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 Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins, 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 DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure 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.

Last update:

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

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 Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
      • 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 RAS Renal artery stenosis (RAS) is the narrowing of one or both renal arteries, usually caused by atherosclerotic disease or by fibromuscular dysplasia. If the stenosis is severe enough, the stenosis causes decreased renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS) and leads to renovascular hypertension (RVH). Renal Artery Stenosis-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 Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of 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 CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
  • Related agents:
    • Imatinib
    • 2nd-generation:
      • Dasatinib 
      • Nilotinib 
Table: BCR-ABL kinase inhibitors
Imatinib Dasatinib Nilotinib
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 CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
  • Imatinib, dasatinib: ALL (Ph+)
  • Imatinib:
    • Systemic mastocytosis
    • CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
    • GIST
    • Dermatofibrosarcoma protuberans
    • CEL CEL Chronic eosinophilic leukemia (CEL) is a chronic myeloproliferative neoplasm caused by autonomous clonal proliferation of normal-appearing eosinophils, resulting in increased eosinophils in the peripheral blood and bone marrow. The disorder is a myeloid variant of hypereosinophilic syndrome (HES) and is associated with tissue infiltration leading to end-organ damage. Chronic Eosinophilic Leukemia
    • MDS/MPD
Adverse effects
  • Myelosuppression
  • TLS
  • Hemorrhage
  • Cardiovascular events (heart failure)
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Dermatologic reactions (e.g., SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome, EM)
  • GI irritation
  • Nephrotoxicity
  • Hepatotoxicity
  • Myelosuppression
  • TLS
  • Hemorrhage
  • Cardiovascular events
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Dermatologic reactions
  • Prolonged QT
  • Pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension
  • Myelosuppression
  • TLS
  • Hemorrhage
  • Cardiovascular events
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Prolonged QT
  • Electrolyte imbalance
  • Hepatotoxicity
Contraindications
  • Hypersensitivity to the drug
  • Nilotinib, dasatinib:
    • ↓ K, Mg
    • Prolonged QT
CEL CEL Chronic eosinophilic leukemia (CEL) is a chronic myeloproliferative neoplasm caused by autonomous clonal proliferation of normal-appearing eosinophils, resulting in increased eosinophils in the peripheral blood and bone marrow. The disorder is a myeloid variant of hypereosinophilic syndrome (HES) and is associated with tissue infiltration leading to end-organ damage. Chronic Eosinophilic Leukemia: chronic eosinophilic leukemia Chronic eosinophilic leukemia Chronic eosinophilic leukemia (CEL) is a chronic myeloproliferative neoplasm caused by autonomous clonal proliferation of normal-appearing eosinophils, resulting in increased eosinophils in the peripheral blood and bone marrow. The disorder is a myeloid variant of hypereosinophilic syndrome (HES) and is associated with tissue infiltration leading to end-organ damage. Chronic Eosinophilic Leukemia
EM: erythema multiforme Erythema multiforme Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by targetoid skin lesions with multiple rings and dusky centers. Lesions may be accompanied by systemic symptoms (e.g., fever) and mucosal lesions (e.g., bullae). Erythema Multiforme
GIST: GI stromal tumors
MDS/MPD: myelodysplastic/myeloproliferative diseases
PDGF: platelet-derived growth factor
Ph+: Philadelphia chromosome–positive
SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome: Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome
TLS: tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. 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 RAS Renal artery stenosis (RAS) is the narrowing of one or both renal arteries, usually caused by atherosclerotic disease or by fibromuscular dysplasia. If the stenosis is severe enough, the stenosis causes decreased renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS) and leads to renovascular hypertension (RVH). Renal Artery Stenosis 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
Vemurafenib Dabrafenib*
Pharmacodynamics Inhibit kinase activity of mutated BRAF (including V600 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations)
Pharmacokinetics
  • Oral
  • Half-life: 57 hours (vemurafenib), 8 hours (parent drug: dabrafenib)
  • Excretion: feces
Indications
  • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
  • Erdheim-Chester disease
  • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
