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Combined Treatments Flashcards

1
Q

How does irinotecan (Camptosar) work?

A
  • Topoisomerase I inhibitor
  • Synthetic analog of camptothecin (CPT), a natural product from the bark and stem of the Camptotheca plant
  • It stabilizes topoisomerase-DNA cleavable complex after cutting DNA
  • This blocks DNA from being re-ligated
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2
Q

How does cetuximab (Erbitux) work?

A
  • Monoclonal Ab against EGFR
  • Inhibits EGFR dimerization
  • Strong synergy with radiation
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3
Q

How does bevacizumab (Avastin) work?

A
  • Humanized monoclonal Ab against VEGF ligand, not VEGF receptor
  • Blocks VEGF-A (angiogenesis)
  • Tumor stroma-directed therapy!
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4
Q

How does Bortezomib (Velcade) work?

A
  • N-protected dipeptide
  • It is a 26S proteasome inhibitor
  • By blocking it, it prevents the degradation of pro-apoptotic factors → apoptosis
  • Approved for multiple myeloma and mantle cell lymphoma

Mnemonic: Bortezomib → bore (proteasome)

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5
Q

How does Sirolimus (Rapamycin) work?

A
  • It is an immunosuppressant
  • Binds to FK-binding protein 12 (FKBP12)
  • Inhibits the target of Rapamycin (mTOR pathway)

Mnemonic: Sirlimus fucks (FKBP12)

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6
Q

How does Rapamycin work?

A

mTOR/FRAP inhibitor

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7
Q

When do we use FLT-3 inhibitors and why?

A
  • Activating mutations in FMS-like tyrosine kinase 3 (FLT3) → 30% pts with AML
  • FLT3 inhibitors (usually TKIs) block FLT3 activity
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8
Q

What are some examples of nitrogen mustards and how do they work?

A
  • Cyclophosphamide, ifosfamide, etc
  • Crosslink DNA → DNA replication & transcription inhibited → cell cycle arrest, apoptosis
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9
Q

What is the role of Cyclooxygenase (COX-2) inhibitors?

A

They block the COX-2 enzyme, which is produced in response to inflammation, and by precancerous and cancerous cells.

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10
Q

What is the role of COX-2?

A
  • Mediate synthesis of eicosanoids (like prostaglandins) from arachidonic acid
  • COX-2 products are inflammatory
  • It is over-expressed in tumors
  • It is normally not produced in healthy tissues
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11
Q

How does erlotinib (Tarceva) work?

A
  • Small-molecule EGFR TKI
  • Reversibly binds to the ATP binding site of the receptor
  • Prevents downstream signaling
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12
Q

How does gemcitabine work?

A
  • It is an anti-metabolite, analog of deoxycytidine
    — Is incorporated into DNA, inhibiting further DNA synthesis
  • Inhibits ribonucleotide reductase (radiosensitization), causing depletion of deoxynucleotide triphosphates necessary for DNA synthesis

Mnemonic: Used for pancreatic cancer (pancreas is a major player in metabolism)

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13
Q

How does etoposide work?

A

Poisons Topoisomerase II

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14
Q

Which cellular feature is responsible for resistance to melphalan?

A

Presence of Glutathione

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15
Q

How does melphalan work?

A

Alkylating agent

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16
Q

How does methotrexate work?

A
  • Anti-metabolite
  • Competitive inhibitor of dihydrofolate reductase
  • Decreased cellular reduced folate levels
  • Decreased synthesis of purines (A,G)
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17
Q

How does chlorambucil work?

A
  • DNA alkylation
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18
Q

How does imatinib (Gleevec) work?

A
  • It’s a TKI
  • Blocks the ATP-binding site of the p210 tyrosine kinase domain of the BCR-ABL fusion protein in CML
  • Most specific for BCR-ABL, but has activity against c-kit, and PDGF-R as well
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19
Q

How does doxorubicin (adriamycin) work?

A
  • Anthracycline
  • MOA1: Blocks Topoisomerase II
  • MOA2: Intercalates within DNA
  • Inhibits both DNA and RNA synthesis
  • Notorious for its cardiotoxicity

doxorubicin → dual actions (RNA/DNA, MOA1/2)

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20
Q

What’s the MOA of Vincristine and Vinblastine?

