Targeted Drugs Flashcards
What is the use of mAb drug contingent upon. Why?
- Test for the Presence of the Target on the Cancer
why:
- Must test because these targets are present on normal tissues too. For the drug to kill the tumor before killing the patient, the tumor must overexpress the receptor
What 3 general types of mAb drugs are there?
Naked - nothing else attached to them
Conjugated - carry a toxic agent
Bispecific - bring immune cells into proximity with cancer cells
CD20 specific mAbs
- Name Them.
- MOA
- Adverse Effects
- Administration
Rituximab, Ofatumumab
MOA:
binds CD20 having 2 effects:
1) CD20 stimulation triggers Apoptotic Pathway
2) IgG can Fix Complement with Fc region
Adverse Effects:
This causes B cell Depletion
Administration:
- IV or SubQ
Diseases Treated with CD20 drugs.
- Name Drugs
Rituximab:
- Chronic Lymphocytic Leukemia (CLC)
- Non-Hodgkin’s Lymphoma (NHL)
Ofatumumab:
- CLL
CTLA-4 specific mAb
- Name.
- MOA
- Administration
Ipilimumab
MOA:
- Immunostimulant binds CTLA-4 blocking CD80/CD86 from binding allos T cells to proliferated because no Treg suppression
Administration:
- IV or SubQ
Disease treated with Ipilimumab.
- what target it is specific for?
Melanoma
- CTLA-4 blocking Treg peripheral tolerance mechanism
EGFR drugs (not including Her-2 drugs)
- Name Them
- MOA
- Administration
Cetuximab and Panitumumab
MOA:
- Bind causing Apoptosis or ADCC
Administration:
- IV or SubQ
What is the adverse effect of the EGFR drugs INCLUDING the HER-2 drugs?
- NAME all of these.
ALL:
- Photosensitivity
Her-2 specifically:
- Cardiac Toxicity
EGFR:
- Cetuximab
- Panitumumab
Her-2:
- Tratuzumab
- Pertuzumab
Her-2 Drugs
- Name them.
- MOA
- Administration
Traztuzumab and Pertuzumab
MOA:
Traztuzumab
- Inhibits Stimulatory Signal by binding HER-2 causing a downregulation of HER-2 and ACCUMULATION OF p-27 causing cell cycle arrest.
- Also apoptosis, ADCC
Pertuzumab:
- Blocks Heterodimerization of HER-2 and HER-3
Administration:
- IV or SubQ
EGFR drugs (including Her-2 drugs):
- Cancer Treated
- NAME THEM.
EGFR:
Cetuximab - colorectal, Head and Neck (H and N)
Panitumumab - Colorectal
Her-2: (traztumab, Pertuzumab)
Both treat breast cancer
VEGF drugs
- MOA
- Toxicity
- Delivery
Bevicizumab
MOA:
- Anti-Angiogenesis
Toxicity:
- Cardiac
- Pulmonary
- GI perforation
Delivery:
- IV or SubQ
What types of cancer are treated with VEGF inhibitors?
- Name the drug.
- Colorectal
- Non-small cell lung carcinoma (NSCLC)
- Large solid tumors
Bevicizumab
Why is VEGF and effective target for large tumors?
Large tumors get hypoxic and need more BVs:
- HIF-1alpha unbinds from VHF which usually targets HIF-1alpha to the 26S proteasome
- Free HIF-1alphs is then able to translate the nucleus and upregulate VEGF signaling
Are mAb drugs ever given orally?
- No they would degrade rapidly in the stomach
Penetrance into the tumor is vital to fighting it. How are mAbs engineered so that they’re better equipped to penetrate?
Fc regions are often removed
How are mAb drugs metabolized and why is this an advantage?
- what can we do to slow down degradation in these?
- Broken down by Lysosomal and Cytosolic processes
- No CYP or Hepatic metabolism means no drug-drug interactions
- mAbs can be formulated with PEG to prevent renal secretion
Besides adding PEG how is the half life of mAbs extended intrinsically?
- where is this receptor found usually?
- FcRn (fetal Brambell receptor)
- FcRn Receptor is found on the surface of Adult epithelial cells and monocytes (these cells bind the Fc region, endocytose, then recycle the mAb)
What are some of the general adverse effects of mAbs?
- Anaphylaxis, Angioedema, Pulmonary Toxicity
- Depletions of Cell populations that express the same target as the tumor
What mAb drug causes increased oxidative stress in cardiac myocytes and cadiotoxicity?
- what is the intended target of this drug?
- Trastuzumab [Herceptin] blocks HER2 activity
- Intended target is Breast Cancer Tissue, but Cardiac Myoctyes also express Her-2 so they get targeted too.
What mAb drug causes HTN, proteinuria, and thrombotic microangiopathy?
- explain why?
- what is the intended target of this drug?
