Onco Exam One FULL

Cyclophosphamide

Alkylating agent

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MOA: covalent attachment of alkyl groups to macro molecule Bis(chlorethyl)amine which forms an ethyleneimonium ion that reacts with a base (ex. N7 of guanine) to produce an alkylated purine - alkylation of nucleophilic sites

Leads to mispairing (mono and bi), ring opening (mono and bi), and cross linking (bifunctional only) → apoptosis if can’t repair

Cisplatin

Platinum analog

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MOA: intra/inter-strand cross linking of cisplatin to DNA inhibits S-phase replication and activates p53 tumor suppressor activating transcription of pro-apoptotic proteins and stimulating intrinsic pathway of apoptosis

Oxaliplatin

Platinum analog

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MOA: intra/inter-strand cross linking of cisplatin to DNA inhibits S-phase replication and activates p53 tumor suppressor activating transcription of pro-apoptotic proteins and stimulating intrinsic pathway of apoptosis

Methotrexate

Antimetabolite

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MOA: inhibits purine and pyrimidine synthesis; competitive inhibitor of DHFR; inhibits cancer cell proliferation; Becomes polyglutinated by FPGS (folo polygluthate synthesis) so it has longer resident time in cells to work longer

5-Fluorouracil

Antimetabolite

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MOA: suicide inhibitor that inactivates thymidylate synthase preventing the production of dTTP depriving cell of needed metabolites, inhibits RNA processing; it’s also incorporated into DNA

Capecitabine

Antimetabolite

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MOA: 5-FU prodrug that is metabolized in the liver by carboxylesterase to 5-DFCR than by cytadine deaminase to 5-DFUR which is then metabolized within the tumor by thymidine phosphorylase to 5-FU; targets more preferentially than 5-FU because tumor cells exhibit increased thymidine phosphorylase expression

Cytarabine

Antimetabolite

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MOA: Cytarabine is a deoxyxytidine analog that is converted to Ara-C via deoxycytidine kinase

Ara-C

Antimetabolite

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MOA: Competitive inhibitor of DNA polymerase causing inhibition of DNA synthesis; it is also incorporated into DNA/RNA to affect elongation and ligation to disrupt the replication process

Gencitabine

Antimetabolite

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MOA: deoxycytidine analog that is a competitive inhibitor of DNA polymerase that inhibits DNA synthesis; it is incorporated into DNA/RNA to affect elongation and ligation; additionally inhibits ribonucleotide reductase to deplete cellular dNTP

6-Mercaptopurine

Purine Antagonist

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MOA: metabolized from azothiprime; converted to 6-thioguanine nucleotides (via HPRT enzyme) that are incorporated into DNA/RNA to arrest replication and trigger cell death - inhibit cancer cell replication

Vincristine

Vinca Alkaloids

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MOA: Binds to beta tubulin to prevent reassembly into a full microtubule, decreasing microtubule formation and leading to mitotic arrest

Vinblastine

Vinca Alkaloids

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MOA: Binds to beta tubulin to prevent reassembly into a full microtubule, decreasing microtubule formation and leading to mitotic arrest

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Paclitaxel

Taxane

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MOA: Binds to beta-tubulin blocking depolymerization of microtubule, which destabilizes the microtubule itself causing mitotic arrest

Docestaxel

Taxane

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MOA: Binds to beta-tubulin blocking depolymerization of microtubule, which destabilizes the microtubule itself causing mitotic arrest

Abraxane

Taxane

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MOA: Albumin bound paclitaxel

Ixabepilone

Vinca alkaloid/taxane

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MOA: MT stabilizer, effective againts resistant tumors

Eribulin

Vinca alkaloid/taxane

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MOA: MT subunit sequester, effective against resistant tumors

Irinotecan

Topoisomerase Inhibitor

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MOA: Prodrug that gets activated by carboxylesterase into the active metabolite, SN-38, which allows for topo I to cause a strand break before freezing/inhibiting topo I to prevent it from resolving the break

Etoposide

Topoisonerase inhibitor

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MOA: stabilizes topo II/DNA complex by preventing the resealing of the cleaved DNA and it can interfere with replication and transcription, triggering apoptosis down the line

Doxorubicin

Topoisonerase inhibitor and anthracycline

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MOA: stabilizes topo II/DNA complex by preventing the resealing of the cleaved DNA and it can interfere with replication and transcription, triggering apoptosis down the line; also intercalates into DNA causing the formation of oxygen radicals and inhibiting DNA/RNA synthasis

Daunorubicin

Anthracycline

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MOA: intercalates into DNA causing the formation of oxygen radicals and inhibiting DNA/RNA synthasis

