targeted therapy

what do targeted therapies do

they are designed to interact with specific molecules that are part of the pathways and processes used by cancer cells to grow, divide and spread throughout the body

types of targeted therapy and their differences

1. monoclonal Ab

   • work outside cell

   • IV or SC

   • target ligands that bind to cell surface receptors or the extracellular portion of cell surface receptors

2. small molecule (kinase inhibitor) drugs

   • work inside the cell

   • oral

   • target the intracellular portion of cell surface receptors, signalling molecules that relay messages through the cell or transcription factors within the cell nucleus

what are protein kinases

enzymes that transfer phosphate from adenosine triphosphate to specific AA on substrate proteins.

phosphorlyation of these proteins leads to the activation of signal-transduction pathways which have a critical role in a variety of biologic processes, including cell growth, differentiation and death

subfamilies of protein kineses

serine-threonine kinases

tyrosine kinases (MAIN)

why are protein kinases attractive targets for targeted therapies

several protein kinases are derugulated and over expressed in human cancers

oral HER1 inhibitor examples + gens

erlotinib (1st gen)

afatinib (2nd)

osimertinib (3rd)

best oral HER1 inhibitor

osimertinib third gen

MOA of HER1 oral inhibitors

orally active small molecule EGFR tyrosine kinase inhibitor that blocks cell transduction cascades responsible for proliferation, survival and metastases of cancer cells

Indication for oral HER1 inhibitors

lung cancer

Toxicities of oral HER1 inhibitors

Rash (1st gen up to 100%), dry skin, NVD

***erlotinib (1st gen) most rash, afatinib most diarrhea, osimertinib hardly ever get rash + good QoL

BCR-ABL and C-Kit inhibitor examples

Imatinib, dasatinib, nilotinib

BCR-ABL kinase and C-Kit inhibitor indications

CML and GIST - Imatinib

CML- Dasatinib and nilotinib

MOA of Imatinib, dasatinib and nilotinib

inhibits BCR-ABL tyrosine kinase created by the Philadelphia chromosome abnormality in CML. it binds to the binding site of the BCR-ABL gene and competitively blocks access to adenosine triphosphate, thereby preventing phosphorylation and activation of cellular proliferation.

also blocks tyrosine kinase activity of c-KIT (stem cell factor receptor) for GIST tumors

AE of BCR-ABL kinase and C-Kit inhibitors

GI distress (NVD), myelosuppression

VEGF/multikinase oral inhibitor example

Sunitinib

what is a multikinase inhibitor

orally active small molecules that inhibit many different receptor kinase pathways, some of which are involved in tumour cell signaling, proliferation, angiogenesis, and apoptosis

moa of Sunatinib

tyrosine kinase inhibitor of multiple receptor tyrosine kinases including; platelet derived growth factor (PDGF), vascular endothelial growth factor receptors (VEGF) and others which are involved in tumor growth and metastasis

Sunitinib indication

advanced renal cell carcinoma

Gastrointestinal stromal tumors (GIST) after disease progression on or intolerance to imatinib

toxicities of sunitinib

stomatitis, increase BP, NVD

BRaf inhibitor ex

Dabrafenib, Vemurafenib

MOA of BRaf inhibitors

in 60% of lethal skin cancers, mutations spontaneously occur in the BRAF protein, a member of the RAF family of cell signaling enzymes, possibly due to sun damage

given in combo with MEK1/MEK2 inhibitors to increase their activity by targeting 2 different kinases in the MAPK/ERK pathway resulting in increased apoptosis (cell death) and reduced tumor growth

BRaf inhibitors indications

metastatic melanoma with BRaf mutations

AE of BRaf inhibitors

arthralgia, photosensitivity rxn, 24% incidence of squamous cell cancer

ex of MEK inhibitors

Trametinib, cobimetinib

MOA of MEK inhibitors

reversibly inhibit MEK1 an MEK2 activation and kinase activity, switching off abnormal signaling along MAPK/ERK pathway which is activated by BRAF V600 mutations

