Millikan IHO Week 4

Question 1

Ways that receptor tyrosine kinase can become over expressed?

Answer 1

DNA amplification, increased transcription, decreased degradation (mRNA or protein)

Question 2

Treatment of Metastatic Colon Cancer

Answer 2

5-fluorouracil with irinotecan or oxaliplatin

Question 3

How long does colon cancer treatment extend survival?

Answer 3

2 years on average; 5 years survivors are no longer rare

Question 4

An established driver of proliferation and survival

Answer 4

EGFR in Colon Cancer (epidermal growth factor receptor): to PI3K to Akt or Ras to Raf to MEK to MAPK

Question 5

What do many cancers have constitutively downstream of EFGR?

Answer 5

Ras and Raf

Question 6

What testing is now universal in patients with metastatic colon cancer?

Answer 6

wild-type Ras and Raf

Question 7

First used for EGFR antibodies

Answer 7

Cetuximab

Question 8

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

Answer 8

Panitumumab

Question 9

What is commonly mutated in Lung cancer but not in Colon Cancer?

Answer 9

EGFR

Question 10

Two phenotypes of the same disease: Chronic Lymphocytic Leukemia

Answer 10

node predominant phenotype (SLL-small lymphocytic lymphoma) and leukemia phenotype (CLL-chronic lymphocytic leukemia)

Question 11

Do people die of or with CLL

Answer 11

with it

Question 12

Autoimmune Phenomena of Chronic Lymphocytic Leukemia?

Answer 12

immune throbocytopenic purpura, auto-immune hemolytic anemia, auto-immune agranulocytosis

Question 13

What often drives Chronic Lymphocytic Leukemia?

Answer 13

Constitutive expression of non-mutated Bruton’s Tyrosine Kinase (BTK)

Question 14

What CD20 antibody is used to tx CLL?

Answer 14

Rituximab

Question 15

Historical tx for CLL?

Answer 15

Chlorambucil

Question 16

What is the combination tx for CLL that was extremely immunosuppressive?

Answer 16

Fludarabine and Cyclophosphamide with Rituximab (FCR)

Question 17

Latest treatment of CLL?

Answer 17

BTK inhibitors

Question 18

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

Answer 18

Ibrutinib

Question 19

Causes of Resistance BTK Inhibitors

Answer 19

C481S changing from nucleophilic -SH in active site to -OH and PLC-gamma (main substrate for BTK)

Question 20

Idelalisib

Answer 20

blocks downstream of BTK is active

Question 21

CLL responds to what Bcl-2 modulator to reset apoptotic threshold?

Answer 21

Venetoclax

Question 22

What is Ibrutinib approved to tx?

Answer 22

CLL and Mantle Cell Lymphoma; useful in the spectrum of B-cell malignancy

Question 23

Name for Eliminating Growth Promoting Signals?

Answer 23

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

Question 24

What arises from single translocation like CML and is nearly always cured?

Answer 24

Acute Promyelocytic Leukemia (APL)

Question 25

Treatment of Acute Promyelocytic Leukemia

Answer 25

all trans retinoic acid, arsenic tri-oxide (induces degradation of chimeric protein and apoptosis at higher doses by uncertain mechanisms)

Question 26

Drugs that can be helpful in in refractory cases (ABCD)

Answer 26

ativan, benadryl, compazine (or olanzapine), dexamethasone

Question 27

Cancers well known for thromobotic diathesis

Answer 27

pancreas, breast, prostate, bladder, lung and CNS

Question 28

Very high risk of DVT

Answer 28

stomach and pancreas

Question 29

High risk of DVT

Answer 29

lung, lymphoma, gynecologic, bladder, testicular

Question 30

What two cancers almost universally affect bone

Answer 30

Breast and Prostate

Question 31

Bone directed treatment extends survival in what 3 cancers, but not in what cancer?

Answer 31

Myeloma, Breast, and Renal Cell but NOT in Prostate

Question 32

What is the most potent and most used bisphosphonate?

Answer 32

Zoledronic acid

Question 33

What 2 cancer drugs in particular cause diarrhea?

Answer 33

5-FU and Irinotecan

Question 34

Treatment of Constipation in Cancer

Answer 34

polyethylene glycol is gentle; mineral oil to prevent tearing

Question 35

Treatment of Diarrhea

Answer 35

electrolyte replacement, fiber supplements, tincture of opium and somatostatin analogues for secretory diarrhea that are unresponsive to other measures

Question 36

What do you see in young people on the long-acting myelosuppressive therapy?

Answer 36

BAD low back pain

Question 37

2 drugs used for refractory ITP (immune thrombocytopenic purpura)

Answer 37

Eltrombopag and Romiplostim

Question 38

Long term side effects of Imatinib

Answer 38

muscle cramps, asthenia, edema, skin fragility, diarrhea and tendon/ligament abnormalities

Question 39

Where is Imatinib metabolized? and what can interact with this?

Answer 39

CYP3A4, grapefruit juice

Question 40

4 types of resistance to Imatinib

Answer 40

1. altered membrane transport 2. loss of p53 3. over expression of BCR-ABL1 4. point mutations (binding domain)

Question 41

induces 'deeper' (lower levels of BCR-ABL transcripts) and faster remissions with a similar sided effect profile to Imatinib

Answer 41

Nilotinib

Question 42

active against BCR-ABL1 and Src family at most point mutations (NOT T315I) and can cause fluid retention and HTN

Answer 42

Dasatinib

Question 43

active against BCR-ABL1 and Src family and most point mutations (NOT t315I)

Answer 43

Bosutinib

Question 44

designed based on crystal structure of T315I mutant and active against this mutation and causes clots and arterial fibrosis that can be fatal

Answer 44

Ponitinib

Question 45

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)

Answer 45

Rituximab

Question 46

Ofatumumab and Obinutuzumab are humanized antibodies that outperform rituximab on what?

Answer 46

low-grade lymphomas

Question 47

Antibody blockade of CTLA-4 permits T cell activation-what drugs do this?

Answer 47

Ipilimumab and Tremelilumab

Question 48

AE of CTLA-4 blockade

Answer 48

auto-immune phenomena: colitis, rash, endocrinopathies, pulmonary toxicity and a host of odd-ball or severe side effects

Question 49

Response rate of CTLA-4 blockade (Ipilimumab) and best in what cancer?

Answer 49

10-20% and best in Melanoma

Question 50

Antibody blockade of PD-1 or one of its ligands permits T-cell activation-what drugs do this?

Answer 50

Pembrolizumab or Nivolumab

Question 51

outperformed Ipi as single agent in melanoma

Answer 51

PD-1/PD-L1 Blockade (Pembrolizumab or Nivolumab)

Question 52

What is active in cancers with mismatch repair defects and other mechanisms of high genetic variation?

Answer 52

PD-1/PD-L1 Blockade

Question 53

Toxicities of PD-1/PD-L1 Blockade (Pembrolizumab or Nivolumab)

Answer 53

colitis, rash, thyroid issues