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MS 2 - Unit 1 > Pharmacology - Cancer IV Lecture AND Cancer Clinical Cases Lecture > Flashcards

Pharmacology - Cancer IV Lecture AND Cancer Clinical Cases Lecture Flashcards

1
Q

What are the two major groups of targeted therapy?

A

Two major groups of targeted therapeutics
Small molecule inhibitors
Monoclonal antibodies

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2
Q

“tinib”

A

tyrosine kinase inhibitor

small molecule inhibitor

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3
Q

“zomib”

A

proteasome inhibitor

small molecule inhibitor

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4
Q

“tu”

A

tumor

mab

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5
Q

“parib”

A

PARP inhibitor

small molecule inhibitor

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6
Q

“ci”

A

“ci” circulatory system

mab

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7
Q

“li”

A

“li” immune system

mab

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8
Q

What is the Ph chromosome of CML?

A

Ph: reciprocal translocation between chromosomes 9 and 22 t(9;22).

The t(9;22) translocation fuses the BCR gene with ABL gene to generate Bcr-Abl fusion protein.

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9
Q

What was the first line CML treatment?

A 
Imatinib (Gleevec)
Start with 400 mg once a day oral everyday.
•  Expectation after three months:
–  Complete hematologic response
–  Some cytogenetic response
–  Molecular response i.e. reduction in BCR-ABL transcripts by about 90%
•  Expectation after 18 months:
–  Complete hematologic response
–  Complete cytogenetic response
–  Major molecular response
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10
Q

What is the mechanism of resistance and relapse after Imatinib treatment for CML?

A

Imatinib


Mechanism of Relapse and Resistance
• Intrinsic Resistance: patients with persistent Bcr- Abl kinase activity.

• Could be due to:
– Mutations in Bcr-Abl kinase making it insensitive to this drug.
– Drug unable to reach its target because of enhanced binding to other proteins in circulation and/or drug efflux.

• Relapse after initial response: reactivation of Bcr- Abl kinase.
– Mutations in Abl kinase domain. Interfere with drug binding. Mutant kinase less sensitive to drug. Many mutations; T315I mutation noteable.
– Bcr-Abl amplification.

• Some who relapse show persistent inhibition of Bcr-Abl kinase.
– additional molecular abnormalities besides Bcr-Abl?

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11
Q

What are the first-line Next Generation TKIs for treatment of CML?

A

Nilotinib
Dasatinib

Bosutinib (Bosulif): Second-line
Ponatinib (Iclusig): Second-line; T315I mutant

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12
Q

T/F: Nilotinib and Dasatinib and Bosutinib are not effective against CML with T3151 mutation.

A

True

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13
Q

What are the side effects of Nilotinib?

A 
Nilotinib
• Myelosuppression: thrombocytopenia, neutropenia and anemia
• QT Prolongation 
• Sudden Deaths 
• Elevated Serum Lipase 
• Hepatotoxicity 
• Electrolyte Abnormalities

Contraindicated for people with Long QT syndrome

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14
Q

Pulmonary Arterial Hypertension is a unique side effect of what CML first line TKI?

A

Dasatinib

Side Effects
• Myelosuppression: thrombocytopenia, neutropenia and anemia
• Bleeding
• Fluid Retention
• Cardiac Problems: abnormal heart rate etc.
• Pulmonary Arterial Hypertension (PAH)
Other Side Effects
• Diarrhea, headache, cough, skin rash, fever, nausea, tiredness, vomiting, muscle pain, weakness, infections

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15
Q

MOA - Bosutinib

A
  • Also an ATP competitive inhibitor of Bcr-Abl.
  • Second-line agent for CML patients resistant or intolerant to other TKIs.
  • Active against most BCR-ABL mutants with clinical resistance to other TKIs. Ineffective against T315I.

**Same MOA as Ponatinib

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16
Q

What are some major side effects of Bosutinib?

A

GI toxicity
Renal toxicity
Hepatic toxicity

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17
Q

What is the boxed warning on Ponatinib for?

A

• VASCULAR OCCLUSION
– Arterial and venous thrombosis and occlusions associated with fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease
• HEART FAILURE
• HEPATOTOXICITY

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18
Q

What are the major side effects of Ponatinib?

