Targeted Therapy and Other Nontraditional Antineoplastic Agents

Targeted therapy exerts antineoplastic activity against cancer cells by interfering with unique properties found in tumors or malignancies. The types of drugs can be small molecules, which are able to enter cells, or monoclonal antibodies, which have targets outside of or on the surface of cells. Among the areas in malignant cells that are blocked or inhibited by targeted therapy are signal pathways (as seen in protein kinase inhibitors), which lead to decreased proliferation and subsequent tumor cell apoptosis. Other means of reducing cancer cells is by eliminating the capacity for DNA repair (seen in poly(ADP-ribose) polymerase inhibitors), blocking the ligand-receptor binding (growth factor inhibitors), and increasing immune activity against the neoplasm (immunotherapies). These agents are used in multiple types of cancer and in combination with traditional chemotherapeutic agents.

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Overview

Cancer therapy development

  • Traditional chemotherapy affects both cancer cells and normal cells.
  • A growing number of new anticancer agents (targeted therapy) are now used in addition to the traditional antineoplastic drugs.
    • Development is based on findings that molecular changes in cells drive progression to malignancy.
    • Drugs are able to block the oncogenic pathway(s) with fewer cytotoxic effects on normal cells.

Targeted cancer therapy

  • Interfere with specific molecules that target particular pathways, affecting the growth and proliferation of cancer cells
  • There are different ways of disrupting pathways; these include prevention of receptor binding and intracellular binding and inhibition of kinases.
  • Most of the available therapies are:
    • Small molecules: 
      • Compounds (that can enter cells) with intracellular targets (e.g., kinases)
      • Inhibition of kinases prevent further activation of different pathways (as seen in protein kinase inhibitors)
      • Most drug names of protein kinase inhibitors end with the syllable “-ib.”
    • Monoclonal antibodies: 
      • Used for targets outside of or on the surface of the cells (e.g., growth factor receptors or receptor ligands)
      • Monoclonal antibody drug names end with the syllable “-mab.”
Schematic mechanism for receptor tyrosine kinase inhibition

Schematic mechanism for receptor tyrosine kinase inhibition:
On the left, the image shows the structure of the receptor of the cell. On the cell surface lies the ligand-binding domain and the kinase domain (in this image, tyrosine kinase) is found intracellularly.
On the right, the image shows how a monoclonal antibody can produce antineoplastic activity, which is via antibody-mediated inhibition of the ligand-binding domain. Small molecules, which can enter cells, are able to produce inhibition of the ATP-binding (tyrosine kinase) domain.

Image: “Schematic mechanism for receptor tyrosine kinase inhibition” by Apraiz A, Boyano MD, Asumendi A. License: CC BY 3.0, edited by Lecturio.

Protein Kinase Inhibitors

Protein kinases

  • There are > 500 different protein kinases in the human genome:
    • The protein kinases function by adding a phosphate group to protein substrates: serine, threonine, or tyrosine.
    • After phosphorylation, the protein undergoes conformational change (“turns the protein on”).
    • Phosphatases (which remove phosphate) reverse the action of kinases.
  • Particular signal transduction cascades follow (e.g., BCR-ABL with tyrosine as a protein substrate, RAF with serine/threonine); modulating activities include:
    • Cell proliferation
    • Gene expression
    • Metabolism
    • Membrane transport
    • Apoptosis
  • However, when kinases are constitutively expressed → oncogenesis, such as that seen in the RAS-RAF-MEK-ERK pathway:
    • Signaling pathway involved in cell proliferation and differentiation
    • Activated in many cancers
    • Regulating signaling affects cancer growth.
  • Protein kinase inhibitors:
    • Block the action of protein kinase enzymes, which are often overexpressed in cancer.
    • Inhibiting protein kinases is a mechanism also used in drugs to treat inflammatory conditions.

