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MS II Pharmacology Unit 1 > Molecular Target Therapy > Flashcards

Molecular Target Therapy Flashcards

1
Q

Stages in Development of New Cancer Drugs

A

1) Preclinical Studies- laboratory studies on normal and cancer cell lines. Animal testing for efficacy and toxicity
2) Investigation New Drug Application- file with FDA for clinical testing in humans
3) Phase I Trial- designed to determine safe and appropriate dose for subsequent studies, if successful then Phase II trial starts
4) Phase II trail- designed to determine effectiveness and side effects
5) Phase III- evaluates effectiveness of new drugs and compares to standard treatment
6) New Drug Application
7) FDA Approval
8) Phase IV trials

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2
Q

CML background

A

-hematopoietic stem cell disorder
-15-20% of all cases of leukemia
-CML progresses through three phases- chronic (stable) phase, accelerated phase, blast crisis
-cytogenetics: philadelphia chromosome >90% of cases
-Ph- reciprocal translocation between chromosomes 9 and 22
-the t(9;22) translocation fuses the BCR gene with
ABL gene to generate Bcr-Abl fusion protein
-treatment options for CML- hydroxyurea or interferon alpha based regimen with allogenic stem-cell transplantation, <20% cure rate

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3
Q

Mechanism of Imatinib

A
  • lead compound with selective activity against Abl tyrosine kinase
  • the Bcr-Abl fusion protein has constitutive tyrosine kinase activity, which results in activation of various signaling pathways important for proliferative, adhesive and survival properties of CML cells
  • Bcr-Abl needs to bind ATP to phosphorylate and activate other proteins involved in maligant tranformation of cells
  • imatinib binds to Bcr-Abl at the same site where ATP binds and thus blocks Bcr-Abls ability to phosphorylate and activate the proteins involved in malignant transformation
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4
Q

Pre-clinical Studies for Imatinib

A
  • specific inhibition of Bcr-Abl expressing cells in vitro and in animals
  • showed acceptable animal toxicity profile
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5
Q

Phase I for Imatinib

A
  • first phase I trial in 1998
  • CML patients in chronic phase who failed INFalpha therapy were enrolled
  • oral doses of 300mg and higher
  • complete hematologic response within 3 weeks of therapy in 98%
  • response maintained in 96% follow up of 310 days
  • cytogenetic response were noted in 53% of the patients with 13% displaying complete cytogenic response
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6
Q

Toxicity of Imatinib

A
  • minimal side effects- nausea, vomiting, fluid retention, muscle cramps, arthralgia
  • myelosuppression in 29% of patients
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7
Q

Pharmacokinetics of Imatinib

A
  • oral administration: long half-life of 13-16 hours
  • good for once-daily dosing
  • 400 mg once-daily dose plasma concentration 2.3 ug/ml
  • higher than needed to inhibit Bcr-Abl kinase
  • primarily metabolized by cytochrome P450 enzyme
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8
Q

Phase II and III trials of Imatinib

A
  • phase II trials enrolled >1000 patients at 27 centers in 6 different countries, results of phase II trials confirmed phase I results
  • phase III randomized trials comparing Imatinib to INF+cytabine-based regimen in newly diagnosed patients; shows better effectiveness and tolerance over INF+cytabine-based regiment
  • became standard first line therapy for CML
  • 8 year follow up data showed Imatinib to be effective ans safe
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9
Q

Imatinib Mechanism of Relapse and Resistance

A
  • 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- some patients: mutations in Abl kinase. Mutant kinase less sensitive to drug, some show Bcr-Abl amplification, mechanism unknown for remaining
  • some who relapse show persistent inhibition of Bcr-Abl kinase- additional molecular abnormalities besides Bcr-Abl?
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10
Q

Second Generation Tyrosine Kinase Inhibitors for CML- Nilotinib

A
  • Nilotinib (Tasigna)-similar structure to imatinib, but better fit in the ABL kinase pocket, 20-30x more potent, active against most BCR-ABL mutants with clinical resistance to Imatinib; 300 mg BID oral, FDA approved 2007
  • Side effects: myelosuppression: thrombocytopenia, neutropenia and anemia, QT prolongation, sudden deaths, elevated serum lipase, hepatotoxicity, electrolyte abnormalities
  • contraindications- hypokalemia, hypomagnesemia, long QT syndrome
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11
Q