A

GI perforation
Tumor Lysis Syndrome
Cardiac Arrhythmias

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19
Q

What is the BRAF mutation?

A

• BRAF gene encodes a serine threonine kinase.
• Mutations in BRAF gene in ~45%-50% (some literature
says 40-60%) of cutaneous melanomas.
• Less common in acral, mucosal and uveal types.
• BRAFV600E mutation in the kinase activation domain is the most common. Results in constitutive activation of BRAF kinase.
• BRAFV600K is the second most common mutation.

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20
Q

What has been the mainline treatment for metastatic melanoma until very recently?

A

Dacarbazine

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21
Q

MOA Vemurafenib

A

Inhibits BRAF kinase.

Used for unresectable stage III and IV or metastatic melanomas that harbor BRAFV600 mutations.

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22
Q

What is the main contraindication for giving Vemurafenib?

A

• Should not be given to melanomas harboring wild type BRAF.

QT syndrome also an issue

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23
Q

What cancer is Dabrafenib used to treat?

A

Considered as a next generation agent.
• Indication: unresectable stage III and IV or metastatic
melanomas that harbor BRAFV600E mutation.

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24
Q

What is the main contraindication for giving Dabrafenib?

A

Should not be given to melanoma harboring wild type BRAF.

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25
Q

What is a major side effect of Dabrafenib?

A

• Serious Febrile Drug Reactions: fever or fever associated with hypotension, rigors or chills, dehydration, or kidney failure.

26
Q

MOA Trametinib

A
  • Trametinib for BRAF V600E or BRAFV600K positive unresectable or metastatic melanomas.
  • Mechanism of action somewhat different from that of vemurafenib or dabrafenib.
  • Trametinib inhibits MEK i.e. extraceullular signal- regulated kinase.
27
Q

What is a major side effect of Trametinib?

A

• Serious Skin Toxicity: rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema.

28
Q

What are the contraindications for Trametinib?

A
  • Should not be given to melanoma harboring wild type BRAF.

* Patients previously treated with BRAF inhibitors.

29
Q

ErbB2 (aka HER2/neu) is overexpressed in what cancers?

A

Breast
Ovarian
Gastric

Overexpression → hyperproliferation and enhanced cell survival.
• Good targets for anticancer therapy.

30
Q

Non-small cell lung carcinoma (NSCLC) includes what kinds of cancers?

A

• Non-small cell lung carcinoma (NSCLC)
– Squamous cell carcinoma
– Adenocarcinoma
– Large-cell carcinoma

31
Q

What are the first line treatment options for metastatic NSCLC?

A

Erlotinib (Tarceva)
Gefitinib (Iressa)
Afatinib (Gilotrif)

Inhibit kinase function of EGFR; downstream signaling events are inhibited.

32
Q

What are the major side effects of Erlotinib (for NSCLC)?

A

Liver failure
Renal failure
Increased bleeding or blood clot formation
GI perforation

33
Q

What are the notable drug interactions for Erlotinib?

A

Drugs that inhibit or activate CYP3A4 can affect Erlotinib metabolism. For example, CYP3A4 inhibitor ketoconazole or CYP3A4 inducer rifampicin.

34
Q

What are the major side effects of Gefitinib?

A

GI perf
Liver damage
Interstitial lung disease

35
Q

What is a notable side effect of Afatinib?

A

Pulmonary toxicity

36
Q

Conjugated monoclonal antibodies mean what is attached to the antibody?

A

Drug, toxin or radioisotope!

37
Q

Trastuzumab (HERCEPTIN) a humanized monoclonal antibody against:

A

ErbB2 (HER2/neu)

ErbB2 overexpressed in 25 –30% of advanced breast cancers and predictive of worse prognosis.

Cancer IV AND Lemke Lecture**

38
Q

Monotherapy with Trastuzumab achieves only a modest response. Better response if combined with:

A

Paclitaxel (side effects: neuropathies, some eye issues per Lemke’s lecture)

Or…
As part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
• With docetaxel and carboplatin
• As a single agent following multi-modality anthracycline based therapy.

39
Q

MOA Trastuzamab

A

Prevents transduction of proliferation and survival signals.
• Growth inhibition due to antibody-induced down-regulation of ErbB2 and subsequent degradation of the receptor.
• May also via ADCC (antibody-dependent cellular cytoxicity).

