Millikan IHO Week 4 Flashcards
Ways that receptor tyrosine kinase can become over expressed?
DNA amplification, increased transcription, decreased degradation (mRNA or protein)
Treatment of Metastatic Colon Cancer
5-fluorouracil with irinotecan or oxaliplatin
How long does colon cancer treatment extend survival?
2 years on average; 5 years survivors are no longer rare
An established driver of proliferation and survival
EGFR in Colon Cancer (epidermal growth factor receptor): to PI3K to Akt or Ras to Raf to MEK to MAPK
What do many cancers have constitutively downstream of EFGR?
Ras and Raf
What testing is now universal in patients with metastatic colon cancer?
wild-type Ras and Raf
First used for EGFR antibodies
Cetuximab
associated with fewer infusion reactions and is active in colon cancer, squamous cancers of the head and neck, squamous (HPV-driven) cancers of cervix and penis
Panitumumab
What is commonly mutated in Lung cancer but not in Colon Cancer?
EGFR
Two phenotypes of the same disease: Chronic Lymphocytic Leukemia
node predominant phenotype (SLL-small lymphocytic lymphoma) and leukemia phenotype (CLL-chronic lymphocytic leukemia)
Do people die of or with CLL
with it
Autoimmune Phenomena of Chronic Lymphocytic Leukemia?
immune throbocytopenic purpura, auto-immune hemolytic anemia, auto-immune agranulocytosis
What often drives Chronic Lymphocytic Leukemia?
Constitutive expression of non-mutated Bruton’s Tyrosine Kinase (BTK)
What CD20 antibody is used to tx CLL?
Rituximab
Historical tx for CLL?
Chlorambucil
What is the combination tx for CLL that was extremely immunosuppressive?
Fludarabine and Cyclophosphamide with Rituximab (FCR)
Latest treatment of CLL?
BTK inhibitors
Covalent modifier of ATP binding site (Cysteine 481) on Bruton’s Kinase that is active against CLL with del 17p and del 11q which were largely refractory to existing options
Ibrutinib
Causes of Resistance BTK Inhibitors
C481S changing from nucleophilic -SH in active site to -OH and PLC-gamma (main substrate for BTK)
Idelalisib
blocks downstream of BTK is active
CLL responds to what Bcl-2 modulator to reset apoptotic threshold?
Venetoclax
What is Ibrutinib approved to tx?
CLL and Mantle Cell Lymphoma; useful in the spectrum of B-cell malignancy
Name for Eliminating Growth Promoting Signals?
lower concentration of hormone in the blood, block the ability of the hormone to interact with its receptor, block the down-stream signaling between the receptor and the effector apparatus
What arises from single translocation like CML and is nearly always cured?
Acute Promyelocytic Leukemia (APL)
Treatment of Acute Promyelocytic Leukemia
all trans retinoic acid, arsenic tri-oxide (induces degradation of chimeric protein and apoptosis at higher doses by uncertain mechanisms)
Drugs that can be helpful in in refractory cases (ABCD)
ativan, benadryl, compazine (or olanzapine), dexamethasone
Cancers well known for thromobotic diathesis
pancreas, breast, prostate, bladder, lung and CNS
Very high risk of DVT
stomach and pancreas
High risk of DVT
lung, lymphoma, gynecologic, bladder, testicular
What two cancers almost universally affect bone
Breast and Prostate
Bone directed treatment extends survival in what 3 cancers, but not in what cancer?
Myeloma, Breast, and Renal Cell but NOT in Prostate
What is the most potent and most used bisphosphonate?
Zoledronic acid
What 2 cancer drugs in particular cause diarrhea?
5-FU and Irinotecan
Treatment of Constipation in Cancer
polyethylene glycol is gentle; mineral oil to prevent tearing
Treatment of Diarrhea
electrolyte replacement, fiber supplements, tincture of opium and somatostatin analogues for secretory diarrhea that are unresponsive to other measures
What do you see in young people on the long-acting myelosuppressive therapy?
BAD low back pain
2 drugs used for refractory ITP (immune thrombocytopenic purpura)
Eltrombopag and Romiplostim
Long term side effects of Imatinib
muscle cramps, asthenia, edema, skin fragility, diarrhea and tendon/ligament abnormalities
Where is Imatinib metabolized? and what can interact with this?
CYP3A4, grapefruit juice
4 types of resistance to Imatinib
- altered membrane transport 2. loss of p53 3. over expression of BCR-ABL1 4. point mutations (binding domain)
induces ‘deeper’ (lower levels of BCR-ABL transcripts) and faster remissions with a similar sided effect profile to Imatinib
Nilotinib
active against BCR-ABL1 and Src family at most point mutations (NOT T315I) and can cause fluid retention and HTN
Dasatinib
active against BCR-ABL1 and Src family and most point mutations (NOT t315I)
Bosutinib
designed based on crystal structure of T315I mutant and active against this mutation and causes clots and arterial fibrosis that can be fatal
Ponitinib
chimeric (human/mouse) antibody against CD20, induces antibody-dependent cellular cytotoxicity (ADCC) as well as complement-dependent cytotoxicity (CDC), for B cell malignancies and auto-immune ds (cure in DLBCL and long term, low morbidity control of indolent lymphomas)
Rituximab
Ofatumumab and Obinutuzumab are humanized antibodies that outperform rituximab on what?
low-grade lymphomas
Antibody blockade of CTLA-4 permits T cell activation-what drugs do this?
Ipilimumab and Tremelilumab
AE of CTLA-4 blockade
auto-immune phenomena: colitis, rash, endocrinopathies, pulmonary toxicity and a host of odd-ball or severe side effects
Response rate of CTLA-4 blockade (Ipilimumab) and best in what cancer?
10-20% and best in Melanoma
Antibody blockade of PD-1 or one of its ligands permits T-cell activation-what drugs do this?
Pembrolizumab or Nivolumab
outperformed Ipi as single agent in melanoma
PD-1/PD-L1 Blockade (Pembrolizumab or Nivolumab)
What is active in cancers with mismatch repair defects and other mechanisms of high genetic variation?
PD-1/PD-L1 Blockade
Toxicities of PD-1/PD-L1 Blockade (Pembrolizumab or Nivolumab)
colitis, rash, thyroid issues