Bevacizumab [avastin]
- These are sides effects caused by Bevacizumab disrupting RENAL HOMOSTASIS
- Intended target of Bevacizumab is VEGF
What mAb causes renal magnesium wasting and hypomagnesemia via effects on the distal convoluted tubule?
Cetuximab [Erbitux]
What mAbs work as checkpoint inhibitors to improve immune response to tumor cells?
- what is their target?
- idea behind these drugs?
CTLA-4 binding drugs:
- Ipilumumab - prevents CTLA-4 from binding B7 (CD80/86)
PD1 binding drugs:
- Nivolumab
- Pemmbolizumab
- Prevents PD1 from repressing activation of T cells in 2˚ lymph tissue
What is a common cancer treated by the checkpoint inhibiting drugs?
- NAME these drugs.
melanoma
- Ipilumumab
- Nivolumab
- Pemmbolizumab
What causes PD1 upreguation on peripheral tissues?
- when and why is this done?
- PD-L1 gets up regulated to protect host tissue from getting attacked
- PD-L1 binds PD-1 on T cells and downregulates them to keep them from affecting host tissue
- IFN-gamma is believed to upregulate this response
What are side effects of the checkpoint inhibiting antibodies that target PD-1 and CTLA-4.
- Black Box Warnings?
- NAME THESE DRUGS.
Autoimmune-type symptoms occur:
- Dermatitis and TOXIC EPIDERMAL NECROLYSIS
- Black Box Warnings - Endocrinopathies, diarrhea, Peripheral Neuropathy, Pregnancy, serious rash.
What drugs act in immuno-stimulatory therapy?
- Aldesleukin [proleukin]
- Interferon-alpha 2b [intron A]
Aldesleukin
- MOA
- Aministration?
- Toxicity (BBW/Contraindications)
MOA:
- Binds to IL-2 receptor inducing the proliferation and differentiation of B and T-cells, monocytes, macrophages, and CTLs including NK cells
Administration:
- IV or SC
Toxicity/BBW/Contradinications:
- CNS impairment
- Cardiac Disease
- Pulmonary Disease
- Renal Disease
What is vascular leak syndrome (VLS)?
- Drug that causes this?
- Underlying Mechanism?
- Organs involved?
Aldesleukin causes VLS
Increased Vascular Permeability leading to:
- Hypotension
- Pulmonary Edema
- Liver Cell Damage
- Renal Failure
Mechanism:
- IL-2 binding to NK cells causing cytokine release
- IL-2 binding to endothelial cells
How does Interferon-alpha 2b work?
- Toxicity
Works like endogenous Interferons:
- Increased CD8+ activation
- Promote NK ability to uses perofrin, granzyme, and FasL
Toxicity (BBWs):
- Autoimmune disease
- Cardiac Disease
- Depression (suicidal idealization)
- Infection
- *Often causes elevated hepatic enzymes
Sipuleuce-T [Provenge]
- MOA
- Adverse Effects
MOA:
- Patient APCs are taken out and cultured with recombinant Prostatic Acid Phosphatase and GM-CSF
- APCs take up the antigen and present it to T and B cells in the sample that are reinfused into the patient
**Goal - destroy cells that use this enzyme to make PSA which is linked to prostate cancer
Adverse Effects:
- Mild Infusion Reactions (fever, chills, dyspnea)
- Paresthesias, Citrate Toxicity
How do the tyrosine kinase inhibitors differ from the mAb drugs?
- how do they differ from alkylating agents and antimetabolites?
- metabolism
mAb vs. TKI:
- They are small and orally bioavailable and metabolized by CYP3A4 (Drug-Drug interactions!)
TKI vs. other Chemo drugs:
- no reduction in white count make it hard to know if the drug is working
What is the main problem with the TKIs not reducing the White count?
You don’t know if the drug is working and Dr’s might tend to underdose which can lead to resistance of the tumor towards the drug
What is the classic way that resistance emerges against the Tyrosine Kinase inhibitors (TKIs)?
- what other features of TKs and their pathways give them the ability to resist TKIs?
Mutations in the ATP binding region of the Tyrosine Kinase Receptor prevents TKIs from binding and the cell resumes its proliferation
Others:
- Mutations downstream from TK receptors, such as those leading to constant activation of KRAS will nullify any effect of the drugs
T or F: for most of the TKI drugs activity is limited to a specific TK.
False, TKIs are promiscuous because of how conserved the ATP binding region is from TK to TK and this can lead to adverse effects
How should patients receiving treatment by TKs be monintored?
Endrocrine Function Monitoring:
- Thyroid Function
- Child Growth
- Diabetes
**Women of Childbearing age need to be made aware of adverse effects
Which of the TKIs produce stocking-glove syndrome?
- Sunitinib
- Sorafenib
- Pazopanib
- Vermurafenib
What are some adverse affects of TKIs other than stocking-glove syndrome?
- name drugs specific to side effects.
