Kearns- Targeted Cancer Therapies

What suffix is used for monoclonal antibodies that have cancer cell growth inhibitory properties?

“mab”

The generic naming formula is prefix + ________ + ________.

What do they mean in regards of the drug?

prefix + subsystem/substem + stem

• subsystem= refers to molecular target

• stem= refers to the drug class

In monoclonal antibodies, the middle of the word aka a “substem or subsystem” indicates its molecular target.

• What are these 3 substems?

• Where do each of these target?

• “-ci-” Circulatory system target

• “-tu-” targets tumor growth

• “-li-” targets the immune system

What is the subsystem name for each of the following:

• tyrosine kinase inhibitor

• proteasome inhibitor

• cyclin-dependent kinase inhibitor

• poly ADP-ribose polymerase inhibitor

• tyrosine kinase inhibitor: -tinib

• proteasome inhibitor: -zomib

• cyclin-dependent kinase inhibitor: -cilcib

• poly ADP-ribose polymerase inhibitor: -parib

Name the source of each of the following:

• -ximab

• -zumab

• -mumab/-umab

• chimeric

• humanized

• fully human

What drug class does the stem name “-ib” refer to?

small molecules with INHIBITORY properties

Which is bigger in size?

a. drug with -mab stem

b. drug with -ib stem

a

PRACTICE:

From the name, what can you tell me about the drug “Adalimumab”?

• it is a mAb

• it is fully human (aka low immunogenicity)

• it targets the immune system

What are the 3 different methods mAb use to kill cancer cells?

Name the types of inhibitors that employ each method.

1. direct tumor cell killing

   • HER2, EGFR, and Leukocyte inhibitors

2. vascular and stromal cell ablation

   • aka inhibiting angiogenesis (decreasing the tumor cell’s ability to grow a blood supply)

   • VEGF inhibitors

3. immune-mediated tumor cell killing

   • PD1/PDL1 inhibitors

   • immune checkpoint inhibitors

Name the types of inhibitors that are small molecule agents used in anticancer tx?

• tyrosine kinase inhibitors

• proteasome inhibitors

• CDK inhibitors

• immunomodulators (note: she said these are not on exam)

What mAbs are HER2 inhibitors? (Human Epidermal Growth Factor Receptor 2)

Which are considered “naked”?

• Trastuzumab- naked

• Pertuzumab- naked

• Ado-Trastuzumab- NOT naked

What does “naked” mean in terms of mAbs?

naked means NOTHING is attached to it!! aka no DRUG CONJUGATE

HER2 is what kind of receptor?

What is the MOA of all HER2 inhibitors?

Downstream Results?

• is an EGFR

• inhibitors MOA:

  • OVERALL—> binds to HER2 RECEPTOR COMPETITIVELY AND BLOCKS DOWNSTREAM PHOSPHORYLATION

  • more specifically: Facilitates (helps) selective recognition/ OPSONIZATION of HER2+ cancer cells

• Results:

  • block receptor kinase activation

  • inhibit transcription

  • inhibit angiogenesis

How is the MOA of Ado-Trastuzumab different from the other HER2 inhibitors? Why?

• is different bc Ado-Trastuzumab is NOT NAKED it is CONJUGATED!!!!!!! is linked to EMTANSINE

• in ADDITION to facilitating selective recognition/ OPSONIZATION of HER2+ cancer cells—> this drug ALSO is a tubulin inhibitor

Answer the following about each:

Generic	Class	Method of killing (direct, vascular ablation, etc.)	Type of mAb	WARNINGS
Trastuzumab
Pertuzumab
Ado-Trastuzumab

Rank each HER2 Inhibitor in order from longest to shortest washout time.

(trastuzumab, pertuzumab, ado-trastuzumab)

1. LONGEST TIME—→ Trastuzumab (up to 7 months)

2. Pertuzumab (18 days)

3. Ado-Trastuzumab (4 days)

Are trastuzumab and Ado-trastuzumab interchangeable? Why?

no—> bc of washout times

PRACTICE:

Which of the following would occur with administration of a HER2 antagonist?

a. dimerization of kinases

b. auto phosphorylation

c. gene transcription

d. competitive antagonism

d

What mAbs are EGFR inhibitors? (Epidermal Growth Factor Receptor)

• Cetuximab

• Panitumumab

Answer the following about Cetuximab:

• warnings

  • pre-medication?