BCR-ABL kinase inhibitors

  • Philadelphia chromosome translocation t(9;22) → BCR-ABL1 fusion gene
    • Fusion leads to constitutive activation of BCR-ABL → uncontrolled cell division → ↑ granulocytic production
    • Seen in CML
  • Related agents:
    • Imatinib
    • 2nd-generation:
      • Dasatinib 
      • Nilotinib 
Table: BCR-ABL kinase inhibitors
ImatinibDasatinibNilotinib
Pharmacodynamics
  • Inhibit BCR-ABL tyrosine kinase (causing apoptosis of BCR-ABL positive cell lines)
  • Inhibit c-KIT, PDGFR
  • Imatinib: also inhibits stem-cell factor
Pharmacokinetics
  • Oral
  • Hepatic metabolism
  • Excretion: mostly in feces
Indications
  • CML
  • Imatinib, dasatinib: ALL (Ph+)
  • Imatinib:
    • Systemic mastocytosis
    • CML
    • GIST
    • Dermatofibrosarcoma protuberans
    • CEL
    • MDS/MPD
Adverse effects
  • Myelosuppression
  • TLS
  • Hemorrhage
  • Cardiovascular events (heart failure)
  • Edema
  • Dermatologic reactions (e.g., SJS, EM)
  • GI irritation
  • Nephrotoxicity
  • Hepatotoxicity
  • Myelosuppression
  • TLS
  • Hemorrhage
  • Cardiovascular events
  • Edema
  • Dermatologic reactions
  • Prolonged QT
  • Pulmonary hypertension
  • Myelosuppression
  • TLS
  • Hemorrhage
  • Cardiovascular events
  • Edema
  • Prolonged QT
  • Electrolyte imbalance
  • Hepatotoxicity
Contraindications
  • Hypersensitivity to the drug
  • Nilotinib, dasatinib:
    • ↓ K, Mg
    • Prolonged QT
CEL: chronic eosinophilic leukemia
EM: erythema multiforme
GIST: GI stromal tumors
MDS/MPD: myelodysplastic/myeloproliferative diseases
PDGF: platelet-derived growth factor
Ph+: Philadelphia chromosome–positive
SJS: Stevens-Johnson syndrome
TLS: tumor lysis syndrome

BRAF kinase inhibitors

  • BRAF: 
    • Protein in the RAF family of serine/threonine kinases
    • Has an important role in mediating signals from RAS to MEK, leading to proliferation 
    • Mutations → persistent intracellular signaling → malignancy 
      • Seen in 60% of melanomas and 15% of colorectal cancers
      • Lead to increased tumor survival and mobility
  • Related agents (block the activity of mutated BRAF):
    • Vemurafenib
    • Dabrafenib
Table: BRAF kinase inhibitors
VemurafenibDabrafenib*
PharmacodynamicsInhibit kinase activity of mutated BRAF (including V600 mutation)
Pharmacokinetics
  • Oral
  • Half-life: 57 hours (vemurafenib), 8 hours (parent drug: dabrafenib)
  • Excretion: feces
Indications
  • Melanoma
  • Erdheim-Chester disease
  • Melanoma
  • NSCLC
  • Thyroid cancer
Adverse effects
  • Cardiovascular: prolonged QT, hypertension
  • Cutaneous malignancy
  • Uveitis
  • Dermatologic reactions
  • Hepatotoxicity
  • Nephrotoxicity
  • Pancreatitis
  • Fibroproliferative disorders
  • Radiation sensitization
  • Cardiovascular: cardiomyopathy, prolonged QT
  • Cutaneous malignancy
  • Uveitis
  • Dermatologic reactions
  • Febrile reactions
  • Hemorrhage
  • ↑ Glucose
  • VTE
ContraindicationsHypersensitivity to the drug
*Combination with trametinib produces greater inhibitory activity.
NSCLC: non–small cell lung cancer
VTE: venous thromboembolism

