SERMS and Aromatase Inhibitors

SERMS

• Tamoxifen exhibits tissue-specific estrogenic and antiestrogenic properties
• Mimics estrogen effects in bone tissue
  • This may increase bone mineral density
• Administered orally
• Uses
  • HR-positive breast cancer
  • Used to prevent further breast cancer in women who have ductal carcinoma in situ
  • Prevents breast cancer in women who are at high risk
• Side effects
  • Menopausal symptoms occur
    • can include hot flashes, night sweats, vaginal dryness, or menstrual changes
  • Increases the risk of blood clots
  • Estrogenic effects
    • Can increase the risk of uterine and endometrial cancer
• Fulvestrant is an Estrogen receptor antagonist without known agonist effects
• Degrades estrogen receptors (SERD)
• Administered via IM injection
• Uses
  • ER-positive breast cancer in postmenopausal women
  • Can be used as monotherapy or with abemaciclib or palbociclib
• Side effects can include menopausal symptoms

Aromatase Inhibitors

• Exemestane is steroidal
• Administered orally
• Used for ER-positive breast cancer in postmenopausal women, sometimes following tamoxifen therapy
• Side effects:
  • Menopausal symptoms
  • Androgenic properties causing acne and/or weight gain
• Anastrozole
  • Nonsteroidal
  • Administered orally
  • Treats HR-positive postmenopausal breast cancer
  • Used for the prevention of breast cancer in those who are at high risk
• Side effects include:
  • Menopausal symptoms
  • Increased risk of heart disease and osteoporosis
• Letrozole
  • Nonsteroidal, competitively and reversibly binds to the heme of P450 unit
  • Administered orally
  • Treats HR-positive breast cancer in postmenopausal women after tamoxifen therapy
• Side effects include:
  • Hypoestrogenism, also called menopausal symptoms
  • Increased risk of osteoporosis

Anti-HER2

• Trastuzumab is IgG1
• Binds to and blocks extracellular domain of HER2 receptors causing cell arrest
• Disrupts dimerization and activation, downregulates signaling pathways.
• Trastuzumab induces immune cells to kill tumor cells via ADCC that causes recycling of HER2
• Uses include:
  • HER2-positive breast cancer
  • Gastric and gastroesophageal cancers
• Administered for up to one year weekly or every 3 weeks by IV infusion
  • No additional benefits beyond one year
• Side effects:
  • Flu-like symptoms, cardiac toxicity, teratogenic
  • Cardiac toxicity is due to downregulation of certain proteins that are essential for the survival of cardiomyocytes and maintenance of cardiac function
    • can lead to ventricular dysfunction and CHF
• Pertuzumab is IgG1
• Targets extracellular domain of HER2, a different epitope than trastuzumab
• Uses
  • Treats HER2-positive breast cancer as both neoadjuvant and adjuvant therapy
  • Injected every 3 weeks
  • Used in combination with trastuzumab and docetaxel
• Side effects:
  • Can cause cardiac toxicity which may cause left ventricular dysfunction
• Trastuzumab Emtansine (ado trastuzumab) is an Anticancer antibody-drug conjugate (ADC)
• Exhibits anti-HER2 activity and targets intracellular delivery of the potent anti-microtubule agent to produce cell cycle arrest and apoptosis
• Administered via IV injection
• Uses
  • HER2-positive breast cancer for those who've already tried taxane and/or trastuzumab or cancer has recurred within 6 months of adjuvant treatment
• Side effects
  • BBW is as follows: hepatotoxicity, teratogenicity, cardiac toxicity
• Trastuzumab deruxtecan is an antibody-drug conjugate
• Exhibits anti-HER2 IgG1 activity in combination with topoisomerase I inhibitor
• Uses for HER2-positive breast cancer
  • patients who have received two or more prior anti-HER2 based regimens
  • HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received prior trastuzumab regimen
• Side effects:
  • Pulmonary toxicity symptoms may show as interstitial lung disease
  • May also cause Teratogenicity and cardiotoxicity, especially with prior anthracycline exposure