• MOA

• type of mAb

• half-life (i don’t think imp)

• dosing (i don’t think imp)

• ADRs (i don’t think imp

• warnings: cardiopulmonary arrest/infusion reactions

  • pre-medicate w/ antihistamine

• MOA: inhibits EXTRACELLULAR EGFR, may also induce cell-mediated cytotoxicity

• chimeric mAb

• t 1/2: short (63-230 hrs)

• dose q1-2 w

• ADRs: fatigue, malaise, pain, neuropathy, rash, weight loss, GI

Answer the following about Panitumumab:

• warnings

• MOA

• type of mAb

• half-life (i don’t think imp)

• dosing (i don’t think imp)

• ADRs (i don’t think imp)

• warning: potential serious derm toxicity

• MOA: inhibits EXTRACELLULAR EGFR ONLY

• human mAb

• t 1/2- short (4-11 days)

• dose q2 w

• ADRs: fatigue, skin rxns, hypomag, GI, ocular toxicity

Which has a higher potential for immunogenicity?

a. Cetuximab

b. Panitumumab

a

What is the target of Leukocyte antigen inhibitors?

direct tumor killing CD antigens expressed on the surface of hematopoietic cells

What is the MOA of mAbs that are leukocyte antigen inhibitors?

• mAbs that OPSONIZE CANCER CELLS

  • How?

    • active antibody-dependent cell mediated cytotoxicity (ADCC)—> phagocytosis

      or/and

    • active complement-dependent cytotoxicity (CDC)

Classification of leukocyte antigen inhibitors is based on the target antigen. What are the 2 drugs used in anticancer therapy and their CD target??

• Rituximab- CD20

• Inotuzumab- CD22

Are CD’s on T cells or B cells?

B cells!!!

Which leukocyte antigen inhibitor is naked? Which is conjugated and with what drug?

• Rituximab- NAKED

• Inotuzumab- conjugated with ozogamicin

Answer the following about Rituximab:

• class

• MOA

• warning

• type of mAb

• effect on B cells (i do not think imp)

• ADRs (i do not think imp)

• Leukocyte Antigen Inhibitors

• binds to CD20 on B cells to initiate ADCC/CDC

• WARNINGS: infusion and mucotaneous reactions, hepatitis B reactivation, progressive multifocal leukoencephalopathy

• CHIMERIC mAb

• depletion of B cells in 6 weeks, last up to 9m

• ADRs: edema, HTN, fatigue, insomnia, HA, infection, etc.

Answer the following about Inotuzumab:

• Class

• MOA

• warning

• type of mAb

  • linked to

• ADRs (i do not think imp)

• Leukocyte Antigen Inhibitors

• binds to CD22, internalization of ADC-receptor complex

  • bc of ozogamicin—> alkylating agent that damages DNA (calicheamicin derivative)

• WARNINGS: hepatotoxicity, post-HSCT non-relapse mortality

• humanized mAb

  • linked to ozogamicin

• ADRs: fatigue, HA, N/V/D/C, BMS, infection, etc.

What are the 2 VEGF inhibitors used in anticancer therapies?

• Bevacizumab- our focus

• Ramucirumab

What is the MOA of VEGF inhibitors?

Results?

• MOA: inhibits the actions of VEGF on the VEGFRs of cancer cells

  • also enhances lymphocyte response

• results: inhibits angiogenesis and limits tumor growth

What type of inhibitor is Bevacizumab?

COMPETETIVE INHIBITOR

Answer the following about Bevacizumab:

• class

• MOA

• WARNINGS

• what route is available?

• ADRs (I don’t think imp)

• VEGF inhibitor

• blocks VEGFR, enhances lymphocyte response

• WARNINGS: GI perforations, surgery/wound healing, hemorrhage

• intravitreal (into the eye) route available

• ADRs: HTN, VTE, fatigue, HA, infections, impaired healing, etc.

What mAbs are programmed cell death receptor inhibitors?

• Pembrolizumab (Keytruda)

• Nivolumab

• Atezolizumab

• Avelumab

• Durmalumab

(just said to “recognize these names”)

The goal of immune checkpoint inhibitors of programmed cell death receptors is to block the interaction between ________ and ________.

PD-1 and PD-L1

Does Pembrolizumab inhibit PD-1 or PD-L1? Therefore, would it act on the T cell or tumor cell?

PD-L1, would act on the TUMOR CELL!!!!!!!

Answer the following about Pembrolizumab:

• inhibits PD-__

• results?