Dasatinib

A
  • structure different from imatinib
  • also an ATP mimetic and binds within the ABL kinase pocket
  • more than 300x more potent than imatinib
  • active against mutants
  • FDA approved 2010
  • Dosage: 100 mg/day oral
  • Side effects: myelosuppression, bleeding, fluid retention, cardiac problems, pulmonary arterial hypertension, diarrhea, headache, cough skin rash, fever, nausea, tiredness, vomiing, muscle pain, weakness, infections
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12
Q

Gastrointestinal Stromal Tumors (GISTs)

A
  • most common mesenchymal malignancies of the GI tract
  • 1% of all GI malignancies
  • stomach most common primary site then is small intestine, esophagus, colon and rectum are less frequent sites
  • generally affect older adults, highest incidence 50-65 age group
  • present with abdominal pain and GI bleeding
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13
Q

Molecular abnormalities in GISTs

A
  • GISTs harbor activating mutations in genes of KIT and PDGFRA receptor tyrosine kinases
  • 75-85% harbors KIT mutations
  • 5-10% harbor PDGFRA mutations
  • 10-15% does not have mutations in either
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14
Q

Management of GISTs

A
  • complete surgical resection of primary tumor approach of choice: 48-65% five year survival
  • some times due to tumor site and or size complete resection is not possible
  • GISTs very high chance of metastatic relapse
  • response to conventional chemotherapy or radiation is poor
  • imatinib beneficial for such patients
  • approved by the FDA for the treatment of unresectable and metastatic GISTs
  • inhibits KIT and PDGFRA and it is used at 400 mg/day
  • some patients show primary resistance other develop secondary resistnace due to secondary KIT and PDGFRA mutations
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15
Q

Acute Promyelocytic Leukemia

A
  • APL: a paradigm for differentiation therapy
  • APL, a type of acute myeloid leukemia (AML)
  • accounts for 7-10% of all AML cases
  • a distinct blockage of myeloid differentiation
  • accumulation of immature promyelocytes in marrow and peripheral blood
  • a reciprocal translocation between chromosome 15 and 17 t(15;17) in 98% of cases
  • the translocation fuses the retinoic acid receptor alpha gene with promyelocytic leukemia gene: PML-RARalpha fusion
  • this fusion protein functions as an oncoprotein: malignant transformation
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16
Q

All trans-Retinoic Acid

A
  • a metabolite of Vit A
  • for treatment of APL
  • in APL the malignant immature promyelocytes continue to self-renew and proliferate without undergoing differentiation
  • retinoic acid induces terminal differentiation of malignant cells, which subsequently undergo natural apoptosis
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17
Q

Dosage of all trans-retinoic acid

A
  • total 25 mg/m to 45 mg/m2 per day in two oral doses
  • complete remission in .80-90% of previously untreated cases
  • invariable relapse if used as a monotherapy
  • given concurrently with anthracycline-based regimens
  • can achieve complete remission in >90% and relapse is < 10% by year 2
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18
Q

Pharmacokinetics

A
  • following oral administration, retinoic acid reaches circulation via the portal vein
  • peak plasma levels are reached within 1-2 hours following ingestion
  • the plasma half life is about 1 hour
  • in plasma, it binds to albumin and transported as a complex
  • retinoic acid is metabolized in liver into various metabolites and conjuated forms
  • its metabolites and glucuronic acid conjugates are mostly secreted into bile and excreted in urine and stools
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19
Q

Toxicity of Retinoic Acid

A
  • increased white blood count: leukocyte activation syndrome or retinoic acid syndome: fever, respiratory distress, weight gain, pleural or pericardial effusion, occasionally renal failure
  • other side effects: dryness of skins and lips, nausea, headache, arthalgias, bone pain
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20
Q

