOR pathway

cell cycle, DNA repair pathways

PARP, CDK4/6

 

3

What are molecularly targeted agents (MTA)?

- examples

 

‘a type of treatment that uses drugs or other substances to target specific molecules involved in the growth and spread of cancer cells’

Target tumor-specific vulnerabilities 

Examples:

  • Oncogene addiction
    • HER2 (breast cancer), BRAF (melanoma), EGFR and ALK (NSCLC), BCR-ABL (CML)
  • Non-oncogene addiction targeting VEGF 
  • Synthetic lethality e.g. PARP inhibition

4

Oncogene addiction

- describe

- examples

  • driver mutaton gives a particular pathway for cancer cells to survive
  • Cancer cells become addicted/dependent on the pathways
  • e.g. HER2 (breast cancer), BRAF (melanoma), EGFR and ALK (NSCLC), BCR-ABL (CML)
  • if the dependnet pathways are disrupted, the cancer cells die

5

How is the target for molecularly targeted agents identified?

 

Targeted therapy needs to be coupled with molecular technology

  • Immunohistochemistry 
  • In situ hybridization 
  • Next generation sequencing: targeted sequencing panels, whole genome sequencing, whole exome sequencing (tumour samples and circulating tumour DNA) 

 

  • Examples of biomarkers: 
    • HER2 amplification predicts for response to trastuzumab
    • KRAS mutation in colorectal cancer predicts for lack of response to cetuximab 

6

KRAS mutation in colorectal cancer predicts what?

 

KRAS mutation in colorectal cancer predicts for lack of response to cetuximab (epidermal growth factor receptor (EGFR) inhibitor)

7

Molecular subtypes of: 

- NSCLC

- breast cancer

- colorectal cancer

- melanoma

- prostate

  • NSCLC
    • EGFR
    • ALK
    • ROS
    • BRAF
    • PD-1
  • breast cancer
    • Hormone receptors
    • HER2
  • colorectal cancer
    • KRAS - wildtype vs. mutation
    • BRAF
    • MSI-high
  • melanoma
    • BRAF - wildtype vs. mutation
    • NRAS
  • prostate
    • BRCA

8

3 Types of molecularly targeting agents

  • monoclonal antibody
  • small molecule inhibitors (most are tyrosine kinase inhibitors)
  • antibody drug conjugates (ADC) 

9

Characteristics of monoclonal antibodies (a type of MTA)

 

Bind to extracellular domain of cell surface receptors (often growth factor receptors)

High specificity 

•Potential to engage and activate immune system 

Intravenous

•End in ‘mab’, e.g. trastuzumab 

10

Characteristics of small molecule inhibitors (e.g. tyrosine kinase inhibitors)

 

  • Interferes with intracellular signaling
  • Usually less specific (↑side effects)
  • Oral
  • End in ‘nib’, e.g. gefitinib

11

Characteristics of antibody drug conjugates (ADC)

 

  • Antibody coupled with a chemotherapy drug
  • Targeted delivery of highly potent cytotoxic agent

12

MTA toxicity

- on target & off target effects

 

On-target effects 

  • Mechanism-based 
  • May act as clinical biomarkers of drug activity
  • Sunitinib  (multi-targeted receptor tyrosine kinase inhibitor) and increased blood pressure
  • Gefitinib, cetuximab (EGFR inhibitors) and acneform rash 

 

Off-target effects 

  • Inhibit other targets
  • Immune reactions 
  • Toxic metabolites
  • Expression in normal tissues 
  • Chemotherapy as an example –hair loss, mucositis 

13

Describe ERBB/HER family

 

transmembrane receptors, ligand will bind extracellular region -> structural rearrangement of receptor -> enzymatic activation -> phosphorylation -> intracellular signalling. 

 

4 closely related tyrosine kinase receptors 

  • ERBB-1 = HER1 = EGFR 
  • ERBB-2 = HER2
  • Also ERBB-3/ HER3 and ERBB-4/ HER4

Involved in key cellular functions including cell growth and survival

Downstream: Ras-Raf-MEK-ERK and PI3K-Akt-mTOR pathways

often involved in oncogenesis either by gaining function or mutation 

14

Describe molecularly targeting agents for EGFR

- 2 main types

- examples

- clinical use

- SE

  • EGFR expression in human tumours high in: 
    • NSCLC 40‐80%
    • Prostate 40‐80%
    • Gastric 33‐74%
    • Breast 14‐91%
    • Colorectal 25‐77%
    • Pancreatic 30‐50%
    • Ovarian 35‐70%
  • High expression generally a/w invasion, metastasis, late stage disease, chemotherapy resistance, hormone therapy resistance, poor outcome 
  • EGFR activation promotes tumour cell proliferation and survival -> blockage to kill tumour cells 