• requires what diagnostic test?

• type of mAb

• WARNING

• inhibits PD-L1

• results—> immune system can recognize and attack tumor cells

• requires PD-L1 IHC 22C3 test to make sure you have high PD-L1 expression

• HUMANIZED mAb

• WARNINGS: NOT for pregnant women

  (mneumonic: Pem is just pregnancy)

If a tumor cell is growing, would it be overexpressing or under expressing PD-L1 markers?

overexpressing

PD-1 is on the ________ cell.

PD-L1 is on the _________ cell.

PD-1 is on the T cell.

PD-L1 is on the tumor cell.

What is the name of an immune checkpoint inhibitor (CTLA-4) that uses immune mediated tumor cell killing and is used in combination with Nivolumab for non-small cell lung cancer?

Ipilimumab

Bispecific T-cell engagers (BiTEs) is another way of targeting…

direct tumor killing

What is unique about BiTEs compared to other drugs in general?

binds to the T cell and tumor cell and acts on both aka “bispecific”

BiTEs consist of 2 single chain variable fragments. What are the 2 fragments?

1. Tumor-associated antigens (TAA) targeting fragment

   • aka binds to the tumor cell

2. T-cell surface antigen fragment

   • aka binds to the T cell

What is the unique MOA of BiTEs?

What are the results?

• MOA: direct cytotoxic T-cell activity against cancer cells

  • forms a link between T cell and tumor cell

  • produces a perforin or “hole” and makes the tumor basically explode

What drug is an example of BiTEs?

Blinatumomab

Answer the following about Blinatumomab:

• WARNINGS:

• type of mAb

• USES

• ADRs (i don’t that imp)

• WARNINGS: Cytokine release syndrome, neurotoxicity

• murine mAb

• Uses: ACUTE LYMPHOBLASTIC LEUKEMIA

  • note: NOT CHRONIC!!! ACUTE!!!!!

• ADRs: edema, pain, HTN, rash, infection, etc.

Blinatumomab acts on what specific CDs on the tumor cell and t cell?

• on tumor cell—> CD19

• on T cell—> CD3

Tyrosine Kinase Inhibitors (TKIs) are mainly used to tx what 3 cancers? What classes of TKIs are used for each cancer?

• chronic myelogenous leukemia (CML)

  • BCR-ABL inhibitors

• melanoma

  • BRAF inhibitors

  • MEK 1 and 2 inhibitors

    • MEK= mitogen-activated extracellular kinase

• non-small cell lung cancer (NSCLC)

  • EGFR inhibitors

  • ALK Inhibitors

    • ALK= anaplastic lymphoma kinase

Review:

How does the tyrosine kinase pathway normally work to have cell growth, proliferation, and differentiation?

• ligand binds to ligand binding

• domains come together to dimerize

• tyrosine kinases on domains are phosphorylated

• phosphorylation drives various cell processes like transcription

How do the mechanisms of action of mAbs that inhibit phosphorylation differ from those of tyrosine kinase inhibitors?

• mAbs bind to the RECEPTOR and block downstream signaling like phosphorylation—→ EXTRACELLULARLY

  • the ligand binding to the ligand binding domain

• tyrosine kinase inhibit dimerization/ phosphorylation of kinases INTRACELLULARLY

  • dimerization

PRACTICE:

If I had a glioma (brain tumor) and I needed tx immediately, would I use a TKI or mAb?

mAb (why? bc we don’t have time for the tyrosine kinase to get intracellularly and produce it’s effect. we are gonna use a mAb that quickly reaches the tumor surface to produce its effect)

What is the goal of TKIs?

inhibit tyrosine kinase activity so that cell growth and proliferation slows down

What TKIs are BCR-ABL Inhibitors and used for the tx of CML?

• Imatinib mesylate

• Nilotinib

• Ponatinib (doesn’t target just BCR-ABL)

What are the CYP interactions with Imatinib and Nilotinib?

• Imatinib- CYP3A4 inhibitors and inducers, CYP450 INDUCERS

• Nilotinib- CYP3A4 inhibitors

Answer the following about Imatinib:

• class

• Uses

• MOA

• WARNINGS

• BRCA-ABL inhibitor/ small molecule TKI inhibitor

• Ph+ CML

• MOA: antagonizes phosphorylation

• WARNINGS: hepatotoxicity, hemorrhage, GI perforation, dermatologic rxns

Answer the following about Nilotinib:

• class

• Uses

• used in adults or kids?