A
  • Binds tubulin dimers
  • Inhibits microtubule assembly
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21
Q

What’s the MOA of cisplatin?

A
  • Alkylates DNA (similar to alkylating agents)
  • Forms inter- and intra-strand DNA strand crosslinks
  • Cell cycle non-specific
  • Inhibits DNA synthesis
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22
Q

What is the MOA of enzalutamide (Xtandi)?

A

Androgen receptor antagonist

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23
Q

What’s the MOA of abiraterone (Zytiga)?

A
  • Inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1)
  • It is an enzyme expressed in testicular, adrenal, and prostatic tumor tissues
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24
Q

What’s the MOA of Leuprolide (Eligard)?

A

It’s an Luteinizing hormone-releasing hormone (LHRH) agonist

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25
Q

What’s the MOA of denosumab (Xgeva, Prolia)?

A
  • Inhibits the ligand (RANKL) for osteoprotegerin
  • Inhibits osteoclast differentiation and activation
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26
Q

How does Ra-223 work?

A
  • It is a bone-seeking (similar to calcium)
  • 95% α -particle emitter (5% β & γ)
  • α-particles have short range, delivering high doses of radiation to osteogenic cells and very low doses to surrounding healthy tissue
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27
Q

What’s the MOA of Ipilimumab (Yervoy)?

A

It binds to CTLA-4

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28
Q

What’s the mnemonic for immune checkpoint inhibitors and their targets?

A
  • NP, ADd IT
    – PD-1: Nivolumab, Pembrolizumab
    – PD-L1: Atezolizumab, durvalumab
    – CTLA-4: Ipilimumab, Tremelimumab
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29
Q

What’s the MOA of crizotinib (Xalkori)?

A
  • Small molecule TKI (tinib)
  • Inhibits ALK and ROS1 kinases
  • Targets the ALK-EML4 fusion gene, and ROS-1 mutated cancers
  • Used for NSCLCs, 5% of which have EML4-ALK translocations
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30
Q

What’s the incidence of cisplatin-induced acute kidney injury (AKI)?

A
  • AKI in 20-30% of patients within 3-5 days
  • More common w/ cisplatin delivered q3 weeks at 100 mg/m2 compared to weekly at 40 mg/m2
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31
Q

How does cisplatin cause AKI?

A
  • Kidney injury is related to mitochondrial density and membrane potential
  • Proximal tubules have the highest density and are most sensitive to cisplatin
  • It can also form superoxide anions in the glomerulus and proximal tubules, but NOT distal tubules

Mnemonic: Cisplatin damages proximal tubules

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32
Q

Which lab abnormality correlates with AKI?

A

Serum Cr > 1.5 x baseline

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33
Q

How does treatment with an anti-angiogenic agent increase tumor sensitivity to radiation?

A

There is a transient normalization of tumor vasculature, which results in increased perfusion and increased O2 delivery, leading to a decrease in hypoxia-induced radioresistance.

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34
Q

Has misonidazole shown any benefit when given together with radiation?

A
  • No
  • Multiple RTOG trials using misonidazole have failed to show a benefit.
  • Only Nimorazole has demonstrated a benefit in a single DAHANCA trial
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35
Q

Why is nimorazole used instead of other drugs (misonidazole, etanidazole, etc) in its class?

A
  • It has acceptable toxicity (peripheral neuropathy)
  • But it is less effective than the other drugs
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36
Q

How do the nitroimidazoles work?

A

They have a NO2 group, which has a longer diffusion distance than O2 and can lead to hypoxic radiosensitization.

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37
Q

What was the effect of hypoxic cell radiosensitizers on LRC and OS according to the Overgaard meta-analysis?

A

They increased both LRC and OS compared to RT alone.

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38
Q

Why can radiosensitizers be advantageous for SBRT?

A

Reoxygenation does not occur as readily during SBRT. Thus, hypoxic cell radiosensitizers can be especially helpful.

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39
Q

Where inside a tumor do cancer stem cells reside?

A

Hypoxic regions

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40
Q

What is the MOA of radiation protector/mitigator flagellin?