HER2 Tyrosine Kinase Inhibitors

• Lapatinib inhibits ERBB-driven tumor cell growth
• Commonly used with capecitabine
• Will not show cross resistance with trastuzumab
• Uses
  • Treats HER2-positive breast cancer that has progressed after treatment with other agents
• Possible side effects include elevated liver enzymes
• Neratinib binds to and irreversibly inhibits HER2 preventing autophosphorylation of tyrosine residues and reduces oncogenic signaling pathways
• Uses
  • Treats HER2-positive breast cancer
  • Commonly given with capecitabine
• Side effects
  • Life-threatening diarrhea, hepatotoxicity, or teratogenic effects
• Tucatinib inhibits phosphorylation of HER2 leading to downstream changes in signaling pathways
• Uses
  • Treats HER2-positive breast cancer + trastuzumab + capecitabine -HER2-positive colorectal cancer following tx with 5-FU, oxaliplatin, and irinotecan chemotherapy
• Side effects include hepatotoxicity

Anti-EGFR

• Cetuximab is IgG1
• Competitively binds to EGFR and competitively inhibits binding of EGF
• Cetuximab causes ADCC
• Uses
  • EGFR-positive head and neck squamous cell carcinoma
  • EGFR-positive CRC
• Side effects:
  • Infusion reactions that are serious and fatal
  • cardiopulmonary arrest or sudden death
  • Pulmonary toxicities include interstital lung disease, interstitial pneumonitis, and exacerbation of pre-existing fibrotic lung disease
• Panitumumab: IgG2 – no immunologic-mediated effects
• Competitively inhibits binding of ligands for EGFR
• Uses include CRC (colorectal cancer)
• Side effects include serious skin, ocular, and mucosal related toxicities
• Necitumumab: -Is IgG1 -Binds EGFR and induces receptor internalization and degradation preventing further activation of EGFR
• Uses:
  • First line for NSCLC + cisplatin + gemcitabine
• Side effects:
  • Poor safety profile and major limitations
  • Cardiopulmonary arrest, venous and arterial thromboembolic events, dermatologic toxicities, and teratogenic

EGFR Tyrosine Kinase Inhibitors

• Erlotinib, Afatinib, and Osimertinib
  • Targets T790M mutation in EGFR
  • Oral route of administration (CYP3A4)
  • Inhibit intracellular autophosphorylation of tyrosine associated with EGFR
  • Afatinib: potent, selective and irreversible ErbB family blocker
• Uses:
  • treats NSCLC (Non-small cell lung cancer)
  • Erlotinib treats pancreatic cancer
• Side effects:
  • pulmonary toxicity, or teratogenicity

Anti-VEGFR

• Ramucirumab
  • An IgG1 against VEGFR2
  • Binds to receptor and prevents VEGF-stimulated receptor phosphorylation and downstream ligand-induced proliferation
• Uses:
  • Gastric or gastroesophageal junction adenocarcinoma as monotherapy or with paclitaxel after prior fluoropyrimidine or platinum therapy
• Side effects:
  • Arterial thromboembolic events, HTN, infusion-related reactions, GI perforation
• Bevacizumab
  • Targets VEGF itself rather than the receptor preventing it from binding to its VEGFR
  • Prevents formation of new blood vessels, decreases tumor vasculature, reduces tumor blood supply
• Uses:
  • Treating CRC, NSCLC, and breast cancer
• Side effects:
  • Linked to impaired VEGF function, which results in HTN, thromboembolic events, bleeding, GI perforation, and wound healing complications

VEGFR Tyrosine Kinase Inhibitors

• Sorafenib, Sunitinib, and Pazopanib
  • Target angiogenesis via inhibition of VEGFR
  • Oral administration (CYP3A4)
• Uses:
  • Renal cell carcinoma, hepatocellular carcinoma, GI stromal tumor (GST), thyroid cancer
• Side effects:
  • Hand-foot syndrome, CHF, hepatotoxicity, HTN