 

MAbs: cetuximab and panitumumab 

  • Use in advanced RAS wild-type colorectal cancer.
  • Cetuximab also in advanced head and neck squamous cell carcinoma
  • SE: acneiform rash (on-target effect), diarrhea, stomatitis, low magnesium 

 

TKIs: Erlotinib, gefitinib (1st generation) and afatinib (2nd generation) 

  • EGFR mutations (Exon 19 del/ 21 mut) in NSCLC → predictive of response to EGFR TKIs (tumor dependence on EGFR signaling) 
  • SE: acneiform rash, diarrhea, fatigue. Also ocular changes, alopecia, nail changes, pulmonary toxicity, elevations in ALT/AST
  • Treatment of skin toxicity: sun protection, skin care, oral antibiotics (minocycline, doxycycline), topical steroids 
  • Rash is a predictive marker (i.e. higher grade rash = higher probability of response)

15

Describe anti EGFR monoclonal antibodies

e.g. cetuximab and panitumumab 

Use in advanced RAS wild-type colorectal cancer.

Cetuximab also in advanced head and neck squamous cell carcinoma

SE: acneiform rash (on-target effect), diarrhea, stomatitis, low magnesium 

16

Describe EGFR tyrokine kinase inhibitors

 

e.g. Erlotinib, gefitinib (1st generation) and afatinib (2nd generation) 

EGFR mutations (Exon 19 del/ 21 mut) in NSCLC → predictive of response to EGFR TKIs (tumor dependence on EGFR signaling) 

SE: acneiform rash, diarrhea, fatigue. Also ocular changes, alopecia, nail changes, pulmonary toxicity, elevations in ALT/AST

Treatment of skin toxicity: sun protection, skin care, oral antibiotics (minocycline, doxycycline), topical steroids 

17

Describe EGFR T790M mutation

T790 mutation = responsible for almost invariable resistance to EGFR TKI

 

  • Treatment resistance inevitably occurs in most people on 1st and 2nd generation EGFR TKIs. T790M mutations are detected in 50% or more of patients. 
  • Osimertinib is a 3rd generation EGFR TKI, effective against T790M mutation, as well as EGFR-TKI sensitising mutations
  • Currently PBS approved in NSCLC second line after failure of first line EGFR TKI with evidence of T790M mutation on tumour biopsy 
  • TGA listed for first line treatment 
  • SE: less serious adverse events c/w earlier generation EGFR TKIs, particularly less skin toxicity. More prolonged QTc c/w earlier TKIs. 

18

What could you use if erlotinib or gefitinib or afatinib don't seem to work/resistance develops? 

Use 3rd generation EGFR TKI = Osimertinib, if T790M mutation present

 

SE: less skin toxiity, but more prolonged QTc than 1st/2nd generations

19

Describe HER2

- overexpressed in which cancers, and what %

- clinical significance

- types of molecularly targeting agents, examples and SE

 

  • Overexpressed in ~20% breast cancer and 15% of gastric/GOJ cancers
  • a/w more aggressive phenotype 
  • Predictive marker for efficacy for anti-HER2 therapy 

 

Molecularly targeting agents: 

  • Mabs: trastuzumab and pertuzumab
    • Distinct mechanisms of action
    • T + P + taxane= First line therapy in HER2+ mBC
    • SE: well tolerated. cardiotoxicity (mostly asymptomatic and reversible). Pertuzumab (diarrhea)
  • TKI: lapatinib
    • dual EGFR/HER2 TKI
    • SE: diarrhea, N/V, mucositis, fatigue, rash, hepatic toxicity (hence some SE related to EGFR)
  • HER2 antibody-drug conjugate e.g. T-DM1 (Trastuzumab emtansine)
    • Trastuzumab covalently linked to emtansine/DM1 (antimicrotubule cytotoxic agent)
    • Intravenous
    • 2nd line therapy in HER2+ mBC cancer
    • Very well tolerated 
    • SE: thrombocytopenia and increased aminotransferases (mostly asymptomatic, if needed managed with decreased dose) 

20

Describe HER2 TKI

  • e.g. lapatinib
  • dual EGFR/HER2 TKI
  • SE: diarrhea, N/V, mucositis, fatigue, rash, hepatic toxicity (hence some SE related to EGFR)