A
  • Flagellin activates NF-kB
  • NF-kB upregulates anti-apoptotic genes
    – Cytokines and growth factors
    – Antioxidant scavengers (MnSOD)
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41
Q

How does Hsp90 inhibition → Radiosensitization?

A
  • Tumor cells exist in very stressful environments, which include acute and chronic hypoxia, increased levels of DNA damage, high levels of ROS, and protein complex imbalances.
  • Their survival is aided by efficient cellular stress response machinery, such as heat shock protein (Hsp90).
  • Inhibition of Hsp90 can make a tumor more radiosensitive.
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42
Q

How does nelfinavir, an HIV protease inhibitor, cause radiosensitization?

A
  • Enhances the effect of ionizing radiation on endothelial cells
  • Downregulates VEGF expression in tumor cells via hypoxia-inducible factor 1α
  • Inhibits PI3K-AKT-mTOR pathway
  • Activates the unfolded protein response
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43
Q

How does ADT act in concert with radiation?

A

It represses an androgen receptor gene expression program governing DNA repair and inhibits the repair of ionizing radiation-induced DNA damage

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44
Q

How does Palifermin decrease mucositis after radiation?

A

Palifermin is a human recombinant keratinocyte growth factor that stimulates the proliferation of GI tract mucosal cells, decreasing the severity of side effects.

Mnemonic: Palifirmin → firms up mucosa using keratin

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45
Q

What is a small molecule drug?

A

A drug that can enter cells easily because it has a low molecular weight. Once inside the cells, it can affect other molecules, such as proteins, and may cause cancer cells to die. This is different from drugs that have a large molecular weight, which keeps them from getting inside cells easily. Many targeted therapies are small-molecule drugs.

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46
Q

How do proteasomes work?

A

They break down proteins targeted for elimination (ubiquitination).

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47
Q

How does capecitabine (Xeloda) work?

A
  • It’s a prodrug of 5-FU taken orally
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48
Q

How does 5-FU work?

A
  • Anti-metabolite
  • Inhibits thymidylate synthase
  • Impairs DNA, rRNA, and mRNA synthesis
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49
Q

How does Sorafenib work?

A
  • Small molecule, a “dirty” multi-kinase inhibitor
  • Approved for use in patients with advanced renal cell carcinoma, hepatocellular carcinoma, and RI-resistant thyroid carcinoma
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50
Q

How does nivolumab (Opdivo) work?

A
  • Human IgG4 monoclonal antibody
  • Binds to programmed death (PD-1) receptor, preventing it from binding to PD-L1 and 2.
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51
Q

How does Rituximab work?

A
  • Ab against CD20
  • Used for CD20-positive lymphomas → apoptosis and cell lysis
52
Q

How does Gefitinib work?

A
  • Small molecule EGFR TKI
  • Approved for EGFR exon 19 deleted or EGFR exon 21 mutated non-small cell lung cancer (NSCLC).
53
Q

How does Misonidazaole work?

A

It is a hypoxic radiosensitizer

54
Q

How does Tirapazamine work?

A
  • Bioreductive drug
    – bioreduced to a toxic radical in hypoxic cells
    – technically not a hypoxic cell radiosensitizer
  • Standard Research # (SR4233)
55
Q

How does topoisomerase I work?

A

It catalyzes transient breaking and rejoining of single-strand DNA, which lets the broken strand rotate around the intact strand.

56
Q

How does topoisomerase II work?

A

It cuts both DNA strands to manage DNA tangles and supercoils

57
Q

What are some topoisomerase I inhibitors?

A
  • Irinotecan
  • Topotecan
58
Q

What are some topoisomerase II inhibitors?

A
  • Etoposide
  • Doxorubicin
  • Daunorubicin
  • Mitoxantrone
59
Q

How does Sunitinib work?

A
  • Dirty multi-target receptor kinase inhibitor
    – Targets include EGFR, FLT3, VEGFR, and KIT
  • Approved for gastrointestinal stromal cells (GIST) and renal cell carcinomas
60
Q

How can multi-drug resistance (MDR) 2/2 membrane transporter be reversed?

A

With Verapamil, a Ca2+ channel blocker

61
Q

How does multi-drug resistance (MDR) normally develop?

