Targeted Cancer Therapies - Drugs & Concepts

Azacitidine

*CLASS:* *Chemical Inhibitors - Epigenetic Pathway Inhibitors: DNMT Inhibitors* *MECHANISM OF ACTION:* -A chemical analogue of cytidine (C), a nucleoside present in DNA and RNA. -Covalently binds between the C6 atom of the cytosine (C) and the DNMTs, inhibiting DNMTs -*Triggers DNA damage signaling resulting in the degradation of trapped DNMTs* -Leading to loss of methylation marks of DNA (hypomethylation of DNA). -*Also, incorporates into RNA, leading to the dissembly of polyribosomes, and inhibition of the production of protein* *INDICATION:* -*myelodysplastic syndrome (MDS)* -*Tx of HIV and HTLV* *ADVERSE:* -Myelosuppression, GI (diarrhea, constipation), skin (pale skin, easy bruising or bleeding) *PK:* *Route:* IV or injection under the skin

Decitabine

*CLASS:* *Chemical Inhibitors - Epigenetic Pathway Inhibitors: DNMT Inhibitors* *MECHANISM OF ACTION:* -A chemical analogue of cytidine (C). -*Deoxy derivative of azacitidine* -*MOA similar to azacitidine* -*Decitabine can only be incorporated into DNA strands while azacitidine can be incorporated into both DNA and RNA chains* *INDICATION:* -*myelodysplastic syndrome (MDS)* *ADVERSE:* -*Same as Azacitidine* -Myelosuppression, GI (diarrhea, constipation), skin (pale skin, easy bruising or bleeding) *PK:* *Route:* IV or injection under the skin

Vorinostat

*CLASS:* *Chemical Inhibitors - Epigenetic Pathway Inhibitors: HDAC inhibitor* Also known as suberanilohydroxamic acid (suberoyl+anilide+ hydroxamic acid abbreviated as *SAHA*) *MECHANISM OF ACTION:* -Binds to the active site of HDACs [HDAC is frequently overactive in tumor cells] -*Acts as a chelator for Zinc ions in the active site of HDACs* -Results in the accumulation of acetylated histones and acetylated proteins. *INDICATION:* -*Cutaneous T cell lymphoma (CTCL)* *ADVERSE:* -*Edema* -Fatigue - GI (diarrhea, constipation) -Proteinuria *PK:* *Route:* Oral

Imatinib (Gleevac)

*CLASS:* *Chemical Inhibitors - Protein Kinase Inhibitors* *MECHANISM OF ACTION:* -*Inhibits Bcr-Abl tyrosine kinase and other receptor tyrosine kinases*, e.g. platelet-derived growth factor receptor (PDGFR), stem cell factor, and c-kit. -Prevents phosphorylation of the kinase substrates by ATP. *INDICATION:* -*CML* -*Philadelphia chromosome-positive ALL, AML* *Note:* Philadelphia (Ph) chromosome is found in >95% of CML; 25-30% of adult ALL (acute lymphoblastic leukemia), 2-10% in pediatric ALL, occasionally in AML (acute myelogenous leukemia) -CML = Chronic myelogenous leukemia = A pluripotent hematopoietic stem cell disorder characterized by the t(9:22) Philadelphia chromosomal translocation. *Philadelphia CreaML cheese* *ADVERSE:* -Acute toxicity: N/V -Delayed toxicity: *Myelosuppression, GI, skin, fluid retention with ankle and periorbital edema*, diarrhea, myalgias, congestive heart failure *PK:* *Route:*Oral *Metabolism:* -Metabolized in the liver, mainly by the CYP3A4 liver microsomal enzyme. *Elimination:* -In feces via the hepatobiliary route (biliary excretion)