(given in combo with BRaf inhibitors)

indications of MEK inhibitors

metastatic melanoma

non small cell lung cancer with BRAF mutation

ae of MEK inhibitors

ocular toxicity (retinal vein occlusion), CV effects (heart failure), pyrexia syndrome

ex of ALK inhibitors

Crizotinib, Cerinitinib (1st gen) (not used)

alectinib, brigatinib (2nd gen)

lorlatinib (3rd gen)

MOA of ALK inhibitors

tyrosine kinase receptor inhibitors which inhibit anaplastic lymphoma kinase (ALK), ALK gene abnormalities due to mutations of translocations may result in expression of oncogenic fusion proteins which alter signalling and expression and result in increased cellular proliferation and survival in tumors which express these fusion proteins

ALK inhibitor indications

anaplastic lymphoma kinase (ALK) positive, metastatic non small cell lung cancer (NSCLC)

AE of ALK inhibitors

elevated transminases

lorlatinib has more hypercholesterolemia and peripheral neuropathy and CNS effects

Which ALK inhibitors cross BBB

Alectinib and Lorlatinib- but lorla has best efficacy for CNS metastasis AND preventing CNS metastasis

3 ways mAB work

1. outside the cell- preventing signalling molecules and receptors from interacting with eachother

2. as delivery vehicles, guiding radioactive molecules or toxins to the cancer cells

3. Abs attached to a cell can trigger an immune response that destroys the cell

Ex of HER2 inhibitor

Trastuzumab, Pertuzumab

MOA trastuzumab

humanized mAB that binds to the extracellular domain of HER-2 (blocks signalling cascade and cell proliferation)

Indications of trastuzumab

Breast cancer, gastric cancer

HER2 receptor is overexpressed in % of gastric cancers and % of breast cancers

20% of gastric, 25-30% breast

AE of trastuzumab

decreased left ventricular EF

moa Pertuzumab

recombinant humanized mAb that targets extracellular human epidermal growth factor receptor 2 protein (HER2) dimerization domain

indication of pertuzumab

breast cancer

AE pertuzumab

decreased left ventricular EF

ex of VEGF inhibitor (mAb)

Bevacizumab

moa bevacizumab

recombinant humanized mAb that binds to VEGF

binding to all circulating VEGF prevents activation of VEGF receptors

indication of bevacizumab

colon, brain, ovarian cancers

AE bevacizumab

htn, bleeding episodes, ATE, VTE, GI perforation, proteinuria

ex of HER1 inhibitor (mAb)

Panitumumab, Cetuximab

MOA of panitumumab/cetuximab

binds to cell surface epidermal growth factor receptor (EGFR1), preventing EGF binding and signal transduction

indication of panitumumab/cetuximab

monotherapy of non mutant wild type K-RAS metastatic or advanced colorectal cancer

what makes panitumumab/cetuximab therapy ineffective

mutated KRAS gene

ex of anti CD20 inhibitor

Rituximab

MOA rituximab

chimeric mAB targets the CD-20 antigen, a protein on the surface of leukemia and lymphoma cells (B lymphocytes)

The MAb binds to any CD-20 antigen it finds whether abnormal or normal, marks them for death, the immune system kills the cells the same way it kills invading bacteria or viruses. the body naturally produces new healthy B cells in a few months

Rituximab indication

lymphoma

AE rituximab

infusion related rxns

pre-meds for rituxumab

tylenol and benedryl (diphenhydramine)

Ex of PD1 inhibitors

Nivolumab and Pembrolizumab

MOA Nivolumab and Pembrolizumab

highly selective anti-PD-1 humanized mAb which inhibits programmed cell death-1 (PD-1) activity by binding to PD-1 receptor on T cells to block PD-1 ligands (PD-L1 and PDL-2) from binding

blocking the PD-1 pathway inhibits the negative immune regulation caused by PD-1 receptor signaling. Anti-PD1 antibodies reverse T cell suppression and induce antitumor responses

indication of nivolumab and pembrolizumab

melanoma, lung cancer

AE nivolumab and pembroluzimab

immune mediated AE: colitis, hepatitis, hephritis, pneumonitis

Tx of immune mediated SE (Such as with immunotherapy PD1 inhibitors)

stop and give steroids