A
  • Usually 2/2 MDR gene
  • Can be caused by either an increase in p100-glycoprotein or other proteins that increase drug efflux non-specifically
  • Can also be caused by amplification of DNA repair genes
62
Q

Which drugs are people w/ fanconi anemia most hypersensitive to?

A
  • They cannot repair DNA interstrand crosslinks, so are most sensitive to:
    – Platinum agents
    – Cyclophosphamide
63
Q

How is the efficacy of mitomycin C related to aeration?

A
  • Bioreductive drug
  • Crosslinks DNA
  • More toxic under hypoxic conditions
64
Q

What is photodynamic therapy (PDT)?

A
  • Uses drugs activated by visible light (600-900 nm)
  • Forms singlet oxygen radicals (NOT hydroxyl); highly toxic
  • Effective in oxic tissues
    — Ineffective in hypoxic tissues
  • Can be used for superficial tumors
  • Can also be used for deep tumors that can be accessed via fiberoptic probes
  • Hematoporphyrin and its derivatives are the most common clinically used photodynamic therapeutics
65
Q

How does the efficacy of cisplatin compare to its isomer, trans-platinum?

A

It is more effective than its isomer.

66
Q

What’s the toxicity most a/w bleomycin?

A

Pulmonary toxicity

67
Q

Which drug is a/w an increased survival when patients develop a grade 2 or higher acneiform rash?

A

Cetuximab!

68
Q

How does Ipilimumab work?

A
  • Small molecule inhibitor
  • Targets CTLA-4
69
Q

What does ALK stand for?

A

Anaplastic lymphoma kinase

70
Q

What is synthetic lethality?

A

It is a concept whereby a defect in one of a pair of genes does not affect survival, but a defect in both results in cell death.

Eg: PARP and BRCA 1/2 genes

71
Q

What’s the MOA of Panitumumab (Vectibix)?

A
  • Humanized IgG2 Ab against EGFR
72
Q

What’s the MOA of Infliximab?

A
  • Monoclonal Ab against TNF-α (Infliximα b)
  • Used for rheumatoid arthritis and psoriasis
73
Q

How is Y-90 used in the tx of lymphomas?

A

Bound to an anti-CD20 Ab (Ibritumomab tiuxetan)

74
Q

What is adaptive immune resistance?

A

It’s the process by which tumor cells change phenotype in response to an immune response (cytotoxicity or inflammation) in an attempt to avoid recognition

75
Q

What risk factors put patients at an increased risk for experiencing an immune-related adverse event?

A
  • Autoimmune disease hx
  • Prior checkpoint blockage therapy
  • Prior radiation therapy
76
Q

What is the dose-limiting toxicity of hypoxic radiosensitizers (“imidazoles”) that has led to disappointing clinical trial results?

A

Peripheral neuropathy

77
Q

What are bioreductive drugs?

A
  • Metabolically reduced to yield cytotoxic species
  • Happens under hypoxic conditions
  • Do not need radiation for effect
78
Q

At what doses and radiation fx sizes are hypoxic cell radiosensitizers most effective?

A
  • High doses
  • Large fx sizes (hypofractionation, SBRT)
79
Q

Is Amifostine a pro-drug? How does it work?

A
  • Pro-drug hydrolyzed to the active form (a free thiol compound) by alkaline phosphatase (fosphatase)
  • Must be given IV for maximum efficacy
80
Q

What are the main side effects of amifostine?

A
  • Fatigue
  • Fever
  • Rash
  • Hypotension
  • Nausea/vomiting
81
Q

Does Cisplatin form more interstrand or intrastrand crosslinks?

A

Intra

82
Q

What pathway is responsible for Cisplatin’s radiosensitization effect?

A

Inhibition of DNA double-strand break repair

83
Q

Under what conditions is temozolomide most effective?

A

When there is epigenetic silencing of the MGMT gene through hypermethylation

84
Q

How does methylation affect the MGMT gene?

A

Silences it

85
Q

How does methylation of the MGMT gene increase the efficacy of radiation & temozolomide?

A
  • Temozolomide creates DNA alkylation, which cannot be repaired by MGMT 2/2 hypermethylation.
86
Q

What’s the function of Wee1 and how does it control radiosensitization?