40
Q

What is contained in the boxed warning for Trastuzamab use?

A

Cardiomyopathy
Infusion reactions
Pulmonary Toxicity

41
Q

How is Ado-trastuzumab emtansine (T-DM1) different from trastuzamab?

A

Trastuzumab is conjugated to DM1.

DM1: a microtubule inhibitor.

Antibody-drugconjugateundergoesreceptor-dependent internalization.
Drug is released inside cancer cells and causes cytotoxicity

42
Q

What is contained in the boxed warming for Ado-trastuzamab?

A

Hepatotoxicity, cardiotoxicity and death.

43
Q

What are the major side effects of Trastuzamab (Herceptin)?

A 
Ventricular Dysfunction (short-term cardiotoxicity, reversible)
Hepatotoxicity
44
Q

What cancer is Ado-trastuzamab indicated for?

A

• In ErbB2 (HER2)-positive metastatic breast cancer patients with prior treatment history of trastuzumab and/or taxane.

45
Q

What cancer is Rituximab used to treat?

A

Non-Hodgkin’s lymphoma

Relapsed or refractory CD20-positive follicular lymphomas as a single agent.
• In combination with first-line chemotherapy regimens for previously untreated follicular lymphomas.

46
Q

MOA Rituximab

A

Rituximab is a chimeric monoclonal antibody with variable region of mice IgG but constant region and Fc portion from human

Binds to CD20 antigen
• CD20 is a transmembrane protein present on all B-cells
• Eliminates CD20-positive follicular lymphoma cells by
• Direct activation of apoptosis
• Complement activation
• Cell-mediated cytotoxicity

47
Q

What is contained in the boxed warning for Rituximab?

A

FATAL INFUSION REACTIONS !
SEVERE MUCOCUTANEOUS REACTIONS! HEPATITIS B VIRUS REACTIVATION!
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) including fatal PML!

48
Q

What are the side effects of Rituximab?

A 
Tumor Lysis Syndrome
 Infections
Cardiovascular: arrhythmias
 Renal Toxicity
Bowel Obstruction and Perforation
49
Q

What cancers can chemotherapy CURE?

A

Hodgkin’s
ALL
lymphomas (in general)
testicular cancer

50
Q

What cancers is Nivolumab used to treat?

A

first used for metastatic/unresectable melanoma

now approved for NSCLC patients who progressed after taking a platinum-based chemotherapy (ie Cisplatin + Gemcitabine) **Dr. Lemke’s lecture

51
Q

MOA - Nivolumab

A

mab, human

Nivolumab inhibits PD-1 (programmed cell death protein-1)

52
Q

What cancer is Lapatinib used to treat?

A

Advanced or metastatic breast cancer over expressing HER2; hormone (+) metastatic breast cancer over expressing HER2 receptor in post menopausal women
Lemke discussed

MOA: Inhibits EGFR and ErbB2 (HER2) tyrosine kinase

53
Q

T/F: Tyrosine kinase inhibitors cross the BBB more often than monoclonal antibodies.

A

True

54
Q

T/F: Trastuzamab and Pertuzamab act synergistically despite both being monoclonal antibodies.

A

True

55
Q

How is ado-trastuzamab (Kadcyla) unique as a mab?

A

Because it gets into the cell, chemotherapy side effects are mostly avoided, but it remains cytotoxic, so myelosuppression is a major side effect (like other chemo)

56
Q

Postoperative treatment with Adriamycin and Cytoxan is considered what kind of therapy?

A

Adjuvant therapy (breast cancer, Lemke lecture)

57
Q

CEF or FEC Combo Tx

A

5FU
Epirubicin
Cyclophosphamide

breast cancer and other stuff

58
Q

CMF

A

Cyclophosphamide
Methotrexate
5FU

59
Q

ABVD

A

Doxorubicin (Adriamycin)
Bleomycin
Vinblastine
Dacarbazine

for Hodgkin’s

60
Q

CHOP

A

Cyclophosphamide
Hydroxydoxorubicin
Vincristine (Oncovin)
Prednisone

Hodgkin’s

61
Q

MOPP

A

Mechorethamine
Vincristine (Oncovin)
Procarbazine
Prednisone

MS 2 - Unit 1 (12 decks)

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