Mechanism of Relapse/Resistance to Retinoic Acid

A
  • the exact mechanism of resistance is not known but could be due to:
  • induction of cytochrome P450 enzymes that enhance retinoic acid catabolism and reduction of retinoic acid in plasma
  • alterations in levels of cytosolic retinoic acid binding protein II (CRBP II) that may affect retinoic acid transport to its target
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21
Q

Immunotherapy

A
  • epidermal growth factor receptor (EGFR) family member as targets
  • monoclonal antibodies
22
Q

What are EGFR family members

A
  • ErbB1 (EGFR or HER1): ligand EGF and TGFalpha
  • ErbB2 (HER2/neu): No ligand
  • ErbB3 (HER3): ligand neuregulin
  • ErbB4 (HER4): ligand neuregulin
23
Q

The EGFR family in cancer development and progression

A
  • ErbB1 and TGFalpha overexpressed in various cancers
  • ErbB2 overexpressed in breast, ovarian and gastric cancers
  • overexpression means hyperproliferation and enhanced cell survival
  • good targets for anticancer therapy
24
Q

Anti-ErbB2 monoclonal antibodies

A
  • Trastuzubmab a humanized monoclonal antibody against Erb-B2
  • ErbB2 overexpressed in 25-30% of advanced breast cancers and predictive of worse prognosis
  • ErbB2 is a good target for immunotherapy
  • FDA approved HERCEPTIN for treatment of ErbB2-overexpressing metastatic breast cancer
25
Q

Mechanism of Action of Trastuzbmab

A
  • prevents transducion of proliferation and survival signals
  • growth inhibition in ErbB2 overexpressing cells due to antibody-induced downregulation of ErbB2 and subsequent degradation of the receptor
  • may also mediate effects via ADCC (antibody-dependent cellullar cytotoxicity)
  • since ErbB2 heterodimerizes with other ErbB receptors, this antibody may disrupt prliferative/survival-signaling emanating from other receptors as well
  • monotherapy with HERCEPTIN achieves only a modest response
  • better response if combined with paclitaxel
26
Q

Dosage of Trastuzumab

A
  • loading dose of 4 mg/kg as a 90 min IV infusion
  • maintenance dose of 2 mg/kg per week as a 30 minute IV infusion
  • given in combination with taxanes (paclitaxel, docetaxel)
27
Q

Pharmacokinetics of HERCEPTIN/Trastuzumab

A
  • plasma concentration of HERCEPTIN varies from patients to patients due to circulating extracellular domain of ErbB2 (the shed receptor)
  • trough serum concentration (concentration just before the next regular dose) of 10 ug/ml-25 ug/ml can be achieved with the indicated dose
  • trough serum concentration of 10 ug/ml- 25 ug/ml has been found to be effective concentration
  • serum half life 8.3 +/- 5 days
28
Q

Toxicity of HERCEPTIN/Trastuzumab

A
  • hypersensitivity reaction (can still occur even with humanized version)
  • ventricular dysfunction and CHF
  • can enhance the cardiac toxicity of doxorubicin. Given in combination with taxanes (paclitaxel, docetaxel)
29
Q

Ado-trastuzumab emtansine (T-DM1): an antibdoy-drug conjugate

A
  • in ErbB2 (HER2)-positive metastatic breast cancer patients with prior treatment history of trastuzumab and/or taxane
  • trastuzumab is conjugated to DM1
  • DM1: a derivative of Maytansine, microtubule inhibitor
  • tumor selectivity: preferential delivery of drug to ErbB2 (HER2) expressing cancers
  • a bifunctional reagent
  • antibody-drug conjugate undergoes receptor-dependent internalization
  • antitumor effects of Trastuzumab remain intact
  • drug is released inside cancer cells and causes cytotoxicity
30
Q

Dose and Toxicity of Ado-trastuzumab emtansine

A
  • dose: 3.6 mg/kg given IV every 3 weeks
  • stop if disease progression occurs or unacceptable toxicities develop
  • side effects: fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases and constipation anemia, hypokalemia, peripheral neuropathy, ventricular dysfunction, interstitial lung disease, and infusion-associated reactions, hepatotoxicity, embryo-fetal toxicity and birth defects
31
Q