MEK inhibitors

  • Mitogen-activated extracellular kinases (MEKs) are serine-threonine kinases participating in the mitogen-activated protein kinase (MAPK) pathway.
  • MAPK is activated in melanomas.
  • Agents:
    • Trametinib (1st approved)
    • Cobimetinib
    • Binimetinib
    • Selumetinib
Table: MEK inhibitors
TrametinibCobimetinib
PharmacodynamicsInhibits MEK activation and kinase activity
Pharmacokinetics
  • Oral
  • Primarily deacetylation
  • Not a substrate of CYP enzymes
  • Half-life: 4–5 days
  • Excretion: feces
  • Oral
  • Hepatic metabolism
  • Half-life: 44 hours
  • Excretion: feces
Indications
  • Melanoma
  • NSCLC
  • Anaplastic thyroid cancer
Melanoma
Adverse effects
  • Myelosuppression
  • Hepatotoxicity
  • Cardiovascular events (heart failure, ↓ LVEF)
  • Dermatologic reactions
  • Hemorrhage
  • Cutaneous cancers
  • Febrile reactions
  • ↑ Glucose
  • Colitis, GI perforation
  • Ocular: retinal detachment
  • VTE
  • Myelosuppression
  • Hepatotoxicity
  • Cardiovascular events (heart failure, ↓ LVEF)
  • Dermatologic reactions
  • Hemorrhage
  • Cutaneous cancers
  • Ocular: retinal detachment, retinopathy
ContraindicationsHypersensitivity to the drug
LVEF: left ventricular ejection fraction
NSCLC: non–small cell lung cancer
VTE: venous thromboembolism

JAK inhibitors

  • Janus-associated kinases (JAKs) are mediators of signals among cells, cytokines, and growth factors in hematopoiesis and immune response.
    • Receptor interacts with a cytokine or growth factor → activate JAKs → tyrosine phosphorylation → activate signal transducer and activators of transcription (STATs)
    • STATs translocate to the nucleus → transcription of effector genes → effects include proliferation, differentiation, migration, apoptosis, and cell survival
  • Related agents:
    • Ruxolitinib (1st in class)
    • Agents with noncancer indications:
      • Baricitinib
      • Tofacitinib (approved for inflammatory conditions such as ulcerative colitis and rheumatoid arthritis)
Table: JAK inhibitors
RuxolitinibBarcitinib
PharmacodynamicsInhibit JAKs
Pharmacokinetics
  • Oral
  • Half-life: 3–6 hours (ruxolitinib), 12 hours (baricitinib)
  • Hepatic metabolism
  • Excretion: mostly urine
Indications
  • Polycythemia vera
  • Myelofibrosis
  • Graft-versus-host disease (acute)
  • Rheumatoid arthritis
  • Off-label: COVID-19 hospitalization (requiring oxygen)
Adverse effects
  • Myelosuppression
  • Serious infections
  • ↑ Hepatic enzymes
  • Cutaneous cancers
  • ↑ Lipid
  • Myelosuppression
  • Serious infections (including TB)
  • ↑ Hepatic enzymes
  • Cutaneous cancers
  • ↑ Lipid
  • Thrombosis
  • GI perforation
ContraindicationsHypersensitivity to the drug
JAK: Janus-associated kinases
COVID-19: coronavirus disease 2019

Cyclin-dependent kinase (CDK) inhibitors

  • CDKs are serine/threonine protein kinases that mediate signaling in the cell cycle progression (G0/G1 to S phase) and thus affect cell proliferation.
  • The complex of cyclin D and CDK → phosphorylate the retinoblastoma gene protein (RB1) → processes lead to induction of S-phase genes.
  • Inappropriate cell cycle progression → tumorigenesis
  • Class of drugs identified by the syllable “-ciclib”
  • Related agents:
    • Palbociclib
    • Abemaciclib
    • Ribociclib
Table: CDK inhibitors
PalbociclibAbemaciclib
PharmacodynamicsCDK inhibitor; prevents progression through the cell cycle, leading to arrest at the G1 phase
Pharmacokinetics
  • Oral
  • Half-life: approximately 30 hours (palbociclib), approximately 18 hours (abemaciclib)
  • Hepatic metabolism
  • Excretion: feces
IndicationsAdvanced breast cancer
Adverse effects
  • Myelosuppression
  • Pulmonary toxicity
  • ↑ Hepatic enzymes
  • Myelosuppression
  • Pulmonary toxicity
  • ↑ Hepatic enzymes
  • Thromboembolism
  • Diarrhea
ContraindicationsHypersensitivity to the drug

