Lecture 9 (targeted therapy) Flashcards

1
Q

2 different methods of cancer treatments:

A
  1. Local- surgery and radiation.
  2. Systemic- Chemo, Hormone and targeted therapies.
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2
Q

Time periods of when these therapies were developed.

A

-Chemotherapy began from the 1960s
-Hormone therapy can next and lead to target therapy.
-Molecular targeted therapy began in the late 1990s.

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3
Q

What is radiotherapy

A

-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

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4
Q

Types of radiotherapy treatments

A

-External beam radiotherapy (XRT)
-Internal radiotherapy (Brachytherapy/ seeded)
-Radio-isotope therapy (eg Iodine -131 for thyroid cancer)

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5
Q

Limitations to radiotheraphy

A

-Non-specificity
-Requires carefully controlled administration
-Unwanted Side effects

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6
Q

Types of
chemotherapy

A

-Alkylating agents
-Anti-metabolites
-Mitotic inhibitors
-Topoisomerase inhibitors
-Anti-tumour antibiotics

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7
Q

Three key molecule for targeted therapies against cancer:

A
  1. Monoclonal antibodies
  2. Small molecule tyrosine kinase inhibitors
  3. Antibody-drug conjugates (ADCs)
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8
Q

First successful antibodies in hematological cancers

A

Rituximab and imatinib

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9
Q

How does monoclonal antibodies work:

A

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

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10
Q

Small molecule TKIs:

A

Are small enough to reversibly bind to the receptor intracellular domain and prevents it from autophorsphorylating to inhibit pathway activation.

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11
Q

Antibody-drug conjugates:

A

-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

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12
Q

HER family in cancer

A

-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

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13
Q

HER family activates what pathways

A

-PI3K pathway (AKT)
-MAPK pathway (RAS, RAF, MEK, ERK)

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14
Q

what are the three approved HER2 targeted TKIs

A

-lapatinib
-neratinib
-tucatinib

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15
Q

what is lapatinib

A

-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

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16
Q

what is neratinib

A

-Pan-HER TKI
-irreversible inhibitor
-approved for sole treatment in early stage HER2 + BC and in combination with chemotherapy (capecitabine) for metastatic HER2 + BC

17
Q

what is tucatinib

A

-HER2-specific inhibitor
-reversible inhibitor
-approved for use in combination with targeted therapy (trastuzumab) and chemotherapy (capecitabine) for metastatic HER2 + BC

18
Q

Following cross comparison of the approved anti-cancer TKIs which was most potent

A

Neratinib was most potent across many cancer types, tucatinib came second in sensitivity

19
Q

What can neratinib be paired with to enhance/cause improvements and why does neratinib need to be enhanced

A

-Prolonged use of neratinib will develop innate and acquired resistance.
-Neratinib can be paired with dasatinib to enhance its action.

20
Q

What is dasatinib

A

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

21
Q

What is the protein K-RAS and why is treating it difficult.

A

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

22
Q

What cancers involve KRAS mutations and why are they hard to treat

A

-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

23
Q

Approved drugs for KRAS treatment

A

-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

24
Q

Potential drugs for KRAS treatment

A

-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

25
Q

what are the different subtypes of breast cancer

A

-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)

26
Q

how many HER altered cell lines are there across different cancer types

A

22 HER altered cell lines across cancer types such as colorectal and ovarian as well as breast