  • NSCLC
  • Thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). Thyroid Cancer
Adverse effects
  • Cardiovascular: prolonged QT, hypertension
  • Cutaneous malignancy
  • Uveitis Uveitis Uveitis is the inflammation of the uvea, the pigmented middle layer of the eye, which comprises the iris, ciliary body, and choroid. The condition is categorized based on the site of disease; anterior uveitis is the most common. Diseases of the Uvea
  • Dermatologic reactions
  • Hepatotoxicity
  • Nephrotoxicity
  • Pancreatitis
  • Fibroproliferative disorders
  • Radiation sensitization
  • Cardiovascular: cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies, prolonged QT
  • Cutaneous malignancy
  • Uveitis Uveitis Uveitis is the inflammation of the uvea, the pigmented middle layer of the eye, which comprises the iris, ciliary body, and choroid. The condition is categorized based on the site of disease; anterior uveitis is the most common. Diseases of the Uvea
  • Dermatologic reactions
  • Febrile reactions
  • Hemorrhage
  • ↑ Glucose
  • VTE
Contraindications Hypersensitivity to the drug
*Combination with trametinib produces greater inhibitory activity.
NSCLC: non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. 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
Trametinib Cobimetinib
Pharmacodynamics Inhibits MEK activation and kinase activity
Pharmacokinetics
  • Oral
  • Primarily deacetylation
  • Not a substrate of CYP enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Half-life: 4–5 days
  • Excretion: feces
  • Oral
  • Hepatic metabolism
  • Half-life: 44 hours
  • Excretion: feces
Indications
  • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
  • NSCLC
  • Anaplastic thyroid cancer
Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
Adverse effects
  • Myelosuppression
  • Hepatotoxicity
  • Cardiovascular events (heart failure, ↓ LVEF)
  • Dermatologic reactions
  • Hemorrhage
  • Cutaneous cancers
  • Febrile reactions
  • ↑ Glucose
  • Colitis, GI perforation
  • Ocular: retinal detachment Retinal detachment Retinal detachment is the separation of the neurosensory retina from the retinal pigmented epithelium and choroid. Rhegmatogenous retinal detachment, the most common type, stems from a break in the retina, allowing fluid to accumulate in the subretinal space. Retinal Detachment
  • VTE
  • Myelosuppression
  • Hepatotoxicity
  • Cardiovascular events (heart failure, ↓ LVEF)
  • Dermatologic reactions
  • Hemorrhage
  • Cutaneous cancers
  • Ocular: retinal detachment Retinal detachment Retinal detachment is the separation of the neurosensory retina from the retinal pigmented epithelium and choroid. Rhegmatogenous retinal detachment, the most common type, stems from a break in the retina, allowing fluid to accumulate in the subretinal space. Retinal Detachment, retinopathy
Contraindications Hypersensitivity to the drug
LVEF: left ventricular ejection fraction
NSCLC: non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. 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 Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription (STATs)
    • STATs translocate to the nucleus → transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of 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 Ulcerative colitis Ulcerative colitis (UC) is an idiopathic inflammatory condition that involves the mucosal surface of the colon. It is a type of inflammatory bowel disease (IBD), along with Crohn's disease (CD). The rectum is always involved, and inflammation may extend proximally through the colon. Ulcerative Colitis and rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis)
Table: JAK inhibitors
Ruxolitinib Barcitinib
Pharmacodynamics Inhibit JAKs
Pharmacokinetics
  • Oral
  • Half-life: 3–6 hours (ruxolitinib), 12 hours (baricitinib)
  • Hepatic metabolism
  • Excretion: mostly urine
Indications
  • Polycythemia vera Polycythemia vera Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of RBCs. In addition, the WBC and platelet counts are also increased, which differentiate PV from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia Vera
  • Myelofibrosis
  • Graft-versus-host disease (acute)
  • Rheumatoid arthritis
  • Off-label: COVID-19 hospitalization (requiring oxygen)
Adverse effects
  • Myelosuppression
  • Serious infections
  • ↑ Hepatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Cutaneous cancers
  • ↑ Lipid
  • Myelosuppression
  • Serious infections (including TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis)
  • ↑ Hepatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Cutaneous cancers
  • ↑ Lipid
  • Thrombosis
  • GI perforation
Contraindications Hypersensitivity to the drug
JAK: Janus-associated kinases
COVID-19: coronavirus Coronavirus Coronaviruses are a group of related viruses that contain positive-sense, single-stranded RNA. Coronavirus derives its name from "κορώνη korṓnē" in Greek, which translates as "crown," after the small club-shaped proteins visible as a ring around the viral envelope in electron micrographs. Coronavirus disease 2019