Bleomycin

Anthracycline

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MOA: iron binding attracts oxygen causing oxygen radical formation which leads to DNA strand breaks and chromosomal damage

Leuprolide

GnRH receptor agonist

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MOA: lowers testosterone levels (following initial upregulation caused by negative feedback) to reduce stimulation of androgen sensitive cancer cells, triggering apoptosis

Goserelin

MOA: synthetic analog of LNRH that reduces the production of testosterone/estradiol leading to decreased stimulation of cancer cell growth

Degarelix

GnRH receptor antagonist

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MOA: synthetic derivative of GnRH decapeptide that lowers testosterone levels via competitive inhibiiton of the GnRH receptor to reduce stimulation of androgen-sensitive cancer cells to trigger apoptosis

Flutamide

MOA: non-steroid competitive inhibitor of androgen receptor that blunts downstream response and inhibits transcription of AR genes to prevent cell growth and trigger apoptosis

Bicalutamide

MOA: non-steroid competitive inhibitor of androgen receptor that blunts downstream response and inhibits transcription of AR genes to prevent cell growth and trigger apoptosis

Enzalutamide

2nd generation

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MOA: non-steroid competitive inhibitor of androgen receptor that reduces subsequent transcription of AR genes and has higher affinity for AR genes than bicalutamide

Abiraterone Acetate

Androgen synthesis inhibitor

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MOA: progesterone derivative that inhibits 17-alpha-hydroxylase (CYP17) irreversibly to reduce testosterone production

Anastrozole

Estrogen synthesis inhibitor

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MOA: Non-steroidal aromatase inhibitor that decreases estrone/estradiol for transcription of HR+ breast canser; binds reversibly to heme

Letrozole

Estrogen synthesis inhibitor

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MOA: Non-steroidal aromatase inhibitor that decreases estrone/estradiol for transcription of HR+ breast canser; binds reversibly to heme

Exemestane

Estrogen synthesis inhibitor

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MOA: steroidal aromatase inhibitor for transcription of HR+/ER+ breast cancer insensitive to tamoxifen; irreversibly inactivates aromatase via reactive intermediate formation

Tamoxifen

SERM

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MOA: affects transcription when bound to ligand; specific effects depend on cofactors present; antagonist in breast tissue so used to treat ER+ breast cancer, but agonist in uterine tissue which leads to increased risk of uterine cancer

Raloxifen

SERM

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MOA: affects transcription when bound to ligand; specific effects depend on cofactors present; treats high risk breast cancer since its' an antagonist in breast tissue, treats osteoporosis since it is an agonist in bone stimulating bone cell proliferation which is good

Fluvestrant

SERD

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MOA: estrogen receptor antagonist that degrades the estrogen receptor by stimulating ubiquitinylation (takes receptor to proteasome and breaks it down)

Megestrol

MOA: progesterone derivative that inhibits pituitary gonadatropin release leading to decreased estrogen secretion; is a partial agonist/antagonist of androgen receptor and is agonist of glucocorticoid receptor

Rituximab

CD20 Receptor Antibody (chimeric mAb)

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MOA: triggers direct Ab-dependent cellular toxicity; complement dependent toxicity; antibody dependent cell-mediated cytotoxicity; antibody-dependent phagocytosis

Ibritumomab tiuxetan

CD20 Receptor Antibody

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MOA: radiolabeled rituximab conjugate

Obinutuzumab

CD20 Receptor Antibody

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MOA: fully humanized mAb derivative of rituximab that is glycoengineered to increase binding to effector cells which enhances ADCC and direct cell death relative to rituximab; CDC and ADP are alt MOA

Ibrutinib

Non-receptor tyrosine kinase inhibitor

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MOA: irreversible potent inhibitor of Brutons tyrosine kinase which inhibits downstream signalling via PLCgamma, blocking cell growth, survival, and proliferation of malignant B-cells by silencing NF-kappaB dependent transcription

Bevacizumab

Tyrosine Kinase inhibitor with Vascular Endothelial Growth Factor signaling targets

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MOA: Binds to the VEGFR and prevents VEGF binding leading to a decrease in angiogenesis

Sorafenib

Tyrosine Kinase inhibitor with Vascular Endothelial Growth Factor signaling targets

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MOA: inhibits VEGFR receptor kinase by blocking ATP binding (short circuits it, preventing dimer polymerization) and inhibits PDGFR signaling

Sutnitinib

Tyrosine Kinase inhibitor with Vascular Endothelial Growth Factor signaling targets

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MOA: inhibits VEGFR receptor kinase by blocking ATP binding (short circuits it, preventing dimer polymerization) and inhibits PDGFR signaling

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Cetuximab (IgG1)

Tyrosine Kinase inhibitor with Epidermal Growth Factor Receptor Signalling targets