CDK Inhibitors

• Palbociclib
  • A CDK4/6 inhibitor
  • Ensures that the cyclin D-CDK4/6 complex cannot aid in phosphorylating Rb which prevents cell from passing R and exiting G1
  • Oral administration (CYP3A4)
• Uses:
  • Treats HR+/HER-negative breast cancer often, can be used with letrozole or fulvestrant
  • Treats head and neck cancer, brain cancer, colon cancer, and solid tumors
• Side effects:
  • Opportunistic infections, pulmonary embolism, teratogenic
• Ribociclib
  • CDK4/6 inhibitor
  • Ensures that the cyclin D-CDK4/6 complex cannot aid in phosphorylating Rb which prevents cell from passing R and exiting G1
• Uses:
  • Treats HR +/HER-negative breast cancer in postmenopausal women, can be used with letrozole or fulvestrant -Treats prostate cancer and solid tumors
• Abemaciclib is A CDK4/6 inhibitor -Ensures that the cyclin D-CDK4/6 complex cannot aid in phosphorylating Rb which prevents cell from passing R and exiting G1
  • Administered orally (CYP3A4)
• Uses:
  • Treats HR+/HER-negative breast cancer
  • Usable as monotherapy
  • Treats lung, brain, colon, and other solid tumors
  • Side effects include infections such as leukopenia, neutropenia, anemia, and thrombocytopenia
• Trilaciclib
  • a CDK inhibitor which has been FDA approved for mediating chemotherapy-induced side effects
  • Improves patient's quality of life during cancer treatment by reducing risk of chemo-induced myelosuppression
  • Temporarily stops hematopoietic stem cells from progressing through the cell cycle, protecting them from cytotoxicity
• Side effects include low levels of calcium, potassium, phosphate, and pneumonia

MEK Inhibitors

• Binimetinib is Reversible, that is noncompetitive with ATP, and is a MEK1/2 inhibitor
• Uses:
  • Treats melanoma related to a BRAF V600E or V600K mutation
  • treats NSCLC with BRAF V600E mutation combined with encorafenib
• Side effects include teratogenic effects, eye and vision problems
• Cobimetinib is a Reversible inhibitor, acts on MEK1/2
• Uses:
  • treats BRAF V600E mutated melanoma combined with vemurafenib to achieve a synergistic effect
• Side effects include photosensitivity, and eye problems
• Trametinib
  • Reversible, selective, allosteric inhibitor of MEK1/2
  • Blocks catalytic activity of MEKs
• Uses:
  • Can be used alone, often with dabrafenib for melanoma and NSCLC with BRAF mutations, which is used for a synergistic effect
• Side effects:
  • HTN, hemoptysis, and eye problems

BRAF Inhibitors

• Encorafenib
  • An ATP competitive BRAF kinase inhibitor
  • Inhibits several phosphorylation of other proteins and downregulates cyclin D1 which arrests the cell cycle in G1 phase, which induces senescence without apoptosis
  • Only effective in melanomas with BRAF V600E mutation
• Uses:
  • with binimetinib: Treats melanoma related to BRAF V600E or V600K mutation and NSCLC with BRAF V600E mutation
  • with cetuximab: Treats colorectal cancer with BRAF V600E mutation
• Side effects:
  • Cutaneous squamous cell carcinoma, teratogenic effects, QT changes, HTN
• Vemurafenib
  • Competitive inhibitor of mutated BRAF kinase
  • Blocks downstream processes to inhibit tumor growth and eventually trigger apoptosis
  • Administered orally
• Uses:
  • treats melanoma with BRAF V600 mutation
• Side effects:
  • cutaneous squamous cell carcinoma
• Dabrafenib
  • Competitive reversible BRAF kinase inhibitor given by binding to ATP pocket
• Uses:
  • As monotherapy: Treats melanoma with BRAF V600E mutation as detected by FDA approved test
  • With trametinib: treats NSCLC, thyroid cancer, pediatric glioma with V600E mutation
• Side effects:
  • Photosensitivity, or cutaneous squamous cell carcinoma

Bcr-Abl Tyrosine Kinase Inhibitors

• Imatinib
  • Inhibits Bcr-Abl tyrosine kinase by binding to ATP pocket in the active site
  • Thus prevents downstream ATP phosphorylation of kinase substrate protein
  • Administered orally
• Uses:
  • treats CML and ALL with Philadelphia chromosome mutation (Ph+)
  • treats GIT tumors expressing related mutations (c-Kit) TK
• Side effects:
  • Bleeding gums, blood in stools, hematuria, CHF
• Nilotinib, Dasatinib, Bosutinib, and Ponatinib
  • inhibits Bcr-Abl tyrosine kinase by binding to ATP pocket in active site preventing downstream ATP phosphorylation of kinase substrate protein
• Uses: treats CML and ALL with Philadelphia chromosome mutation (Ph+)
• Side effects: Myelosuppression