Cyclin-dependent kinase (CDK) inhibitors

  • CDKs are serine/threonine protein kinases that mediate signaling in the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle progression (G0/G1 to S phase) and thus affect cell proliferation.
  • The complex of cyclin D and CDK → phosphorylate the retinoblastoma Retinoblastoma Retinoblastoma is a rare tumor but the most common primary intraocular malignancy of childhood. It is believed that the condition arises from a neuronal progenitor cell. Retinoblastoma can be heritable or nonheritable. Retinoblastoma gene protein (RB1) → processes lead to induction of S-phase genes.
  • Inappropriate cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle progression → tumorigenesis
  • Class of drugs identified by the syllable “-ciclib”
  • Related agents:
    • Palbociclib
    • Abemaciclib
    • Ribociclib
Table: CDK inhibitors
Palbociclib Abemaciclib
Pharmacodynamics CDK inhibitor; prevents progression through the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. 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
Indications Advanced breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
Adverse effects
  • Myelosuppression
  • Pulmonary toxicity
  • ↑ Hepatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Myelosuppression
  • Pulmonary toxicity
  • ↑ Hepatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Thromboembolism
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
Contraindications Hypersensitivity to the drug

Bruton tyrosine kinase (BTK) inhibitors

  • The BTKs are important for the survival, proliferation, chemotaxis, and adhesion of B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. 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
Ibrutinib Acalabrutinib
Pharmacodynamics Inhibit 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 CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia/SLL
  • Mantle cell lymphoma
  • Marginal cell lymphoma
  • Waldenström macroglobulinemia
  • CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia/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 Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
Contraindications Hypersensitivity to the drug
SLL: small lymphocytic lymphoma
TLS: tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. 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 Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. 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
Crizotinib Alectinib Ceritinib
Pharmacodynamics Inhibit 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 Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, nausea and vomiting
  • Hepatotoxicity
  • Pulmonary toxicity
Contraindications Hypersensitivity 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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations)
Table: Monoclonal antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins binding EGFR
Cetuximab Panitumumab
Pharmacodynamics
  • Monoclonal antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins 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 Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer (KRAS wild type or without mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations)
  • Cetuximab: head and neck, squamous cell cancer
Adverse effects
  • Rash (acneiform)
  • Pruritus
  • Headache
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • ↓ Mg
  • Interstitial lung disease
  • Cardiopulmonary arrest
Contraindications Hypersensitivity to drug or its components
Table: Protein tyrosine kinase inhibitors of EGFR
Afatinib Erlotinib Gefitinib
Pharmacodynamics Inhibitor 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
Indications NSCLC (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
Contraindications Hypersensitivity to the drug or its components
EGFR: epidermal growth factor receptor
NSCLC: non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. 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 Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins 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
Bevacizumab Ziv-aflibercept Sorafenib
Pharmacodynamics Monoclonal antibody targeting VEGF ligand Recombinant fusion protein acting as a decoy receptor Inhibit 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 Cervical cancer Cervical cancer, or invasive cervical carcinoma (ICC), is the 3rd most common cancer in women in the world, with > 50% of the cases being fatal. In the United States, ICC is the 13th most common cancer and the cause of < 3% of all cancer deaths due to the slow progression of precursor lesions and, more importantly, effective cancer screening. Cervical Cancer