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Externally

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MOA: Chimeric mAb directed against EGFR, blocks ligand binding domain, inhibiting EGFR signalling pathway (only works if no KRAS mutation)

Panitumumab (IgG2)

Tyrosine Kinase inhibitor with Epidermal Growth Factor Receptor Signalling targets

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Externally

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MOA: fully humanized mAb that targets EGFR (only works if no KRAS mutation)

Erlotinib

First generation Tyrosine Kinase inhibitor with Epidermal Growth Factor Receptor Signalling targets

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Internally

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MOA: reversible EGFR kinase inhibitor that blocks all ATP binding

Afatinib

Second generation Tyrosine Kinase inhibitor with Epidermal Growth Factor Receptor Signalling targets

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Internally

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MOA: Irreversible inhibitor of EGFR kinase and HER2

Osimertinib

Third generation Tyrosine Kinase inhibitor with Epidermal Growth Factor Receptor Signalling targets

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Internally

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MOA: irreversible EGFR inhibitor

Lapatinib

Tyrosine kinase inhibitor Human Epidermal Growth Factor Receptor 2 (HER2) Signalling targets

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Internal

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MOA: reversible inhibitor of EGFR and Her2/neu tyrosine kinases (blocks ATP binding site of kinase)

Trastuzuab

Tyrosine kinase inhibitor Human Epidermal Growth Factor Receptor 2 (HER2) Signalling targets

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External

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MOA: binds to HER2/neu to prevent dimerization leading to Ab dependent cellular toxicity, decreased proliferation, and antiangiogenic effects

Enhertu

Tyrosine kinase inhibitor Human Epidermal Growth Factor Receptor 2 (HER2) Signalling targets

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MOA: antibody drug conjugate where humanized anti-HER2 mAb (identical sequence to trastuzumab) is covalently linked to topo I inhibitor via cleavable tetrapeptide linker

Gleevec (Imatinib)

TKi that Targets Bcr-Abl

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MOA: Specific inhibitor of Bcr-Able; binds to catalytic cleft in Bcr-Abl, preventing the activation loop from swinging out into an active configuration via H-bonds and van der waals which has an inhibitory effect on ATP binding; also inhibits PDGF alpha and beta, Kit and Arg protein

Ponatinib

TKi that Targets Bcr-Abl

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MOA: approved for T3151 gleevec resistance mutations since it avoids the steric clash

AMN107 (Nilotinib)

TKi that Targets Bcr Abl

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MOA: a predicted molecule that is 20x more potent than Gleevec and developed based on resistant mutation data to target Bcr-Abl

Dasitinib

TKi that Targets Bcr-Abl

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MOA: Increased binding affinity for Bcr-Abl vs Gleevec

Midostaurin

TKi that with with FLT3 mutation

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MOA: small molecule inhibitor of FLT-3 that prevents dimerization of the receptor to silence downstream signaling associated with cancer cell proliferation and survival which leads to decreased cell proliferation while stimulating apoptosis; also inhibits PDGFR, Kit, and PLC

Bortezomib

Proteasome Inhibitor; serine protease

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MOA: regulation of protein content by protease-mediated degradation of target proteins through ubiquitination of proteins to tag them for degredation

Carfilzomib

Proteasome Inhibitor

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MOA: regulation of protein content by protease-mediated degradation of target proteins through ubiquitination of proteins to tag them for degredation; irreversibly inhibits threonine protease activity of proteosome

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Ivosidenib

Cell Differentiation Inducer

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MOA: isocritrate dehydrogenase inhibitor that promotes differentiation of myeloid cells thus terminating their over proliferation

Nivolumab (Opdivo)

Immune checkpoint blockade inhibitor

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MOA: Anti-PD-1 monoclonal antibody that blocks PDL-1 binding to PD-1

Pembrolizumab (Keytruda)

Immune checkpoint blockade inhibitor

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MOA: Anti-PD-1 monoclonal antibody that blocks PDL-1 binding to PD-1

Durvalumab (imfinzi)

Immune checkpoint blockade inhibitors - PD-L1 inhibitor

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MOA: inhibit PD-L1 interaction with PD-1 protein

Avelumab (Banvencio)

Immune checkpoint blockade inhibitors - PD-L1 inhibitor

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MOA: inhibit PD-L1 interaction with PD-1 protein

Atezolizumab (Tecentriq)

Immune checkpoint blockade inhibitors - PD-L1 inhibitor

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MOA: inhibit PD-L1 interaction with PD-1 protein

Kymriah

Chimeric Antigen Receptor T-Cells (CAR-T)

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MOA: genetically engineered T-Cells

What does a “Grade One” adverse effect mean?

Mild, no intervention necessary

What does a “Grade Two” adverse effect mean?