A
  • Wee1 controls the G2/M checkpoint
  • This checkpoint is important after RT for DNA damage repair
  • Wee1 inhibition, through MK1775, causes cells to go into mitosis w/ damaged DNA → mitotic catastrophe
87
Q

What’s the fx of LAG3?

A
  • It is an immune checkpoint inhibitor, much like PD-1 and CTLA-4
  • It’s main ligand is MHC class II
88
Q

What’s the MOA of alectinib?

A
  • TKI
  • Used for ALK (ALeKtinib)-fusion +ve NSCLC
  • Efficacy demonstrated in J-ALEX and ALEX trials
  • Less toxic than Crizotinib
  • Crosses BBB and can delay CNS brain met the progression
89
Q

What tumor feature is a/w response to immune checkpoint blockade?

A
  • Somatic mutation load
  • The more mutation a tumor has → the higher the chance that it will respond well to immune checkpoint blockade
90
Q

What’s the MOA of superoxide dismutase?

A
  • SOD contains a redox-active metal ion that is oxidized in the presence of superoxide (O2-)
  • Mechanism of action involves converting superoxide (O2-) into hydrogen peroxide (H2O2)
  • Can protect against RT- and chemotherapy-induced oral mucositis
91
Q

What are some other names for Amifostine?

A

Ethyol
WR 2721

92
Q

What side effect is amifostine FDA-approved to protect against?

A

H&N cancer treatment-related xerostomia

93
Q

What side effect is amifostine FDA-approved to protect against?

A

H&N cancer treatment-related xerostomia

94
Q

How does Ibritumomab work?

A
  • Radiotherapeutic
  • B-cell CD-20 antibody
    – Mnemonic: ritu like rituximab
  • Radiolabelled w/ Y-90
95
Q

How do small molecule tyrosine kinases (TKIs) work?

A
  • ATP-mimetics
  • Bind to the ATP-binding domain of receptor TKs
  • Activity against multiple tyrosine kinases (as opposed to antibodies, which are highly specific)
  • Can inhibit both stromal and cancer cell TKs, in a ligand-independent manner
  • All TKIs, not just small molecule TKIs, can be given with radiation and chemotherapy
96
Q

If a drug has tinib in its name, what does it mean?

A
  • It is a small molecule TKI (antibody TKIs will have mabs at the end of their names)
97
Q

How are all TKIs administered?

A

Orally

98
Q

What’s the MOA of bleomycin?

A
  • Produces free radicals → single and double-strand DNA break
  • “Radiomimetic”
99
Q

Why is bleomycin most effective in oxic tissues?

A

Because metals and O2 are required for Bleomycin to cause DNA damage.

100
Q

What is the MOA of dactinomycin?

A
  • Inhibitor of RNA synthesis
  • Strong synergy with radiation
101
Q

What’s the MOA of Ara-C?

A
  • Converted to its active form, ara-CTP
  • Competitive DNA polymerase inhibitor
    – Menmonic: Ara-C (C is one of the bases in DNA)
102
Q

What’s the MOA of vorinostat (suberoylanilide hydroxamic acid (SAHA)), valproic acid, and MS-275?

A
  • It is a histone deacetylase inhibitor (HDACI)
  • Enhances acetylation
  • Acetylation relaxes DNA, making it more accessible to the transcription machinery
  • HDACIs can cause growth arrest, apoptosis, autophagy, mitotic catastrophe, senescence, anti-angiogenesis, and cell death.
103
Q

What is the MOA of PARP inhibitors?

A
  • Impair base excision repair (BER) specific for single-strand breaks
  • Cause dsDNA breaks, which require HR to repair
  • Toxic in tumors with BRCA1/2 mutations
  • Important within the context of synthetic lethality
104
Q

What are halogenated pyrimidines?

A
  • They have a halogen in place of a methyl group (I-dUdR, Br-dUdR
  • Incorporated into the DNA in place of T
  • DNA is weakened, making it more susceptible to damage by UV light or radiation
  • Need to be given for several generations for efficient DNA integration
  • Not used clinically as much
105
Q

What does Br-dUdR sensitize the cells that I-dUdR does not?