PD-1 Inhibitors

• Pembrolizumab:
  • An IgG4
  • Checkpoint inhibitor that blocks protective mechanism of cancer cells that evade the immune system
  • Enhanced tumor immunosurveillance, immune reactivity, and the anti-tumor immune response
  • Targets PD-1 receptor on T cells
  • Administered with IV infusion
• Uses:
  • HER2-negative: Treats breast cancer, melanoma, NSCLC, bladder, cervical, head and neck, and Hodgkin's lymphoma
  • Treats HER2-positive gastric or gastroesophageal cancers combined with trastuzumab, 5-FU, and cisplatin
• Side effects:
  • Severe immune-related adverse effects
  • Lung inflammation and inflammation of endocrine organs including thyroid and pancreas
• Nivolumab is IgG4
  • Checkpoint inhibitor that blocks protective mechanism of cancer cells and allows them to evade the immune system
  • Enhanced tumor immunosurveillance, immune reactivity, and anti-tumor immune response
  • Targets PD-1 receptor on T cells.
• Uses:
  • treats Melanoma, NSCLC, SCLC, renal cell carcinoma, Hodgkin lymphoma, squamous cell carcinoma of head and neck, urothelial carcinoma, CRC, hepatocellular carcinoma, esophageal cancer
  • HER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma + 5-FU and platinum therapy, and first line for urothelial carcinoma + cisplatin and gemcitabine
• Side effects:
  • Severe immune-mediated inflammation can occur in the lungs, thyroid, pancreas, colon, liver, kidneys, and eye, which is called iridocyclitis

PD-L1 Inhibitors

• Durvalumab
  • Is IgG1
  • Immune checkpoint inhibitor against PD-L1
• Uses:
  • Treats Urothelial carcinoma and NSCLC
• Side effects:
  • Bladder pain, urge to urinate, bloody urine, immune-mediated reactions, and possible teratogen
• Avelumab is IgG1
• Uses:
• Urothelial carcinoma after platinum therapy, Merkel cell carcinoma, and renal cell carcinoma
• Side effects:
• Musculoskeletal and joint pain, peripheral edema, and infusion-related reactions
• Has Uses

Anti CTLA-4

• Ipilimumab is an IgG1
• Disables off-switch on T cells, prevents cancer cells from delivering suppressive signals to T cells and activates the immune response to attack cancer cells
• Uses:
• Treats Melanoma or Melanoma with nivolumab for other cancers
• Side effects:
• Severe and potentially fatal immunological adverse effects occur
• Checkpoint inhibitor-induced colitis and severe neurologic disorders may occur

Anti CD-20

• Rituximab:
  • Is an IgG1
  • Targets CD20 on malignant B cells
• Uses:
  • Treats CD20-positive B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia(CLL), and rheumatic arthritis
  • Gene testing restrictions apply
• Side effects:
  • May commonly cause Anemia and neutropenia.
• Ofatumumab
  • IgG1
  • Targets different epitope than rituximab
  • Causes cytotoxicity by means of both CDC and ADCC
  • Causes rapid B cell depletion
• Uses:
  • In Certain types of CLL
• Side effects:
  • Infections, anemia, neutropenia, and lymphopenia BBW is potential risk for causing progressive multifocal leukoencephalopathy and hepatitis B reactivation

Anti CD-52

• Alemtuzumab is IgG1
• Tags lymphocytes for destruction
• Depletes circulating T and B cells
• Activation of ADCC and complement-mediated lysis
• Binds to Ag, which causes other immune cells to recognize the cell-bound Ag and trigger lysis and apoptosis
• Uses:
• treats CLL and MS
• Side effects:
• Upper respiratory tract infections, UTIs, and herpes virus infections

Anti CD-38

• Daratumumab
  • IgG1
  • Binds to CD38 causing cells to undergo the process of apoptosis via ADCC, CDC, or ADC
  • Binds to is a different epitope than isatuximab
• Uses:
  • multiple myeloma
• Side effects:
  • Susceptibility to bacterial/viral infections due to killing of NK cells
  • Frequently causes CMV reactivation
• Isatuximab
  • IgG1
  • Binds to CD38 causing cells to undergo apoptosis via ADCC, CDC or ADC
• Uses:
  • Relapsed or refractory multiple myeloma
• Side effects:
  • Neutropenia, infusion reactions, pneumonia, and upper respiratory tract infections