Moderate, non-invasive intervention indicated

What does a “Grade Three” adverse effect mean?

Severe, hospitalization indicated

What does a “Grade Four” adverse effect mean?

Life-threatening, urgent intervention indicated

What does a “Grade Five” adverse effect mean?

Death

What is the TNM model for staging of cancer?

T \= tumor size (0-4) N \= Nodal involvement (0-3) M \= Metastatic (organ to organ) disease (0-1)

How does cancer spread/what are the stages of spread?

Stage 1-3 (pre-metastatic) -Normal cells initially, then one abnormal cell appears, then it multiplies until angiogenesis (development of new blood vessels to the abnormal cells) occurs at which point it is malignant or invasive cancer Stage 4 (metastatic) - Local breakdown of the tumor/cancer occurs allowing for it to spread through the blood vessel to a new location where a secondary tumor forms

What is RECIST?

Response Evaluation Criteria in Solid Tumors Methodology to evaluate activity and efficacy of cancer therapeutics in solid tumors

According to the RECIST criteria, what is considered a complete response?

Disappearance of all target lesions

According to the RECIST criteria, what is considered a partial response?

At least 30% decrease in the sum of diameters of target lesions from baseline

According to the RECIST criteria, what is considered an objective response?

OR \= CR + PR ; sum of patients who has any degree of positive response

What is a key function of neutrophils?

Protection against infection

What do B cells ultimately become?

Plasma cells that produce immunoglobulin (antibody) specific for an antigen

Where is leukemia isolated to?

Peripheral blood and bone marrow

Where is lymphoma isolated?

Lymph nodes

What is the origin of luekemia?

Myeloid or lymphoid

What is the origin of lymphoma?

Always lymphoid

What are the key differences between acute and chronic leukemia?

Acute - rapid onset, symptomatic, rapidly fatal if untreated, primarily immature blast cells, leukocytosis or leukopenia Chronic - slowly progressive, mostly asymptomatic (diagnosed on routine labs), may survive years without treatment, immature and mature cells, typically leukocytosis

What is the most common form of acute leukemia among adults?

Acute myeloid leukemia

What are the risk factors for acute myeloid leukemia?

Older age; prior chemotherapy (alkylating agents, topo II inhibitors, antimetabolites); ionizing radiation exposure; benzene exposure; cigarette smoking; antecedent blood disorders (MDS, aplastic anemia, myelofibrosis; hereditary chromosomal abnormalities (Down’s, Blooms, Klieninfelter’s)

How does a patient with AML present?

Fatigue and dyspnea (due to anemia) Infection (neutropenia) Bleeding (thrombocytopenia, coagulopathy) Confused (CNS involvement, leukostasis)

What are thrombocytopenia, anemia, and neutropenia caused by in AML?

Overcrowding (“clogged pipe”)

What are laboratory findings for AML?

1/3 pancytopenia, 1/3 WBC WNL, 1/3 leukocytosis Anemia, thrombocytopenia, neutropenia Spontaneous tumor lysis syndrome (release intracellular contents) Disseminated intravascular coagulopathy (increased risk bleeding and clotting at same time)

What is leukocytosis and how does it present?

Oncologic emergency - hyper-viscosity syndrome (“blood slugging”) Stupor; SOB; vision changes; stroke; respiratory failure; cardiac ischemia; renal failure; renal hemmorhage

How do you manage leukocytosis?

Hydroxyurea - antimetabolite used for cytoreduction Leukapheresis

What is the world health definition of AML?

At least 20% myeloid blasts isolated on bone marrow biopsy or peripheral blood

What is the cytogenetic definition of AML?

Detection of cytogenetic abnormalities known to indicate AML such as t(8;21), t(15;17), t(16:16), inv(16)

What molecular mutations are associated with AML?

FLT3, IDH1, IDH2, TP53

What is the role of the FLT3 gene?

It encodes a receptor tyrosine kinase that regulates hematopoiesis

What does a FLT3 internal tandem duplication indicate in AML and when is it considered high?

It is a poor prognostic factor of AML and if the ratio is over 0.5 then it is considered high

What cytogenetic markers are high risk in AML?

Del 5q, -5 Del 7q, -7 11q23 t(9,22)

What molecular marker is considered high risk in AML?

FLT3-ITD mutation

What is a favorable genetic abnormality in AML?

Mutated NPM1 without FLT3-ITD or with FLT3-ITD

What are poor/adverse genetic abnormalities in AML?

t(v;11q23.3) -5 or del(5q) Wild type NPM1 and FLT3-ITD

What are other factors outside of genetic abnormalities that indicate poor prognosis?

Increasing age; secondary or treatment-related AML, High WBC at diagnosis (\>100,000), relapsed AML