15th March- Future directions in cancer therapeutics II Flashcards
What is induced essentiality?
When cancer cells become dependent on normal cellular functions that are not themselves mutated
How is protein quality control affected in cancer?
Increased stress on pathway due to aberrant proteins and OE
What is velcade?
a specific inhibitor of the peptidase activity in the 20S proteasome
What is the use of velcade in cancer treatment?
Disrupts intracellular protein metabolism, thus useful for cancer treatment due to induced essentiality of the protein quality control pathway
What cancers is velcade approved for?
Multiple myeloma
Mantle cell lymphoma
What is multiple myeloma?
A B cell malignancy
2nd most common haematological malignancy
What is a key biomarker of multiple myeloma?
IgG
Why does velcade effectively treat multiple myeloma?
OE of IgG means that their protein homeostasis pathway is pushed to capacity
Velcade blocks IkBalpha degradation thus inhibiting NFkB
Overcomes the UPR threshold –> apoptosis
Outline the typical treatment course for multiple myeloma
- 1st line chemotherpay with thalidomide and dexomethasone
- Stem cell transplantation
- Velcade and dexamethasone
- Lenalidomide
What are the key sources of resistance to velcade in multiple myeloma?
PSMB5 mutation or OE
May develop resistance to UPR
What is HSP90?
A dimeric chaperon that assists client proteins to fold with the help of ATP and other proteins, which acts as a buffer against stress
What is NUP-AUY922?
A HSP-90 inhibitor
What are the potential therapeutic applications of a HSP-90 inhibitor?
NSCLC with ALK translocation which are resistant to crizotinib
HER2+ breast cancer which are resistant to Herceptin