21

Describe anti HER2 monocloncal antibody

  • e.g. trastuzumab and pertuzumab
  • Distinct mechanisms of action
  • T + P + taxane= First line therapy in HER2+ mBC
  • SE: well tolerated. cardiotoxicity (mostly asymptomatic and reversible). Pertuzumab (diarrhea)

22

Describe HER2 antibody-drug conjugate

  • e.g. T-DM1 (Trastuzumab emtansine)
  • Trastuzumab covalently linked to emtansine/DM1 (antimicrotubule cytotoxic agent/potent chemotherapy) -> specific targets
  • Intravenous
  • 2nd line therapy in HER2+ mBC cancer
  • Very well tolerated.  no chemotherapy related SE due to specific targets
  • SE: thrombocytopenia and increased aminotransferases (mostly asymptomatic, if needed managed with decreased dose) 

23

 Describe VEGF receptor and multikinase inhibitors

- indications

- examples

 

  • Diverse effects: affect multiple pathways involved in cancer cell growth, in addition to blocking VEGF receptor
  • e.g. 
    • Sorafenib (HCC, thyroid, clear cell RCC). oldest medication
    • Sunitinib, pazopanib, axitinib, cabozantinib (clear cell RCC)
    • Lenvatinib, vandetanib (RAI-refractory differentiated thyroid)
  • Indications for inhibition of angiogenesis:
    • growth and progression of cancer
    • diabetes (retinopathy, cardiovascular)
    • macular degeneration of the aged
    • rheumatoid arthritis
    • psoriasis
  • given multiple TKR inhibited, multiple SE: 
    • VEGF-related: HT, proteinuria. Uncommon but serious: thromboembolism, reversible posterior leukoencephalopathy, haemorrhage 
    • GI: mucositis, diarrhea
    • Cutaneous: rash, hand-foot syndrome
    • Transaminitis, thyroid dysfunction, CCF
  • Treated supportively +/-dose interruption/ reduction
  • Hypertension seen as a PREDICTIVE marker - i.e. high likelihood of effectiveness of VEGF inhibitor

24

What is sorafenib used for?

HCC, thyroid, clear cell RCC.

oldest VEGF R + multikinase inhibitor 

 

25

What are sunitinib, pazopanib, axitinib, cabozantinib used for?

clear cell RCC

types of VEGF receptor and multikinase inhibitors

 

sunitinib also used for GIST

26

What are Lenvatinib, vandetanib used for?

 

RAI-refractory differentiated thyroid

Types of VEGF receptor + multikinase inhibitor

27

Describe Cyclin-D/CDK/Rb in role of cancer

 

  • a key pathway in cell cycle progression 
  • Loss of cell cycle control is a hallmark of cancer
  • CDK4/6 + cycline D1 -> inactivate Rb -> cell progression.
  • inhibition of above mechanism with CDK inhibitors -> Rb reactivation -> cell cycle arrest at G1
  • Luminal ER+ breast cancer cell lines have high rates of cyclin D/CDK activation and maintained expression of Rb, a/w sensitivity to CDK4/6 inhibitor 
  • dual inhibition of CDK 4/6 and ER signaling may be synergistic

28

Describe targeting CDK4/6

- example

- clinical use

- SE

 

  • e.g. Ribociclib
  • Selective CDK 4/6 inhibitor 
  • Oral, given in combination with aromatase inhibitor as first line therapy in ER+ HER- metastatic breast cancer (post-menopausal)
  • Well tolerated 
  • Side effects: neutropenia (usually asymptomatic. febrile neutropaenia/sepsis uncommon c.f. chemotherapy related neutropaenia), LFT abnormalities, diarrhea

29

What do you use in combination with aromatase inhibitor as first line therapy in ER+ HER- metastatic breast cancer (post-menopausal)?

Ribociclib (a selective CDK 4/6 inhibitor)

30

How do you target DNA repair pathways?

via synthetic lethality

PARP (Poly ADP Ribose Polymerase) = protein that repairs single stranded breaks

BRCA (homologous recombination) = protein that repair double stranded breaks

  • DNA repair deficiency occurs in BRCA mutated cancers (breast, ovarian, prostate cancer) 
  • BRCA mutations selectively render tumour cells susceptible to PARP inhibition while sparing normal cells, that possess a normal BRCA allele 
  • Single stranded break usually gets repaired with PARP. If PARP inhibitor used, single stranded break -> double stranded break. In BRCA mutated cells (due to loss of heterozygosity, both genes of BRCA are not working), this is unable to be repaired -> cell dies.