A
  • Fluorescent light
  • Pts get a skin rash
106
Q

What are hypoxic radiosensitizers?

A
  • Oxygen substitutes that diffuse into poorly vascularized areas of the tumor
  • Reach all hypoxic cells (diffuse further than O2)
  • Not rapidly metabolized by cells
  • Highly soluble in water and lipids
107
Q

What is suicide gene therapy?

A
  • A gene for an enzyme is inserted into the tumor cells via a viral vector.
  • A non-toxic prodrug is administered
  • This prodrug is converted into the active toxic drug by the enzyme → cell killing
108
Q

How does hydroxyurea work?

A

It inhibits ribonucleotide reductase → DNA synthesis inhibition

109
Q

What are Farnesyl transferase inhibitors (FTI)?

A
  • Inhibit the fx RAS
  • RAS requires farnesylation to function
110
Q

What’s the MOA of taxanes?

A
  • Promote microtubule assembly (stabilize them)
  • Prolong G2/M phase
  • Synergize with radiation
111
Q

How does Cytarabine work?

A
  • A nucleoside analog that blocks DNA synthesis
  • Specific to the S phase
112
Q

What tumor feature is predictive of a good response to PD-1/PD-L1 inhibitors?

A
  • Tumor infiltration by CD9+ T-cells!
  • High levels of cancer cell PD-L1 expression
  • High cancer genome mutational burden
113
Q

What’s pleiotropic chemoresistance?

A
  • When resistance to one chemotherapy drug results in cross-resistance to other drugs
  • Usually occurs in cancer cells w/ the MDR gene/protein product
114
Q

What were the results of the accelerated radiotherapy plus carbogen inhalation and nicotinamide (ARCON) trial?

A
  • Carbogen and nicotinamide are two agents thought to overcome hypoxia
    – Nicotinamide overcomes acute hypoxia by preventing transient changes in blood flow
    – Carbogen (95% O2, 5% CO2) overcomes chronic hypoxia by increasing passive O2 diffusion into tissues
  • ARCON showed:
    – Similar rates of local control (78% vs. 79%)
    — Failed primary endpoint
    – Improved regional control (93% vs. 97%)
    – Similar toxicity
115
Q

What’s the target and MOA of Vemurafenib?

A
  • Targets B-Raf V600E mutation
  • Commonly used for melanomas
116
Q

What’s the target and MOA of Osimertinib?

A
  • Small molecule TKI against EGFR
  • Targets T790M mutation
    – Frequently acquired after exposure to erlotinib and gefitinib
117
Q

Which newer class of medications are a/w significant risk of immune side effects?

A
  • PD1/PD-L1 inhibitors
118
Q

What’s I-131 used for?

A
  • I-131: Radionuclide used to tx thyroid ca and hyperthyroidism
  • Dose:
    – Thyroid Ca s/p resection: 0.5-1 Gy
119
Q

Dose-survival cure for most chemotherapies follows what order kinetics?

A
  • First-order kinetics
    – A given dose kills a constant fx of cells, regardless of the population size
  • On a log scale, this looks very much like that of ionizing radiation
  • There are exceptions to this, such as adriamycin and bleomycin
120
Q

Which chemotherapeutic/systemic txs have better BBB penetration?

A
  • Nucleoside analogues
  • alkylating agents
  • antimetabolites
121
Q

Which chemotherapeutic/systemic txs have poorer BBB penetration?

A
  • Antibiotics (-mycins)
  • Taxanes
  • Topoisomerase inhibitors
122
Q

Which taxane can cross the BBB, which the general drug class normally cannot do?

A
  • Cabazitaxel
    – Mnemonic: B for the brain
123
Q

Which drug inhibits CDK4/6?

A

Palbociclib
– Mnemonic: “cyclib” → inhibits cell cycle

124
Q

What’s the MOA of Relatimab?

A
  • Targets LAG-3 (relagtimab)
  • Expressed in activated T cells, LAG-3 prevents excess T cell activation.
    – Inhibiting LAG-3 leads to increased T cell activation
125
Q

Combination of a targeted agent against which proteins and radiation give elevated GI toxicity?

A

VEGF/VEGFR

RadBio (10 decks)

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