  • Metastatic CRC
  • Metastatic HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
  • Recurrent GBM
  • NSCLC
  • Ovarian, fallopian tube, peritoneal cancer
  • RCC RCC Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma
Metastatic CRC
  • Advanced HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
  • Advanced RCC RCC Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma
Adverse effects
  • Myelosuppression
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Heart failure
  • Hemorrhage
  • GI perforations
  • ↑ Arterial thromboembolic events (e.g., TIA TIA Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA), stroke)
  • Wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. 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 Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer) as sorafenib ↑ their toxic effects
CRC: colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer
GBM: glioblastoma
HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases: hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
NSCLC: non small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
PDGF: platelet-derived growth factor
RCC RCC Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma: renal cell carcinoma Renal cell carcinoma Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma
TIA TIA Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA): transient ischemic attack Transient ischemic attack Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA)
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 Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins against HER2/Neu:
    • Trastuzumab
    • Pertuzumab
  • TKI: lapatinib
Table: Agents inhibiting HER2
Trastuzumab Pertuzumab Lapatinib
Pharmacodynamics Monoclonal 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 Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer
Breast cancer Breast cancer
Adverse effects
  • Cardiotoxicity: cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies
  • Pulmonary toxicity
  • Renal toxicity
  • Dermatologic reactions
  • Birth defects
  • Cardiotoxicity
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Birth defects
  • Cardiotoxicity
  • Hepatotoxicity
  • Pulmonary toxicity
  • Myelosuppression (with capecitabine)
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Dermatologic reactions
Contraindications Hypersensitivity 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 Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. 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 DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure 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 Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription and cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. 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
Olaparib Rucaparib Niraparib
Pharmacodynamics PARP 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 Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer
  • Metastatic breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Metastatic pancreatic cancer
  • Metastatic prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer
  • Advanced ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer
  • Metastatic, castration-resistant prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer
Ovarian, fallopian tube or primary peritoneal cancer
Common adverse effects
  • Myelosuppression
  • Vomiting
  • Secondary malignancy
Adverse effects
  • Pulmonary toxicity
  • Thromboembolic events
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • ↑ Cholesterol
  • Cardiovascular effects (hypertension)
  • Posterior reversible encephalopathy syndrome
Contraindications Hypersensitivity to the drug None listed Hypersensitivity to the drug

Other Targeted Therapy, Immunotherapy, and Miscellaneous Agents

BCL2 inhibitors

  • The BCL2 protein family is involved in governing programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and 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 CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia, 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 CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia
      • AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia

