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
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
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
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
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
6
Q
Toxicity of Imatinib
A
- minimal side effects- nausea, vomiting, fluid retention, muscle cramps, arthralgia
- myelosuppression in 29% of patients
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
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
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?
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
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
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
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
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
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
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
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
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
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
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
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