Bruton tyrosine kinase (BTK) inhibitors

  • The BTKs are important for the survival, proliferation, chemotaxis, and adhesion of B cells.
  • Inhibiting BTK is a mechanism used in treating B-cell malignancies.
  • Related agents:
    • Ibrutinib (1st generation)
    • Acalabrutinib (2nd generation, with higher selectivity for BTK)
Table: BTK inhibitors
IbrutinibAcalabrutinib
PharmacodynamicsInhibit BTK, leading to reduced B-cell proliferation and tumor growth
Pharmacokinetics
  • Oral
  • Half-life: 4–6 hours (ibrutinib), 1 hour (acalabrutinib)
  • Hepatic metabolism
  • Excretion: feces
Indications
  • Graft-versus-host disease (chronic)
  • CLL/SLL
  • Mantle cell lymphoma
  • Marginal cell lymphoma
  • Waldenström macroglobulinemia
  • CLL/SLL
  • Mantle cell lymphoma
Adverse effects
  • Myelosuppression
  • Cardiovascular effects (arrhythmias, hypertension)
  • Hemorrhage
  • Serious infections
  • Secondary malignancies
  • Renal toxicity
  • TLS
  • Myelosuppression
  • Cardiovascular effects (arrhythmias)
  • Hemorrhage
  • Serious infections
  • Secondary malignancies
  • ↑ Hepatic enzymes
ContraindicationsHypersensitivity to the drug
SLL: small lymphocytic lymphoma
TLS: tumor lysis syndrome

Anaplastic lymphoma kinase (ALK) inhibitors

  • Anaplastic lymphoma kinase is a tyrosine kinase that is noted to be aberrantly expressed in certain tumors, such as non–small cell lung cancer (NSCLC).
  • The gene ALK is able to form fusion genes that become oncogenic drivers.
    • ALK-NPM fusion gene → anaplastic large cell lymphoma (ALCL)
    • EML4-ALK fusion gene → found in some NSCLCs 
  • Related agents:
    • Crizotinib
    • Alectinib
    • Ceritinib
Table: ALK inhibitors
CrizotinibAlectinibCeritinib
PharmacodynamicsInhibit ALK, preventing proliferation and survival of ALK-positive tumors
Pharmacokinetics
  • Oral
  • Half-life: 42 hours
  • Hepatic metabolism
  • Excretion: feces
  • Oral
  • Half-life: approximately 33 hours
  • Hepatic metabolism
  • Excretion: feces
  • Oral
  • Half-life: 41 hours
  • Hepatic metabolism
  • Excretion: feces
Indications
  • NSCLC (ALK-positive), metastatic
  • Anaplastic large cell lymphoma (ALK-positive)
Adverse effects
  • Cardiovascular toxicity (bradycardia, prolonged QT)
  • Diarrhea, nausea and vomiting
  • Hepatotoxicity
  • Pulmonary toxicity
ContraindicationsHypersensitivity to the drug

Growth Factor Receptor Inhibitors

Epidermal growth factor receptor (EGFR) agents

  • EGFR: 
    • Part of the ErbB family of growth factor receptors, with an important role in growth and differentiation of epithelial cells
    • Overexpressed in some cancers
    • Ligand binds to the EGFR extracellular domain → intracellular signaling (intracellular domain with tyrosine kinase) by cross-phosphorylation leading to:
      • Cellular growth
      • Angiogenesis
      • Invasion and metastasis
  • Monoclonal antibody inhibitors of EGFR:
    • Recognize the extracellular domain of EGFR, leading to:
      • Blocking of ligand binding
      • Recruitment of immune cells, producing an immune response
    • Include:
      • Cetuximab 
      • Panitumumab
  • Protein tyrosine kinase inhibitors (TKIs) of EGFR:
    • Enter the tumor cells, inhibiting EGFR tyrosine kinase
    • Include:
      • Gefitinib
      • 2nd-generation inhibitor: erlotinib, afatinib 
      • 3rd-generation inhibitor: osimertinib (for NSCLC previously treated with earlier generation of drugs and with T790M mutation)
Table: Monoclonal antibodies binding EGFR
CetuximabPanitumumab
Pharmacodynamics
  • Monoclonal antibodies that bind the EGFR extracellular domain
  • Subsequently block the ligand-dependent activation of receptor kinases
  • Mutations in KRAS (part of the EGFR signaling cascade): ↓ effect of cetuximab
Pharmacokinetics
  • IV
  • Half-life: 5 days
  • IV
  • Half-life: 7.5 days
Indications
  • Metastatic colorectal cancer (KRAS wild type or without mutation)
  • Cetuximab: head and neck, squamous cell cancer
Adverse effects
  • Rash (acneiform)
  • Pruritus
  • Headache
  • Diarrhea
  • ↓ Mg
  • Interstitial lung disease
  • Cardiopulmonary arrest
ContraindicationsHypersensitivity to drug or its components
Table: Protein tyrosine kinase inhibitors of EGFR
AfatinibErlotinibGefitinib
PharmacodynamicsInhibitor of EGFR tyrosine kinase
Pharmacokinetics
  • Oral (↓ absorption with fatty meals)
  • Half-life: 37 hours
  • Minimal enzymatic metabolism
  • Excretion: feces
  • Oral (↑ absorption with food)
  • Half-life: 36 hours
  • Hepatic metabolism
  • Excretion: feces
  • Oral
  • Half-life: 48 hours
  • Hepatic metabolism
  • Excretion: feces
IndicationsNSCLC (with mutations)
  • NSCLC (with mutations)
  • Pancreatic cancer (advanced)
NSCLC (with EGFR mutations)
Adverse effects
  • Skin rash
  • Anorexia, diarrhea
  • Left ventricular dysfunction
  • Interstitial lung disease
  • Hepatotoxicity
  • Nephrotoxicity
  • Erlotinib: ↑ warfarin anticoagulant activity
ContraindicationsHypersensitivity to the drug or its components
EGFR: epidermal growth factor receptor
NSCLC: non–small cell lung cancer