CD20 inhibitors

  • CD20 is a cell surface antigen in B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells and is found in 90% of B-cell neoplasms.
  • Monoclonal antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins 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 CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia
    • Non- Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. 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 Basal cell carcinoma Basal cell carcinoma is the most common skin malignancy. This cancer arises from the basal layer of the epidermis. The lesions most commonly appear on the face as pearly nodules, often with telangiectatic blood vessels and ulceration in elderly individuals. Basal Cell Carcinoma (uncontrolled proliferation of basal cells in the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin).
  • Inhibitory agents generally bind a protein component and inhibit the Hedgehog signal transduction.
  • Related agents:
    • Vismodegib
    • Sonidegib
    • Glasdegib
  • Indication: basal cell carcinoma Basal cell carcinoma Basal cell carcinoma is the most common skin malignancy. This cancer arises from the basal layer of the epidermis. The lesions most commonly appear on the face as pearly nodules, often with telangiectatic blood vessels and ulceration in elderly individuals. 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 T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells) from harming normal cells.
  • With checkpoints present, tumor cells evade immunosurveillance.
  • These drugs allow proliferation and activation of effector T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells by inhibiting immune checkpoints:
    • Programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and 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 HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases)
    • Malignant pleural mesothelioma Mesothelioma Malignant mesothelioma (usually referred to as simply "mesothelioma") is the malignant growth of mesothelial cells, most commonly affecting the pleura. The majority of cases are associated with occupational exposure to asbestos that occurred > 20 years before clinical onset, which includes dyspnea, chest pain, coughing, fatigue, and weight loss. Malignant Mesothelioma
    • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
    • NSCLC
    • Renal cell carcinoma
    • Nivolumab is also used for urothelial carcinoma, Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. 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 Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. 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 Tuberous sclerosis complex Tuberous sclerosis or tuberous sclerosis complex (TSC) is an autosomal dominant disorder with mainly neurocutaneous symptoms. Mutation in the TSC genes causes excessive tumor-like growths in the brain, eyes, heart, kidney, and lungs. Cutaneous manifestations include hypopigmentation (i.e., ash leaf spots, confetti lesions) or excessive growth (i.e., angiofibroma, shagreen patch). Tuberous Sclerosisassociated partial-onset seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, renal angiomyolipoma, and subependymal giant cell astrocytoma Astrocytoma Astrocytomas are neuroepithelial tumors that arise from astrocytes, which are star-shaped glial cells (supporting tissues of the CNS). Astrocytomas are a type of glioma. There are 4 grades of astrocytomas. Astrocytoma 
      • Neuroendocrine tumors
      • Breast cancer
    • Temsirolimus: renal cell carcinoma Renal cell carcinoma Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma
    • Sirolimus: 
      • Lymphangioleiomyomatosis 
      • Prevention of transplant rejection
  • Adverse effects: 
    • Serious infections
    • Pulmonary toxicity
    • Angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. 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 Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. 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 Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ɑ, ↑ natural killer cells and interleukin-2) and antiangiogenic effects
  • Related agents and indications:
    • Thalidomide:
      • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
      • Erythema nodosum Erythema nodosum Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum leprosum
    • Lenalidomide:
      • Follicular lymphoma
      • Mantle cell lymphoma
      • Marginal zone lymphoma
      • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. 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
Drugs Activity
Protein kinase inhibitors:
  • BCR-ABL inhibitors
  • BRAF inhibitors
  • MEK inhibitors
  • JAK inhibitors
  • CDK inhibitors
  • BTK inhibitors
  • ALK inhibitors
Inhibit action of protein kinase enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
Growth factor receptor inhibitors:
  • EGFR agents
  • VEGFR agents
  • HER2/Neu agents
  • PDGFR agents
  • Monoclonal antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins bind the extracellular domain, blocking the ligand.
  • Small molecules inhibit kinase activity.
PARP inhibitors DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure repair capability
BCL2 inhibitors Promote apoptosis of cancer cells (which are dependent on this pathway)
CD20 inhibitors Bind cell surface antigen and initiate B-cell lysis
Hedgehog pathway inhibitors Bind protein component and inhibit the Hedgehog signal transduction, ↓ proliferation of cells (in basal cell carcinoma Basal cell carcinoma Basal cell carcinoma is the most common skin malignancy. This cancer arises from the basal layer of the epidermis. The lesions most commonly appear on the face as pearly nodules, often with telangiectatic blood vessels and ulceration in elderly individuals. Basal Cell Carcinoma)
Immune checkpoint inhibitors Inhibit immune checkpoints (CTLA4, PD-1), allowing activation and proliferation of T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
mTOR inhibitors Inhibit mTOR kinase activity, leading to reduced protein synthesis, cell proliferation and angiogenesis
Proteasome inhibitors Block proteasome activity, disrupting signaling and increasing cellular apoptosis
Asparaginase Depletes 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

USMLE™ is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). MCAT is a registered trademark of the Association of American Medical Colleges (AAMC). NCLEX®, NCLEX-RN®, and NCLEX-PN® are registered trademarks of the National Council of State Boards of Nursing, Inc (NCSBN®). None of the trademark holders are endorsed by nor affiliated with Lecturio.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

User Reviews

0.0

()

¡Hola!

Esta página está disponible en Español.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details