1/10 Biological Chemotx - Weber

Question 1

APL

what is it?

tx

tox of treatment - how to treat it

Answer 1

acute promyelocytic leukemia

PML-RAR fusion protein

acute differentiation arrest of abnormal promyelocytes

tx: ATRA (all trans retinoic acid)

• leukocytosis (hi neutrophil count)
• cap leak syndrome (pulm edema, resp failure)
• renal failure

occurs shortly after initiation of tx

• treat with steroids, chemo, supportive measures

Question 2

ATRA

ATRA syndrome

Answer 2

used to treat acute promyelocytic leukemia (APL): alphaRAR-PML fusion

• leukocytosis (hi neutrophil count)
• cap leak syndrome (pulm edema, resp failure)
• renal failure
• occurs shortly after initiation of tx

treat with steroids, chemo, supportive measures

Question 3

arsenic

Answer 3

targets PML-RARalpha fusion protein

Question 4

role of Tyr kinases

Answer 4

crucial mediators of cell signaling during PROLIFERATION and DIFFERENTIATION

Question 5

imatinib

Answer 5

breakthrough tyrosine kinase inhibitor

treatment for CML (chronic myelogenous leukemia)

• CML characteristic translocation: t(9;22) [Philadelphia chromosome] → BCR-ABL fusion: consitutively active Tyr kinase

mechanism: binds to catalytic cleft of ABL

high rate of long term cytogenetic remission

Question 6

HER2

associated conditions

Answer 6

HER2: human epidermal gf receptor 2

• heterodimerizes with other HERs
• overexpressed/amplified in 20% of breast cancer

Question 7

trastuzumab

(Herceptin)

Answer 7

mechanism:

• interferes with HER2-dependent signaling
• antibody-dependent cellular cytotoxicity (immune-mediated)

induces response in up to 50% of HER2+ breast cancers

side effect: CARDIAC TOXICITY

Question 8

erlotinib

Answer 8

small molecule tyrosine kinase inhibifor specific for EGFR (epidermal growth factor receptor 1aka HER1)

Question 9

crizotinib

Answer 9

inhibits ALK, ROS1, HGFR, other TKs

• 4% of nsclc have translocation involving EML4-ALK1 → constitutive kinase activity
• younger non-smokers who are wild type for EGFR and RAS

Question 10

cetuximab

(Erbitux)

Answer 10

engineered chimeric monoclonal antibody to EGFR

• mutations assoc with lack of response to cetuximab:
  
  • KRAS
  • BRAF

Question 11

vemurafenib

Answer 11

small molecule RAF inhibitor targeting V600E BRAF mutation

(melanoma, among others)

toxicity: SKIN CANCERS!!!

• new strategy: add a MEK inhibitors (tremetinib)

*olon cancers with BRAF V600E → predicts poor response to EGFR inhibitors (5% response rate compared to 80% in melanoma)

Question 12

thalidomide

Answer 12

originally developed as anti-emetic/sedative BUT WAS FOUND TO BE TERATOGENIC!!! (phocomelia)

brought back into play when found to be potent anti-inflammatory for tx of erythema nodosum leprosum

tx for multiple myeloma

mech: IMiD class, mech of action unclear. potential role for TNFalpha?

Question 13

bortezomib

Answer 13

proteasome inhibitor

multiple myeloma

(originally designed for cachexia)

Question 14

rituximab

Answer 14

chimeric monoclonal antibody against CD20 (surface of preB cells, mature B cells)

tx: some B cell malignancies, standard tx of Bcell NHL

mech: immune activation, possible interference with normal CD20 fx

Question 15

alemtuzumab

Answer 15

humanized monoclonal ab - recognizes CD52 on the surface of mature lymphocytes (B and T)

tx: B cell CLL, some T cell malignancies

side effects: prolonged T cell depletion, immunosuppression

Question 16

sorafenib

sunitinib

Answer 16

SORAFENIB

broadspectrum kinase inhibitor

targets:

• VEGFR
• cKIT
• RAF

hepatocellular carcinoma, renal cell carcinoma

SUNITINIB

tyrosine kinase inhibitor targeting VEGFR, PDGFR (dual inhibition)

adv renal cell carcinoma

Question 17

role of VEGFR

Answer 17

vascular endothelial growth factor receptor

imp growth factor for endothelial cells (angiogenesis), but also for many other cell types

Question 18

bevacizumab

Answer 18

targets VEGFR

limited single agent activity in SOLID TUMORS (lung, colon, breast)

tox: hypertension, pulmonary hemorrhage, proteinuria

Question 19

PD1/PDL1 inhibitor mech of action

ex.

Answer 19

1. binds to programmed death receptor 1 →

• inhibits programmed T cell death
• inhibits negative immune regulation
• reverses T cell suppression, induces antitumor response

nivolumab

Question 20

nivolumab

Answer 20

PD1 inhibitor

tx: Hodgkin lymphoma, melanoma, nsclc, renal cell carcinoma, head/neck cancer

tox: iMMUNE MEDIATED..

• pneumonitis
• colitis
• hepatitis
• endocrinopathies

adv reactions: fatigue, rash, MSK pain, pruritis

also can be used in combo with ipilimumab for tx of pt with BRAF V600 wildtype, unresectable, metastatic melanoma