Trastuzumab Gastric or Gastro-oesophogeal junction center

A
  • ToGA trial or Trastuzumab for Gastric cancer, a phase 3 trial
  • for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer
  • trastuzumab plus chemotherapy versus chemotherapy alone
  • 122 institutions in 34 countries
  • outcome: Trastuzumab plus Chemo significantly increases survival versus chem alone
  • FDA approved in Oct 2012
  • Trastuzumab and cisplatin (plus either capecitabine or 5-FU)
32
Q

Anti-Erb1 (EGFR) monoclonal antibodies

A
  • cetriximab and panitumumab

- binds to ErbB1 with similar affinity as EGF or TGFalpha

33
Q

Mechanism of action for Cetriximab

A
  • competes for binding to ligands and inhibits ErbB1 tyrosine kinase activity, growth promiting and survival signals
  • predicted to work better in combination with other chemotherapeutic agents
34
Q

Clinical Studies with Cetriximab

A
  • as of July 2012, approved in combo with Irinotecan, 5-FU, and leucovorin as first-line option for EGFR expressing metastatic colorectal ancer with wild type K-ras
  • Dose: 400 mg/m2 IV infusion given 120 minute as an initial dose than 250 mg/m2 infused over 30 minutes weekly in combo with FOLFIRI
  • other indications are Head and Neck Cancer
  • in combo with radiation therapy
  • also as a single agent in individuals treated previously with platinum based regimen
35
Q

Toxicity of Cetriximab

A
  • allergic reaction
  • cardiac events leading to suddent death
  • derm- acne like rash, skin drying and cracking, infections
  • renal failure
  • pulmonary embolism
  • hypomagnesemia, Hypocalcemia, Hypokalemia
  • other common effects: asthenia/malaise, fever, nausea, constipation and diarrhea
36
Q

Non-Hodgkin’s Lymphoma

A
  • lymphoid neoplasms
  • include more than 20 distinct entities affecting B or T cells
  • sixth most common cause of cancer-related deaths in the US
37
Q

Follicular Lymphoma

A
  • a type of Non-Hodgkin’s lymphoma
  • involves mature B cells
  • 75-80% of indolent B-cell lymphomas are follicular lymphomas
  • most affects older adults
  • classified into Grade 1,2 and 3
  • about 40% transforms into diffuse large B cell lymphomas
  • follicular lymphomas transformed into diffuse form are aggressive with worse prognosis
38
Q

Standard Treatment of Non-Hogkins

A
  • 15% of Grade 1 and 2 are early stage lymphomas; directed radiation therapy is effective
  • majority of Grade 1 and 2 follicular lymphoma patients have advanced disease; for them two approaches: conservative approach: no initial treatment, single agent (Chlorambucil), combo chemo (CHOP) and/or radiation as needed, aggressive approach: initial combo chemo plus radiation
  • meaningful response lasts up to 2 years
  • different approach needed for relapsed disease
39
Q

Treatment with Rituximab

A
  • Rituximab is chimeric monoclonal antibody with variable region of mice IgG but constant region and Fc portion from human
  • effective in many relapsed or refractory follicular lymphomas
  • standard dose and schedule: 375 mg/m2 weekly IV infusion for 4 weeks
40
Q

Side effects for Rituximab

A

-minimal toxicities: hypotension, flushing, fever and chills, asthenia, hypersensitivity Reaction, Nausea

41
Q

Mechanism of Action for Rituximab

A
  • binds to CD20 antigen
  • C20 is a transmembrane protein present on all B-cells
  • eliminates CD20+ follicular lymphoma cells by direct activation of apoptosis, complement activation, cell-mediated cytotoxicity
42
Q

Melanoma

A
  • a highly aggressive malignancy
  • arises in melanocytes
  • classified into various types: cutaneous, acral, mucosal and uveal melanomas
  • the cutaneous type is the most common; affects skin, association with exposure to UV
  • the acral type affects skin of palms, soles and the area underneath fingernails or toenails
  • the uveal type affects melanocytes in other organs for example in the iris of the eye
43
Q

