TKIs in Colon Cancer, CLL Flashcards
Many colon cancers have constitutively active ________
Ras or Raf mutations downstream from EGFR
Panitumumab class
EGFR antibody
Panitumumab quite active in
EGFR driven diseases:
colon cancer
Squamous cancers of the head and neck,
Squamous (HPV-driven) cancers of cervix and penis
Panitumumab vs Cetuximab
Cetuximab was the first, but is now seldom used.
Panitumumab is associated with fewer infusion reactions.
EGFR in colon vs lung
EGFR is often overexpressed in colon cancer, but unlike in Lung, is not commonly mutated
Blocking antibodies against EGFR only work when
the cells have wild-type RAS and RAF
most common leukemia in adults
Chronic lymphocytic leukemia
CLL: Chronic example of a disease of _____, not ______
accumulation, not over proliferation
CLL phenotypes
Has a node-predominant phenotype (SLL) and a leukemia phenotype (CLL). These are the same disease.
CLL cure rate
Is generally considered incurable, but most patients die with it, not of it.
CLL commonly presents with
autoimmune phenomena such as:
Immune thrombocytopenic purpura (ITP)
Auto-immune hemolytic anemia (AIHA)
Auto-immune agranulocytosis
CLL patients typically have
hypogammaglobulinemia and often present with unusually virulent infections
CLL often driven by
constitutive expression of non-mutated Bruton’s Tyrosine Kinase (BTK)
historical standard tx for CLL
chlorambucil
Rituximab
CD20 antibody
CLL
Use of fludarabine and cyclophosphamide with Rituximab (FCR) was an incremental advance but —
what disease
this was extremely immunosuppressive and dangerous
CLL
what revolutionized treatment for CLL
BTK inhibitors
Site of action for ibrutinib
Covalent modifier of ATP binding site (Cysteine 481) on Bruton’s Kinase
what does ibrutinib treat
active when?
CLL
Active against CLL with del 17p and del 11q which were largely refractory to existing options
most common source of resistance to BTK inhibitors (CLL)
Most common is C481S, changing from nucleophilic –SH in active site to –OH.
Other source of resistance to BTK inhibitors for CLL
Others are mutations in PLC-gamma, the main substrate for BTK (make constitutively active PLC-gamma)
Idelalisib
blocks downstream of BTK (CLL)
Venetoclax
the first Bcl-2 modulator to reset apoptotic threshold (CLL)
single most successful approach to treating CLL yet.
inhibition of BTK
