Lecture 9 (targeted therapy) Flashcards
2 different methods of cancer treatments:
- Local- surgery and radiation.
- Systemic- Chemo, Hormone and targeted therapies.
Time periods of when these therapies were developed.
-Chemotherapy began from the 1960s
-Hormone therapy can next and lead to target therapy.
-Molecular targeted therapy began in the late 1990s.
What is radiotherapy
-Created by Marie Curie in 1900s
-Exposure to ionizing radiation causes extensive cellular damage and formation of free radicals
-1 ray causes damage to >1000 bases in DNA, ~100 SSBs and ~40 DSBs
Types of radiotherapy treatments
-External beam radiotherapy (XRT)
-Internal radiotherapy (Brachytherapy/ seeded)
-Radio-isotope therapy (eg Iodine -131 for thyroid cancer)
Limitations to radiotheraphy
-Non-specificity
-Requires carefully controlled administration
-Unwanted Side effects
Types of
chemotherapy
-Alkylating agents
-Anti-metabolites
-Mitotic inhibitors
-Topoisomerase inhibitors
-Anti-tumour antibiotics
Three key molecule for targeted therapies against cancer:
- Monoclonal antibodies
- Small molecule tyrosine kinase inhibitors
- Antibody-drug conjugates (ADCs)
First successful antibodies in hematological cancers
Rituximab and imatinib
How does monoclonal antibodies work:
They bind to the receptor extracellular domain to inhibit pathway activation.
-This is done by receptor internalisation as greater internalisation reduces its activity
-They induce antibody-dependent cellular cytotoxicity which activates immune cell against receptor and leads to intrinsic apoptosis pathway
Small molecule TKIs:
Are small enough to reversibly bind to the receptor intracellular domain and prevents it from autophorsphorylating to inhibit pathway activation.
Antibody-drug conjugates:
-Bind to the receptor extracellular domain to inhibit pathway activation receptor
-Receptor internalisation occurs followed by payload delivery which results in antibody-dependent cellular cytotoxicity
HER family in cancer
-Receptor tyrosine kinases
-EGFR (HER1) HER2, HER3, HER4
-EGFR is overexpressed in lung, head, neck and colorectal cancers
-HER2 is over-expressed in breast cancer
HER family activates what pathways
-PI3K pathway (AKT)
-MAPK pathway (RAS, RAF, MEK, ERK)
what are the three approved HER2 targeted TKIs
-lapatinib
-neratinib
-tucatinib
what is lapatinib
-dual HER2/EGFR TKI
-reversible inhibitor
-first HER2 targeted TKI to be FDA approved
-approved in combination with chemotherapy (capecitabine) for HER2 + BC and with hormone therapy (letrozole) for HER2 + BC + HR
what is neratinib
-Pan-HER TKI
-irreversible inhibitor
-approved for sole treatment in early stage HER2 + BC and in combination with chemotherapy (capecitabine) for metastatic HER2 + BC
what is tucatinib
-HER2-specific inhibitor
-reversible inhibitor
-approved for use in combination with targeted therapy (trastuzumab) and chemotherapy (capecitabine) for metastatic HER2 + BC
Following cross comparison of the approved anti-cancer TKIs which was most potent
Neratinib was most potent across many cancer types, tucatinib came second in sensitivity
What can neratinib be paired with to enhance/cause improvements and why does neratinib need to be enhanced
-Prolonged use of neratinib will develop innate and acquired resistance.
-Neratinib can be paired with dasatinib to enhance its action.
What is dasatinib
It is an orally active multi-kinase inhibitor
-Commonly paired with naratinib
-targets SFK (src family kinase), c-Abl, c-KIT, PDGFR, and ephrinA
-most potently inhibits Src kinase and c-Abl
-already FDA approved for treatment of myeloid leukaemia and Philadelphia-positive acute lymphocytic leukaemia so its safety profile was known
What is the protein K-RAS and why is treating it difficult.
KRAS is an oncogene involved in the ERK pathway that is mutated in about 25% of all cancers
-KRAS is active when bound to GTP and inactive when bound to GDP
-Treating KRAS mutations is difficult as mutations often keep it in its active stage but we want it locked in its inactive state to be targeted by drugs
What cancers involve KRAS mutations and why are they hard to treat
-KRAS mutations common in pancreatic, colorectal, and non-small cell lung cancers
-KRAS is hard to treat because they cycle between active and inactive states and also because of the small size of KRas and its lack of binding sites
Approved drugs for KRAS treatment
-Sotorasib, first KRAS mutant inhibitor approved, used in targeting KRAS in non-small cell lung cancer, covalent inhibitor so binds irreversibly to KRAS
-Adagrasib, is also a KRAS mutant inhibitor, used in targeting KRAS in non-small cell lung cancer covalent inhibitor so binds irreversibly to KRAS
Potential drugs for KRAS treatment
-New pan-KRAS mutant inhibitors and KRAS-SOS1/SHP2 disrupters
-Both are non-covalent inhibitors so give a more generalised response with more side effects
what are the different subtypes of breast cancer
-luminal A (most common)
-normal like
-luminal B
-HER2 enriched
-triple negative is the most aggressive (within triple negative there are 11 more different subtypes)
how many HER altered cell lines are there across different cancer types
22 HER altered cell lines across cancer types such as colorectal and ovarian as well as breast