Vascular endothelial growth factor receptor (VEGFR) agents

  • Angiogenic growth factor
  • Important for tumors, which need intact vascular structures for growth.
  • Different ways and agents to inhibit VEGFR signaling:
    • Direct inhibitors of VEGFR tyrosine kinase or VEGF TKIs:
      • Sorafenib (multikinase inhibitor)
      • Pazopanib (multikinase inhibitor)
      • Sunitinib
    • Monoclonal antibodies targeting the VEGF ligand: 
      • Bevacizumab
      • Ramucirumab
    • Vascular endothelial growth factor (VEGF) trap or a soluble receptor made of extracellular domains of VEGFR (binding the VEGF ligand, thus ↓ signaling): Ziv-aflibercept 
Table: Agents inhibiting VEGFR by different mechanisms
BevacizumabZiv-afliberceptSorafenib
PharmacodynamicsMonoclonal antibody targeting VEGF ligandRecombinant fusion protein acting as a decoy receptorInhibit VEGFR tyrosine kinases (and also PDGF)
Pharmacokinetics
  • IV (for cancer)
  • Half-life: 20 days in adults
  • IV
  • Half-life: approximately 6 days
  • Oral
  • Half-life: 1–2 days
  • Hepatic metabolism
Indications
  • Advanced cervical cancer
  • Metastatic CRC
  • Metastatic HCC
  • Recurrent GBM
  • NSCLC
  • Ovarian, fallopian tube, peritoneal cancer
  • RCC
Metastatic CRC
  • Advanced HCC
  • Advanced RCC
Adverse effects
  • Myelosuppression
  • Hypertension
  • Heart failure
  • Hemorrhage
  • GI perforations
  • ↑ Arterial thromboembolic events (e.g., TIA, stroke)
  • Wound healing complications
  • Proteinuria
  • Bevacizumab: ↑ cardiotoxicity of anthracyclines
Contraindications
  • Hypersensitivity to the drug
  • Untreated CNS metastasis
None listed
  • Hypersensitivity to the drug
  • Avoid use with carboplatin and paclitaxel (for lung cancer) as sorafenib ↑ their toxic effects
CRC: colorectal cancer
GBM: glioblastoma
HCC: hepatocellular carcinoma
NSCLC: non small cell lung cancer
PDGF: platelet-derived growth factor
RCC: renal cell carcinoma
TIA: transient ischemic attack
VEGFR: vascular endothelial growth factor receptor

