ON6 Targeted Therapies

Targeted cancer therapies are products of ❌ drug design, act on ❌ molecular targets, and are generally ❌. They interfere with specific molecules involved in cancer cell ❌. Can be:
1. ❌ drugs, easily enter tumour cell
or
2. ❌, bind to specific targets on cell surface

Products of activated oncogenes include cell surface receptors that ❌ tyrosine kinases. Tyrosine kinase ❌ the receptors in the cell to make: ❌ derived growth factor receptors, human ❌ growth factor, and ❌-derived growth factor receptors. These stimulate ❌ and block ❌.

Chromosomal abnormalities are in cancer cells but not normal cells. ❌ fusion gene which causes the abnormality makes fusion proteins that❌ cancer development. We can identify cancerous proteins and ❌ their production. Example: Chronic ❌ often have the Philadelphia chromosome, which creates a ❌ fusion protein. In cancer it causes constitutively active ❌ activity.

Imatinib: First NIB approved by FDA. The suffix "nib" indicates a small-molecule ❌ ("nib" is verbal shorthand for "inhibit") of kinase enzymes.
- A small molecule ❌ inhibitor of tyrosine kinase
- Treats chronic myeloid leukaemia; as it is selective for ❌ TK fusion protein and competes with ❌ for binding siten inhibiting phosphorylation (and ❌).

Other NIBs in clinical use: gefitinib, erlotinib, sorafenib, sunitinib, and dasatinib.
- Share ❌ mechanism of action (competitive ATP inhibition at catalytic binding site of TK) BUT difference is the ❌ of targeted kinases
e.g. ❌ inhibits signals from several Rs including VEGF and PDGRF families.

NIBs are well tolerated but frequently cause ❌, arthralgia, & myalgia. Rarely
cumulative cardiotoxicity: ❌ needed.

Targeted therapy with monoclonal antibodies:
Target is angiogenesis, specifically the key targets ❌.

Bevacizumab (brand name Avastin): ❌ monoclonal v VEGF-A, given by ❌ infusion, first line for ❌ cancer.
Mode of action:
Prevents VEGF-A ❌ and so prevents tumour vascularisation and growth. Serious unwanted effects:, ❌tension
• Infections (from ❌), impaired ❌ healing, bleeding, GI perforation, haemorrhage. ❌ in the elderly.

Target: Human epidermal growth factor 2 (HER-2)
Receptor coupled ❌, binds to EGF.
• Normally promotes growth and ❌
• Integral ❌ activity inhibits p27 (cyclin dependent cell cycle ❌)
• Stimulates ❌
• HER2 is found in 20-30% of breast tumours.

Trastuzumab (Herceptin):
❌ monoclonal of HER2, for ❌ breast cancer.
Mode of action: G1 ❌ - less proliferation(no change in HER2 expression). Downregulates ❌ activation, causing less ❌, which activates ❌ and halts cell cycle.

Pertuzumab:
inhibits HER2 ❌.

Unwanted effects of monoclonal ABs:
Mechanism dependent.
Common:
• ❌ related SEs (❌ release syndrome), 1st infusion
• ❌ nausea and vomiting, hypersensitivity
More Serious
• ❌ - release of cellular contents: high K+, P, uric acid, N, low Ca2+ = kidney ❌, seizures, ❌ arrhythmias, death.
• Increased ❌ risk (HepB/reactivation)
• Caution: autoimmune disease, HIV

Target: Cell surface glycoproteins.
❌ antigen found on the surface of normal and malignant B lymphocytes, function unknown. Can activate ❌ cells.

Drug: Rituxumab.
Mediates B cell ❌.
- ❌ dependent cytotoxicity (CDCC)
- ❌ dependent cell-mediated cytotoxicity (ADCC)
- Apotosis
• ❌ NK cell success from 40-80%
Unwanted effects, most serious:
• Cardiomyopathy
• ❌ related SEs
• Hypersensitivity (❌ infusion)
• Myelosupression