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Flashcards in Cancer IV Deck (32):
1

List the stages in development of New Cancer Drugs

1. Preclinical studies (test normal and cancer cell lines; animal testing for EFFICACY and TOXICITY)
2. Investigational New Drug Application (FDA)
3. Phase I trial (determine safe and appropriate dose)
4. Phase II trial (determine effectiveness and side effects)
5. Phase III trial: evaluate effectiveness of drug, compare to standard treatments
6. New Drug Application (file this with FDA, submit the phase III trial data)
7. FDA could approve this new drug (can be marketed under label which includes drug's dosage, safety, indications and side effects)
8. Phase IV trials (determine long-term safety and effectiveness)

2

What type of disorder is CML? What is the big chromosome and translocation to think of?

Clonal hematopoietic stem cell disorder; Ph due to translocation of 9;22 to make BCR-ABL fusion protein

3

What does ABL code for? What is it in general? What happens upon its fusion with Bcr?

Protooncogene that normally codes protein that functions as tyrosine kinase; constitutively active

4

What are the phases of CML? What was the old treatment used? What is used now?

Chronic/stable, accelerated, blast;
hydroxyurea or interferon-alpha with allogenic stem-cell transplantation; imatinib (selective activity against Abl tyrosine kinase)

5

How does imatinib work? What are some side effects? How often do you have to give it?

Binds to Bcr-Abl at same site where ATP would bind and blocks Bcr-Abl's ability to phosphorylate and activate proteins involved in malignant transformation;
Nausea, vomiting, fluid retention, muscle cramps, arthralgia, myelosuppression; once-daily dosing

6

Despite its proven effectiveness over INF and cytarabine, what types of resistance occur to imatinib?

1. Intrinsic (mutations in Bcr-Abl kinase, drug can't reach target, maybe drug efflux)
2. Relapse after initial response (mutations in Abl kinase means less drug sens, some Bcr-Abl amplification, even some persistent inhibition of Bcr-Abl kinase)

7

After imatinib, what are some second generation tyrosine kinase inhibitors?

Nilotinib (similar to imatinib, but better fit in Abl kinase pocket; more potent that imatinib; active against BCR-ABL mutants resistant to imatinib);
Dasatinib (ATP mimetic and is also considerably more potent than imatinib; active against most BCR-ABL mutants clinically resistant to imatinib)

8

Side effects of nilotinib? Contraindications?

Myelosuppression, QT prolongation, sudden DEATH, elevated SERUM LIPASE, hepatotoxicity, electrolyate abnormalities;
hypokalemia, hypomagnesemia, long QT SYNDROME!!

9

What's the big side effect of dasatinib?

PULMONARY ARTERIAL HYPERTENSION!! (PAH)

10

What are the most commom _______ malignancies of the GI tract?

Mesenchymal; GIST

11

What is the primary site of GIST? What are the molecular abnormalities with GIST?

Stomach; activating mutations in genes that encode two different receptor tyrosine kinases: KID and PDGFRA

12

How can one manage GIST therapeutically?

Complete surgical resection, conventional chemo or radiation (poor); imatinib is beneficial in such cases

13

How does imatinib actually act on GIST? What could be problematic with using imatinib?

Inhibits KIT and PDGFRA; secondary KIT and PDGFRA mutations

14

What does acute promyelocytic leukemia consist of? What is the translocation chromosome-wise and what is being fused??

Immature promyelocytes accumulate in marrow and peripheral blood; 15 and 17; retinoic acid receptor alpha fused with promyelocytic leukemia gene (oncogenic)

15

What is used to treat APL? How does it do this?

All-trans retinoic acid; induces terminal differentiation of malignant (immature promyelocytes) cells, which undergo natural apoptosis (makes sure that RARalpha is turned on and genes are turned on)

16

If you just use retinoic acid on its own, what are the main side effects? What is it used with nowadays?

Leukoycte acitvation syndrome: fever, respiratory distress, weight gain, pleural or pericardial effuction, and occasionally renal failure; arsenic trioxide

17

What are four members of the EGFR family? What are their ligands?

ErbB1 (aka EGFR or HER1): ligands are EGF and TGFalpha;
ErbB2 (HER2/neu): no ligand;
ErbB3 (HER3): ligand is neuregulin
ErbB4 (HER4): see ErbB3

18

When do you see ErbB1 and TGFalpha overexpression? ErbB2 overexpression?

various cancers; breast, ovarian, gastric cancers (BOG)

19

Since ErbB2 doesn't have a ligand, what does it have to do to result in cell proliferation and survival?

It can homodimerize or heterodimerize with e.g. ErbB1

20

What is used to target ErbB2? What are the possible mechs for dealing with ErbB2? What do we see if this drug is combined with doxorubicin or paclitaxel?

Trastuzumab; could use Ab-induced downreg of ErbB2 or ADCC; better response, meaning that the apoptotic effects of other cytotoxic drugs could be enhanced

21

Possible toxicity of trastuzumab?

Hypersens reaction, ventricular dysfunction, CHF; can enhance doxorubicin cardiac toxicity

22

How can we ensure trastuzumab gets to its target?

Conjugate (Ado-trastuzumab emtansine, an antibody-drug conjugate);

23

What does cetuximab bind?

Anti-ErbB1 (EGFR) (binds with similar affinity as EGF or TGFalpha)

24

For cetuximab, what are some major toxicity issues?

cardiac events leading to sudden death, renal failure, allergic reaction, PE, hypomagnesemia, calcemia, kalemia (CAR, PE, HYPO's)

25

What is an example of Non-Hodgkin's Lymphoma? Describe what this lymphoma would involve and what is the translocation involved? What can be used to treat it?

Follicular lymphoma; it involves MATURE B CELLS, mostly affects older adults, grades 1, 2, and 3, and you have translocation between 14 and 18;
stage I and II: no initial treatment, then do single agent, combo chemo, and/or rad as needed vs. stage III and IV: initial combo chemo and rad;
RITUXIMAB!!

26

How can rituximab deal with Non-Hodgkin's lymphoma?

Bind CD20 antigen, and eliminate the CD20-positive follicular lymphoma cells by direct apoptosis activation (intrinsic pathway), complement activation (C1, then C4/C2, then C3, then C5, then C5b-C9), cell-mediated cytotoxicity

27

How do melanomas arise? What is the most common type? What is it associated with?

From melanocytes; cutaneous (compared to acral, mucosal, uveal); UV exposure

28

What is the most common of cutaneous melanoma?

Superficial spreading melanoma

29

What is the mutation seen in melanoma most often? What did the original gene encode? What specifically is the most common mutation? What can inhibit these mutations?

BRAF mutations; serine threonine kinase; BRAF V600E in the kinase activation domain; vemurafenib

30

What is a major side effect of vemurafenib? What are contraindications?

cutaneous SCC and keratoacanthoma, along with QT prolongation; not for melanomas harboring wild type BRAF, electrolyte abnormalities, long QT syndrome, or patients on drugs that could cause long QT interval

31

What about dabrafenib and what it's used for? Side effects and contraindications?

Next generation agent for unresectable stage III and IV, or metastatic carcinomas with BRAF V600E mutations; serious febrile drug reactions, uveitis, iritis, possible male infertility, and don't give to melanoma harboring wild type BRAF

32

Lastly trametinib? Indication, SE, contraindications

For BRAF V600K or V600E positive unresectable or metastatic melanomas; inhibits MEK (EC signal-regulated kinase); serious skin toxicity: rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema, and cardiomyopathy, retinal vein occlusion, interstitial lung disease; do not give to melanoma harboring wild type BRAF or patients treated with BRAF inhibitors