Human epidermal growth factor receptor 2 (HER2) agents

  • HER2: also called Neu or ErbB2
  • Overexpression → intracellular tyrosine kinase activation → oncogenic signaling
  • Overexpressed HER2: seen in up to 30% of breast cancers 
  • Monoclonal antibodies against HER2/Neu:
    • Trastuzumab
    • Pertuzumab
  • TKI: lapatinib
Table: Agents inhibiting HER2
TrastuzumabPertuzumabLapatinib
PharmacodynamicsMonoclonal antibody binding HER2 (extracellular domain)Dual kinase inhibitor (inhibits EGFR and HER2)
Pharmacokinetics
  • IV
  • Half-life: approximately 5.8 days
  • IV
  • Half-life: 18 days
  • Oral
  • Hepatic metabolism
  • Half-life: approximately 24 hours
  • Excretion: feces
Indications
  • Breast cancer
  • Gastric cancer
Breast cancerBreast cancer
Adverse effects
  • Cardiotoxicity: cardiomyopathy
  • Pulmonary toxicity
  • Renal toxicity
  • Dermatologic reactions
  • Birth defects
  • Cardiotoxicity
  • Diarrhea
  • Birth defects
  • Cardiotoxicity
  • Hepatotoxicity
  • Pulmonary toxicity
  • Myelosuppression (with capecitabine)
  • Diarrhea
  • Dermatologic reactions
ContraindicationsHypersensitivity to the drug

Platelet-derived growth factor receptor (PDGFR) agents

  • Platelet-derived growth factors (PDGFs) bind receptor and activate the receptor protein kinases.
    • Important in the survival and proliferation of mesenchymal cells
    • Cancer growth facilitated by dysfunctional signaling and role in angiogenesis
  • TKIs (agents with PDGFR activity):
    • BCR-ABL kinase inhibitors: imatinib, dasatinib, nilotinib
    • VEGFR kinase inhibitors: sunitinib, sorafenib
  •  Monoclonal antibody targeting PDGFR: olaratumab
    • Pharmacodynamics: binds PDGFRɑ, blocking activation of receptor and signaling
    • Pharmacokinetics: IV, with half-life of approximately 11 days
    • Indication: soft tissue sarcoma
    • Adverse effects:
      • Neutropenia, thrombocytopenia
      • Nausea, vomiting, diarrhea
      • Infusion-related reactions
      • Embryo/fetal harm
    • Contraindication: hypersensitivity to the drug

PARP Inhibitors

Poly(ADP-ribose) polymerase (PARP)

  • A product of DNA damage repair genes
  • Catalyzes the transfer of ADP-ribose to target proteins (process called PARylation)
  • Roles:
    • Important in base excision repair and nucleotide excision repair
    • Also involved in transcription and cell cycle regulation
  • Inhibiting PARP → ↓ repair capability → tumor cell apoptosis and ↑ sensitivity of cells to other chemotherapeutic agents (e.g., alkylating drugs)

Inhibitors of PARP

  • Olaparib
  • Rucaparib
  • Niraparib
Table: PARP inhibitors
OlaparibRucaparibNiraparib
PharmacodynamicsPARP enzyme inhibitor
Pharmacokinetics
  • Oral
  • Metabolized by CYP3A
  • Half-life: approximately 15 hours
  • Excretion: urine and feces
  • Oral
  • Hepatic metabolism (CYP2D6, CYP3A, CYP1A2)
  • Half-life: 26 hours
  • Excretion: urine and feces
  • Oral
  • Crosses blood–brain barrier
  • Metabolism: CYP3A4
  • Half-life: 36 hours
  • Excretion: feces and urine
Indications
  • Advanced ovarian cancer
  • Metastatic breast cancer
  • Metastatic pancreatic cancer
  • Metastatic prostate cancer
  • Advanced ovarian cancer
  • Metastatic, castration-resistant prostate cancer
Ovarian, fallopian tube or primary peritoneal cancer
Common adverse effects
  • Myelosuppression
  • Vomiting
  • Secondary malignancy
Adverse effects
  • Pulmonary toxicity
  • Thromboembolic events
  • Edema
  • ↑ Cholesterol
  • Cardiovascular effects (hypertension)
  • Posterior reversible encephalopathy syndrome
ContraindicationsHypersensitivity to the drugNone listedHypersensitivity to the drug