Radioimmunotherapy

• Ibritumomab tiuxetan is IgG1
• Binds to is directed against CD20 antigen on B cells allowing radioactive yttrium to destroy the cells via production of beta emission -Antibody may trigger ADCC, CDC and apoptosis
• Uses are non-Hodgkin's lymphoma
• Side effects:
  • Myelosuppression, SJS, avoid live vaccines, and infusion-related effects

Anti-SLAMF7

• Elotuzumab:
• Is a IgG1
• Immunostimulant effect and directly activates NK cells through the SLAMF7 pathway and Fc receptors
• Targets SLAMF7 of myeloma cells and flagging them for NK cell-mediated destruction through ADCC
• Uses:
• Multiple myeloma + lenalidomide, used for synergistic effect and enhanced activation of NK cells
• Side effects:
• Peripheral neuropathy
• dinutuximab and dinutuximab beta
  • are IgG1s
• Uses: treats Pediatric neuroblastoma
• Side effects: Severe neuropathic pain and possible teratogen Binding action

IMiDs

• Thalidomide, lenalidomide, and pomalidomide
  • Are Cereblon E3 ubiquitin ligase modulators Binds to cereblon in the E3 ubiquitin ligase complex and changes which substrates can be ubiquitinated
  • Degrades transcription factors IKZF3 and IKZF1 Enhances T cell and NK cell-mediated immunity Modulates and inhibits the release of inflammatory mediators Antiangiogenic effects that involve VEGF
• Uses: Treats first line multiple myeloma, use with dexamethasone
• Side effects: Has severe teratogenicity -Enantiomers switch in vivo -Increased risk of infection that may cause liver damage

###IMiDs

• Thalidomide, lenalidomide, and pomalidomide are Cereblon E3 ubiquitin ligase modulators
• Bind to cereblon in the E3 ubiquitin ligase complex and changes which substrates can be ubiquitinated.
• Degrades transcription factors IKZF3 and IKZF1 Enhances T cell and NK cell-mediated immunity.
• Modulates and inhibits the release of inflammatory mediators with antiangiogenic effects that involve VEGF
• Uses:
  • treats First line multiple myeloma, use with dexamethasone
• Side effects:
  • REMS requirements for both men & women
  • The Enantiomers switch in vivo - this means that one enantiomer may be the safe one, but in the body it may switch to an unsafe enantiomer
  • increased risk of infection with Liver damage

26 Proteasome Inhibitors

• 26S proteasome is a protein complex that degrades ubiquitinated proteins within the ubiquitin-proteasome pathway
• causes of abnormal or misfolded cell proteins.
• Cause reversible/irreversible inhibition of 26S leading to cell cycle arrest and apoptosis May prevent degradation of pro-apoptotic factors
• Use/Treat multiple myeloma with thalidomide and dexamethasone
• Bortezomib is given by injection
• a Reversible inhibitor Boron Binds catalytic site of 26S with high affinity, causing changes in levels.
• Side Effects:*
• Peripheral neuropathy and pain dose. Carfilzomib :Injection /Irreversible inhibitor. Ixazomib: Oral/Reversible inhibitor.

Antiparasitic Drugs

• Nitroimidazoles (metronidazole, secnidazole, tinidazole)

  • prodrugs that enter cells via passive diffusion to form nitroso radicals that disrupt/inhibit the cell process

• Uses:

  • Treating trichomoniasis, bacterial infections, and preventing postoperative infections, including the H pylori virus Caps, can be supppository

• Side Effects:

  • Can have a metallic taste/Possible carcinogen.
    • Used for infections only

• Pyrimethamine (anti- parasitic)

• Folic acid antagonists/interfere with DNA synthesis

• competitive inhibitors for DNA synthesis

  • used in patients with HIV

• Sulfadiazine anti viral medication

• Side Effects:

• GI symptoms/Anemia

Antihelminites

• Mebendazole;
• Caused by cell walls/mitotic changes Enteobius vermicularis
• Headaches/Acute Inflamtion