- Blood Dyscrasias (weird b/c not expected from targeted therapy)
- QT prolongation
- Cardiomyopathy (Trametinib and Dabrafenib)
- Dermal Toxicity (Erlotinib, Gefitinib, Lapatinib)
What TKIs and mAb have the affects of increased UV sensitivity in commmon?
- what pathway do ALL of these drugs act on.
EGFR pathway (so EPIDERMIS) is affected:
mAbs:
- Cetuximab
- Panitumumab
TKIs:
- Erlotinib
- Gefitnib
- Lapatinib
BE SURE TO GO BACK AND LOOK AT TKI CARDS IN THE OTHER DECK.
BE SURE TO GO BACK AND LOOK AT TKI CARDS IN THE OTHER DECK.
What cancer is associated with the Sonic Hedgehog Signaling pathway?
- when is this pathway usually active?
- what drug targets this pathway?
Vismodegib [Erivedge]
Cancer:
- Basal Cell Carcinomas
- Pathways involved in early development and regulates body patterning and organ development.
- Goes Quiescent and is only involved in tissue repair after that
What factors are produced as the end product of the Sonic Hedgehog pathway?
- what drug targets this pathway?
- Cancer associated with re-emergence of this path?
Vismodegib [Erivedge]
- Bcl-2
- VEGF
- *Both of these are very advantageous for a tumor cell
- BASAL CELL CARCINOMAS often use this path
Vismodegib
- cancer targeted?
- what pathway does it act on?
- Most Common Side Effects?
- BBWs?
- Acts on SMO in the Sonic Hedgehog pathway that produces Bcl-2 and VEGF
- Targets BASAL CELL CARCINOMAS
most common side effects:
- Alopecia
BBWs:
- INTRAUTERINE FETAL DEATH
- MALE-MEDIATED TERATOGENICITY
- PREGNANCY
How do the mTOR inhibiting drug work?
- Name the drugs.
Form Three Way:
- FK + BP-12 + mTOR
Drugs:
- Temsirolimus
- Sirolimus
- Everolimus
What are the end products of the mTOR path that makes it advantageous for cancers to up-regulate this path?
mTOR end pdts:
- Nutrient Uptake
- Angiogenesis
- Ribosome Biogenesis
- Cell Growth and Proliferation
What drug prevents IkB-alpha (inhibitor of NFkB) from getting targeted for breakdown?
- How does it do this?
Bortezomib - prevents targeting of IkB-alpha to the 26S proteosome by INHIBITING THE 26S proteosome
- This Prevents NFkB from getting released and promoting cell proliferation
Besides IkB-alpha what else gets targeted to the 26S proteosome?
HIF-1alpha gets targeted to the 26S proteosome in normal cells
What is the method of administration for Bortezomib?
- toxicity?
Bortezomib:
- IV or SC injection
Toxicity:
- Cardiotoxicity
- Sensory and Motor Neuropathy
- Hypotension
What is the problem with using single targets, especially with RTKs?
Often more than one RTK can converge on a single pathway.
- This means we would need to treat multiple RTKs to truly shut down the pathway
Can Targeted therapies erradicate cancer?
NOOOO
What drugs are given to fight Advanced renal cell carcinoma?
MTOR inhibitors:
Termsirolimus
Everolimus
Which of the TKI drugs target the thyroid as a side effect?
- Commonly?
- Less Commonly?
Common:
Sorafenib
Imatinib
Sunitinib
Moderate: Dasatinib Erlotinib Nilotinib Pazopanib
Which of the TKI drugs are associated with cardiomyopathy and QT prologation?
- Trametinib
- Dabrafenib
Which of the TKI drugs are associated with dermal toxicity?
- Erlotinib
- Gefitinib
- Lapatinib
(mAbs Cetuximab and Panitumumab also cause this)
Which of the TKI drugs act on BRAF?
- V600E or V599E?
- side effects?**
V600E
- Dabrafenib (QT prolongation)
- Vemurafenib (Stocking glove syndrome)
V599E
- Sorafenib (Stocking Glove Syndrome, Common Thyroid Dysfunction)
Which of the TKI drugs act on VEGFR?
- side effects?**
Pazopanib (Stocking Glove Syndrome)
Sunitinib (Stocking Glove Syndrome, Common Thyroid Dysfunction)
Which of the TKI drugs act on EGFR?
- side effects?**
Erlotinib (DERMAL TOXICITY, Sometimes Thyroid Dysfunction)
Gefitinib (DERMNAL TOXICITY)
Lapatinib (DERMAL TOXICITY)
Which of the TKI drugs act on Bcr-abl mutant cells?
- side effects?**
Nilotinib (Sometimes Thyroid Dysfunction)
Imatinib (Common Thyroid Dysfunction)
Crizotinib
- target
- cancer treated
Crozotinib
- Tyrosine Kinase Inhibitor
- EML4-ALK ADENOCARCINOMAS (usually found in non-smokers)