Other Targeted Therapy, Immunotherapy, and Miscellaneous Agents

BCL2 inhibitors

  • The BCL2 protein family is involved in governing programmed cell death (apoptosis).
    • Antiapoptotic proteins have BH1 and BH2 domains.
    • Proapoptotic proteins have BH3 domain.
  • When antiapoptotic proteins are promoted, there is increased cell survival, as seen in cancers such as CLL, in which BCL2 is overexpressed.
  • Related agent: venetoclax
    • 1st in class
    • BH3 mimetic
    • Targets BCL2 interaction → ↓ inhibitory effect on proapoptotic proteins → apoptosis of cancer cells
    • Indications: 
      • CLL
      • AML

CD20 inhibitors

  • CD20 is a cell surface antigen in B cells and is found in 90% of B-cell neoplasms.
  • Monoclonal antibodies bind CD20 and initiate B-cell lysis via complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC).
  • Related agents:
    • Rituximab
    • Ofatumumab
    • Obinutuzumab
  • Indications:
    • CLL
    • Non-Hodgkin lymphoma

Hedgehog pathway inhibitors

  • Hedgehog pathway is involved in cell growth and differentiation.
  • Mutations in the components of the pathway are associated with basal cell carcinoma (uncontrolled proliferation of basal cells in the skin).
  • Inhibitory agents generally bind a protein component and inhibit the Hedgehog signal transduction.
  • Related agents:
    • Vismodegib
    • Sonidegib
    • Glasdegib
  • Indication: basal cell carcinoma
  • Adverse effects: birth defects, dermatologic toxicity

Immune checkpoint inhibitors

  • Immune checkpoints are normally present to prevent the immune system (e.g., T cells) from harming normal cells.
  • With checkpoints present, tumor cells evade immunosurveillance.
  • These drugs allow proliferation and activation of effector T cells by inhibiting immune checkpoints:
    • Programmed cell death 1 (PD-1) activity 
    • Cytotoxic T-lymphocyte antigen 4 (CTLA4)
  • Related agents:
    • Anti-CTLA4 antibody:
      • Ipilimumab
      • Tremelimumab
    • Anti–PD-1 antibody: nivolumab
  • Indications:
    • Colorectal cancer
    • Hepatocellular carcinoma (HCC)
    • Malignant pleural mesothelioma
    • Melanoma
    • NSCLC
    • Renal cell carcinoma
    • Nivolumab is also used for urothelial carcinoma, Hodgkin lymphoma, and gastric cancer.
  • Adverse effects: immune-related effects (e.g., nephritis, pneumonitis)

mTOR inhibitors

  • The mTOR signaling pathway is involved in regulating cell growth, metabolism, and immune cell differentiation.
    • The pathway is abnormally activated in some tumors.
    • Agents inhibit mTOR serine/threonine kinase activity.
    • Inhibition leads to the halting of the cell cycle, decreasing proliferation.
    • Agents also have antiangiogenic effects.
  • Related agents (rapamycin analogs (rapalogs)) and indications:
    • Everolimus:
      • Renal cell carcinoma
      • Prevention of transplant rejection
      • Tuberous sclerosis complex associated partial-onset seizures, renal angiomyolipoma, and subependymal giant cell astrocytoma 
      • Neuroendocrine tumors
      • Breast cancer
    • Temsirolimus: renal cell carcinoma
    • Sirolimus: 
      • Lymphangioleiomyomatosis 
      • Prevention of transplant rejection
  • Adverse effects: 
    • Serious infections
    • Pulmonary toxicity
    • Angioedema
    • ↑ Lipid
    • Secondary malignancy

Proteasome inhibitors

  • Proteasomes are complexes that break down proteins into peptides.
    • Generally affect different signaling pathways
    • An important effect leading to antineoplastic activity involves nuclear factor kappa B (NF-κB) (bound to IκB).
    • Under cellular stress, NF-κB enters the nucleus to activate genes needed for in cell survival
    • Proteasomes degrade IκB to release NF-κB.
    • With inhibition of proteasomes, there is increased apoptosis and decreased survival of cancer cells.
  • Related agents:
    • Bortezomib
    • Carfilzomib
    • Ixazomib
  • Indications: 
    • Multiple myeloma 
    • Bortezomib is also used for mantle cell lymphoma.
  • Adverse effects:
    • Cardiotoxicity
    • Myelosuppression
    • Hepatotoxicity
    • Neuropathy
    • Thrombotic microangiopathy
    • Tumor lysis syndrome (TLS)