• WARNINGS:

• BRCA-ABL inhibitor/ small molecule TKI inhibitor

• Ph+ CML —> ONLY IF RESISTANCE TO IMATINIB

• used in adults

• WARNINGS: prolongs QT interval, avoid drugs that also prolong QT interval, CYP3A4 inhibitors

Answer the following about Ponatinib:

• target/class

• uses

• MOA

• multitarget, can inhibit BCR-ABL1/ BRCA-ABL inhibitor/ small molecule TKI inhibitor

• USES: for Ph+ CML when there is a T3151 MUTATION!!!!!!!!!

• MOA: antagonizes phosphorylation—> antiangiogenic/antieoplastic

What is something that would cause resistance to Imatinib and would make you use Nilotinib?

if the tumor cell would activate alternative signaling pathways to increase phosphorylation and transcription not the BCR-ABL pathway

What does Ph+ or Ph- CML refer to? Why is it important?

• Ph+ means you are POSITIVE for the Philadelphia chromosome aka the BCR-ABL1 gene mutation

• In CML, 95% of cases are Ph+ so it’s key in the tx of CML

  (think: if most cases of CML are caused by the BCR-ABL1 mutation, why would I use a BCR-ABL inhibitor on CML that doesn’t HAVE THE GENE????)

What is the T3151 mutation?

a PAN-MUTATION in BCR-ABL at site T3151!!! (means everywhere in the gene)

The EGFR pathway is initiated by what and activates what 3 pathways to result in cell proliferation, growth, progression, etc.?

• initiated by binding of extracellular ligand

• activates:

  • RAS/MAPK

  • PIP3K

  • JAK/STAT

What is the MOA of EGFR Tyrosine Kinase Inhibitors?

(FYI: she didn’t really mention any specific drugs for this class just talked about the class in general)

• small molecule EGFR TKIs bind to the kinase domain and block function of the EGF receptor

What drug is a TKI that inhibits VEGF?

Sunitinib

Answer the following about Sunitinib:

• class

• MOA

• results

• WARNINGS!!!

• VEGF inhibitor/ small molecule TKI

• MOA: competitively inhibit binding of ATP to TK domain on the VEGF RECEPTOR

• Results: inhibit angiogenesis

• WARNINGS: HEPATOTOXICITY

In general, what are some mechanisms of resistance to ALL TKIs?

• point mutations in the kinase domain that prevent binding of the drug and lock the enzyme in the open position

• amplification of kinase gene

• drug efflux (ex: Pg-p)

• altered kinase trafficking

What do proteasome inhibitors do in targeted anticancer therapies? Results?

1. inhibitors bind the proteasome and inhibit protein degradation

2. prevent the proteolytic degeneration of TF NF-kb

results: decrease anti-apoptotic factors, cell adhesion, and proliferation

What is the overall strategy proteasome inhibitors use?

• cancer cells make lots of extra proteins and use proteasomes to degrade them so they don’t die

• we inhibit the proteasome so that all the extra proteins build up and kill the cancer cell!!

What drug is a proteasome inhibitor?

Bortezomib

Answer the following about Bortezomib:

• admin (route, formulation)

• MOA

• Metabolism

• Resistance with ___________________.

• admin: IV/SQ administered DIPEPTIDE for relapsed/refractory multiple myeloma

• MOA: dipeptide boronic acid inhibitor that INHIBITS 26S PROTEASOME

• Metabolism: CYP3A4, CYP2C19

• resistance with prolonged tx

Specifically, how does Bortezomib inhibit the 26S proteosome?

the boronic acid on Bortezomib is specific for the active site of the proteasome and forms a complex. this inhibits the proteolysis activity of the proteasome

Cyclin-dependent kinases play an important role in ___________________.

cell cycle regulation

Overall, CDK inhibitors inhibit…

cell cycle progression

What is the most present cyclin in G1 phase?

cyclin D

What small molecule targeted anti-cancer drug is a CDK inhibitor?

Palbociclib

Answer the following about Palbociclib:

• MOA

  • results

• Uses

• admin

• METABOLISM

• SELECTIVE INHIBITOR of CDK4 and CDK6

  • results: blocks phosphorylation of retinoblastoma tumor suppressor protein, G1 phase arrest

• breast cancer

• oral

• CYP3A4 METABOLISM—> avoid strong inhibitors/inducers