Types of Cutaneous Melanoma

A
  • superficial spreading melanoma: 70% of all cases of melanomas
  • nodular melanoma 5% of all cases of melanomas. Common in males 60 and older but can occur at any age
  • Acral lentiginous melanoma: 5% of all cases of melanomas. More common in darker skin people
  • Lentigo Maligna Melanoma: 10% of all cases of melanomas. Common in middle aged to older population
44
Q

BRAF mutation

A
  • BRAF gene encodes a serine threonine kinase
  • mutations in BRAF gene in 45-50 of cutaneous melanomas
  • less common in acral, mucosal and uveal types
  • BRAFV600E mutation in the kinase activation domain in the most common- results in constitutive activation of BRAF kinase
  • BRAFV600K is the second most common mutation
45
Q

Management of Melanoma

A
  • surgical excision with or without lymphadenectomy for cutaneous melanoma
  • metastatic melanoma managed medically by dacarbazine- the only FDA approved drug for metastatic melanoma but the response rate remains low
46
Q

Vemurafenib for treatment of melanomas

A
  • used for melanomas harboring BRAF mutations

- it inhibits BRAF kinase

47
Q

Current status for Vemurafenib

A
  • clinical trials indicated vemurafenib to be effective and well tolerated
  • vemurafenib was approved by the FDA for unresectable stage III and IV or metstatic melanomas that harbor BRAFV600 mutations
  • european commission approved sale in EU in 2012
  • given in 906 mg BID orally
  • duration of treatment: until disease progression or unacceptable side effects
48
Q

Side effects/ Contraindications for Vemurafenib

A
  • Arthalgia, Fatigue, photosensitivity, alopecia, nausea, and diarrhea
  • cutaneous squamouns cell carcinoma, keratocanthoma or both
  • can cause QT prolongation and thus, enhanced risk of ventricular arrhythmias
  • newly primary cutaneous melanoma
  • Contraindications: should not be given to melanomas with wildtype BRAF, electrolyte abnormalities, long AT syndrome, patients on drugs that will cause prolongation of QT interval
49
Q

Dabrafenib

A
  • approved 2013
  • next generation agent
  • indication: unsectable stage III and IV metastatic melanomas that harbor BRAFV600E mutation
  • 150 mg BID orally
  • duration: until disease porgression or unacceptable side effects
50
Q

Side effects/Contraindications of Dabrafenib

A
  • higher risk to develop cutaneous squamous cell carcinoma, keratoacanthoma and melanoma
  • serious febrile drug reactions: fever or fever associated with hypotension, rigors or chills, dehydration or kidney failure
  • uveitis and iritis
  • hyperglycaemia; would require modification in diabetes management
  • hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmar-plantar erythrodysesthesia, rash, back pain, coughm constipation, myalgia, nasopharyngitis
  • may inhibit fertility in males
  • contraindications- should not be given to melanoma harboring wild type BRAF
51
Q

Trametinib

A
  • approved by FDA 2013 for BRAFV600E or BRAF600K positive unsectable or metastatic melanomas
  • mechanism somewhat different from vemurafenib or dabrafenib
  • trametinib inhibits mEK extracellular signal regulated kinases
  • 2 mg orally once daily
  • duration: unitl disease prgression or unacceptable side effects
52
Q

Trametinib side effects and contraindications

A
  • cardiomyopathy
  • retinal pigment epithelial detachment
  • retinal vein occlusion
  • interstitial lung disease
  • serious skin toxicty: rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthsia syndrome, and erythema
  • other common side effects: rash, diarrhea, lymphedema, dermatitis acneiform, stomatitis, hypertension, abdominal pain, hemorrhage, dry skin, pruitis and paronychia
  • may inhibit fertility in females
  • contraindications: should not be given to melanoma harboring wild type BRAF and patients previously treated with BRAF inhibitors

MS II Pharmacology Unit 1 (10 decks)

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