Thalidomide and lenalidomide

  • Thalidomide was originally withdrawn owing to teratogenicity and dysmelia.
  • Found to have immunomodulating activity (↓ tumor necrosis factor ɑ, ↑ natural killer cells and interleukin-2) and antiangiogenic effects
  • Related agents and indications:
    • Thalidomide:
      • Multiple myeloma
      • Erythema nodosum leprosum
    • Lenalidomide:
      • Follicular lymphoma
      • Mantle cell lymphoma
      • Marginal zone lymphoma
      • Multiple myeloma
      • Myelodysplastic syndrome

L-asparaginase

  • Leukemic cells require exogenous asparagine for growth.
  • L-asparaginase, an enzyme, depletes serum asparagine (deamidation of asparagine to aspartic acid and ammonia).
  • Indication: ALL
  • Adverse effects:
    • Hepatotoxicity
    • Hemorrhage
    • ↑ Glucose
    • ↑ Lipid

Comparison of Nontraditional Agents

Table: Nontraditional antineoplastic agents
DrugsActivity
Protein kinase inhibitors:
  • BCR-ABL inhibitors
  • BRAF inhibitors
  • MEK inhibitors
  • JAK inhibitors
  • CDK inhibitors
  • BTK inhibitors
  • ALK inhibitors
Inhibit action of protein kinase enzymes
Growth factor receptor inhibitors:
  • EGFR agents
  • VEGFR agents
  • HER2/Neu agents
  • PDGFR agents
  • Monoclonal antibodies bind the extracellular domain, blocking the ligand.
  • Small molecules inhibit kinase activity.
PARP inhibitors↓ DNA repair capability
BCL2 inhibitorsPromote apoptosis of cancer cells (which are dependent on this pathway)
CD20 inhibitorsBind cell surface antigen and initiate B-cell lysis
Hedgehog pathway inhibitorsBind protein component and inhibit the Hedgehog signal transduction, ↓ proliferation of cells (in basal cell carcinoma)
Immune checkpoint inhibitorsInhibit immune checkpoints (CTLA4, PD-1), allowing activation and proliferation of T cells
mTOR inhibitorsInhibit mTOR kinase activity, leading to reduced protein synthesis, cell proliferation and angiogenesis
Proteasome inhibitorsBlock proteasome activity, disrupting signaling and increasing cellular apoptosis
AsparaginaseDepletes asparagine, thus reducing source of leukemic cells
Thalidomide
  • Immunomodulator
  • Antiangiogenesis

References

  1. Bhullar, K. S., et al. (2018). Kinase-targeted cancer therapies: progress, challenges and future directions. Molecular Cancer 17:48. https://doi.org/10.1186/s12943-018-0804-2
  2. Chu, E. (2021). Cancer chemotherapy. Chapter 54 of Katzung, B.G., Vanderah, T.W. (Eds.), Basic & Clinical Pharmacology, 15th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250603422
  3. Cohen, S., Reddy, V. (2021). Janus kinase inhibitors for rheumatologic and other inflammatory disorders: Biology, principles of use and adverse effects. UpToDate. Retrieved Oct 7, 2021, from https://www.uptodate.com/contents/janus-kinase-inhibitors-for-rheumatologic-and-other-inflammatory-disorders-biology-principles-of-use-and-adverse-effects
  4. Katzung, B.G., et al. (Eds.). (2021). Cancer chemotherapy. Chapter 54 of Katzung & Trevor’s Pharmacology: Examination & Board Review, 13th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=3058&sectionid=255307933
  5. Sausville, E.A., Longo, D.L. (2018). Principles of cancer treatment. Chapter 69 of Jameson, J, et al. (Eds.), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192014984
  6. Thomson, R.J., Moshirfar, M., Ronquillo, Y. (2021). Tyrosine kinase inhibitors. StatPearls. https://www.ncbi.nlm.nih.gov/book,s/NBK563322/
  7. Wellstein, A., Giaccone, G., Atkins, M.B., Sausville, E.A. (2017). Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. Chapter 67 of Brunton, L.L., Hilal-Dandan, R., & Knollmann, B.C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=172487438
  8. National Cancer Institute. (2021). Targeted cancer therapies. https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet

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