Targeted Cancer Therapy

Question 1

Targeted Therapy for Cancer

Answer 1

• foundation of precision medicine

- cancer treatment that targets proteins that control how cancer cells grow, divide, and spread

Question 2

Small molecule drugs

Answer 2

• small enough tot enter cells easily

- used for targets that are inside cells

Question 3

Monoclonal Antibodies

Answer 3

• proteins designed to attach to specific targets found on cancer cells
• – can mark cancer cells so they are better seen and destroyed by the immune system
• – can directly stop cancer cells from growing or cause them to self-destruct
• – can carry toxins to cancer cells

Question 4

Tamoxifen

Answer 4

• metabolized into compounds that also bind the estrogen receptor but do NOT activate it
• blocks binding to cancer cells in some breast cancers

Question 5

Imaging Mesylate

Gleevec

Answer 5

• approved for chronic myelogenous leukemia, gastrointestinal stromatolites tumor, and some other types of cancer

Question 6

Gefitnib and Erlotinib

Answer 6

• target epidermal growth factor receptor (EGFR) tyrosine kinase and is approved in the US for non small cell lung cancers which have activating mutations in EGFR

Question 7

PARP inhibitors

Answer 7

• inhibit PARP whose activity is critical for survival of cells with defects in homologous recombination
• under clinical trials to treat breast/ovarian cancers with mutations in BRCA genes

Question 8

BRAF inhibitors

Answer 8

• approximately half of melanomas harbor the V600E activating mutation in the BRAF gene
• majority of cancer cells rely on sustained hyper activation of the oncogene for growth

Question 9

Chronic Myelogenous Leukemia

Answer 9

• kinase mutation allows over expression of Philadelphia chromosome -> cell growth

Question 10

Gleevec

Imantinib

Answer 10

• tyrosine kinase inhibitor
• binds to catalytic cleft of ABL
• remarkable effective in treating CML as a single agent
• leads to high rate of long term cytogenic remission

Question 11

BCR-ABL

Answer 11

• promotes cell growth, inhibits cell death
• inhibited by Imantinib
• CML (chronic myelogenous leukemia)

Question 12

ERBB Family of Receptor Tyrosine Kinases

Answer 12

• when overexpressed becomes oncogene and is problematic
• mutations/amplifications of EGFR (ERBB) gene are common in non-small cell lung cancer and epithelial cancers
• found on Extracellular domain
  — dimerization must occur to become active

Question 13

Targeting ERBB family of receptor tyrosine kinases

Answer 13

• ** SMALL MOLECULES EFFECTIVE ***
• antibodies bind Extracellular domain & block dimerization (can’t activate)
• inhibit kinase activity => shut off transduction
• inhibit fold eyeing helpers

Question 14

Tratuzmab

Answer 14

Targets the Her2 (ErB2) receptor expressed in some types of breast cancers

Question 15

Cetuximab

Answer 15

• binds Extracellular domain of ERBB and blocks dimerization

- prevents activation

Question 16

Lapatnib

Answer 16

• inhibits tyrosine kinase activity shutting off signal transduction (targeting ERBB)

Question 17

17-AAG

Answer 17

• inhibits folding of helpers

- targeting ERBB family of receptor tyrosine kinases

Question 18

HER2

Answer 18

• very over-expressed in breast cancer

Question 19

Trastuzumab

Answer 19

• weaponized humanized portion of chimeric mouse-human antibody (which causes immune response)
• bind Extracellular domain and prevent activation of HER2 (which causes increased pathway proliferation)
• recruits immune cells to kill tumor cells
• Cardiac toxicity

Question 20

BRCA proteins

Answer 20

• required for homologous recombination (DNA double strand break repair)

Question 21

PARP-1

Answer 21

• acts as tag for DNA repair enzymes for single strand breaks

Question 22

Original theory of PARP inhibition

Answer 22

• results in accumulation of SSBs, which lead to broken replication forks during the S phase that require HR and thus BRCA 1/2 for repair

Question 23

PARP Inhibitors

Answer 23

SYNTHETIC LETHALITY
- lock PARP onto DNA
- very problematic ( increases PARP affinity for DNA)
— stalls replication fork, and blocks DNA replication (unless have healthy BRCA to repair issue)
- selectively kills tumor cells because healthy cells will still have BRCA and will be able to overcome the stall and continue replication; tumor cells lacking BRCA will die

Question 24

Mechanism of Resistance to PARPi

Answer 24

• secondary “reversion” mutations in BRCA1, BRCA2, RAD51C/D
• restoration of HRR in BRCA1 mutant tumor cells via loss of 53BP1, REV7
• loss of PARP1 expression
• pharmacological resistance

Question 25

BRAF-V600E

Answer 25

• most common recurrent oncogene mutation in melanomas

Question 26

Vemurafenib

Answer 26

• extends life short period of time in melanoma with BRAF mutation
• BRAF mutation makes MAPK pathway overactive
  — leads to increased ERK which promotes cell growth and inhibits cell death