Erlotinib

*CLASS:* *Chemical Inhibitors - Protein Kinase Inhibitors* *MECHANISM OF ACTION:* -*Inhibits EGFR tyrosine kinase leading to inhibition of EGFR signaling* *INDICATION:* -*Non-small cell lung cancer* *ADVERSE:* -Acute toxicity: Diarrhea -Delayed toxicity: Skin rash, diarrhea, anorexia, *interstitial lung disease* *PK:* *Route:* Oral *Metabolism:* Metabolized in the liver by the CYP3A4 enzyme system *Caution must be taken when using these agents with drugs that are also metabolized by the liver CYP3A4 system, such as phenytoin and warfarin* *Elimination:* Hepatic, excretion in feces

Crizotinib

*CLASS:* *Chemical Inhibitors - Protein Kinase Inhibitors* *MECHANISM OF ACTION:* -Functions as an *ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor* -Compete for binding within the ATP-binding pocket of target kinases -~ 4% of patients with non-small cell lung carcinoma (NSCLC) have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK, leading to constitutive ALK kinase activity that contributes to carcinogenesis. -Inhibits the fusion ALK kinase activity and the growth, migration, and invasion of malignant cells. *INDICATION:* -*non-small cell lung carcinoma (NSCLC)* *ADVERSE:* -N/V -rash or diarrhea -trail of lights phenomena (Trails' from lights in peripheral vision in low light conditions) *PK:* *Route:*Oral

Bortezomib

*CLASS:* *Chemical Inhibitors- Proteosome Inhibitors* *Note:The first therapeutic proteasome inhibitor to be tested in humans* *MECHANISM OF ACTION:* -*The boron atom in bortezomib binds the catalytic site of the 26S proteasome* -The 26S proteosome plays a role in maintaining the immortal phenotype of myeloma cells, and in solid tumor cancers. *INDICATION:* -*Multiple Myeloma* *ADVERSE:* -*Peripheral neuropathy* -Gastro-intestinal (GI) effects (constipation, nausea)* -Myelosuppression -Neutropenia -Thrombocytopenia -Shingles -Asthenia *PK:* *Route:* IV

Everolimus

*CLASS:* *Chemical Inhibitors- mTOR inhibitors* *MECHANISM OF ACTION:* -*Works as an inhibitor of mammalian target of rapamycin (mTOR)* -*Binds to its protein receptor FKBP12 (FK506 binding protein 12), which directly interacts with mTORC1, inhibiting its downstream signaling* *INDICATION:* -*Renal cell carcinoma* -ER+/HER2- breast cancer -*Immunosuppressant to prevent rejection of organ transplants* *ADVERSE:* -*Lung or breathing problems* -Infections -Kidney failure -Delayed wound healing *PK:* *Route:* Oral *Metabolism:* Metabolized hepatically via CYP450 3A4

Temsirolimus

*CLASS:* *Chemical Inhibitors- mTOR inhibitors* *MECHANISM OF ACTION:* -A mTOR inhibitor and an immunosuppressive agent as well -*SAME MOA AS EVEROLIMUS* -*Works as an inhibitor of mammalian target of rapamycin (mTOR)* -*Binds to its protein receptor FKBP12 (FK506 binding protein 12), which directly interacts with mTORC1, inhibiting its downstream signaling* *INDICATION:* -*Renal cancer* -Breast cancer *ADVERSE:* -fatigue, skin rash, stomatitis, hematologic abnormalities *PK:* *Route:* IV

All-trans-retinoic acid (ATRA)

*CLASS:* *Differentiation Agents* *MECHANISM OF ACTION:* -*A derivative of vitamin A* -*In most APL (acute promyelocytic leukemia ) cases, RAR-alpha (retinoic acid receptor-alpha) gene on chromosome 17 has a reciprocal translocation with the PML (promyelocytic leukemia) gene on chromosome 15, a translocation denoted as t(15;17)(q22;q21). -The fusion PML-RAR-alpha hybrid protein binds to DNA, blocking transcription and differentiation of granulocytes -ATRA can inhibit the binding of PML-RAR-alpha on DNA, and promote transcription and differentiation of granulocytes *INDICATION:* -*Cancer: Used exclusively in acute promyelocytic leukemia (APL) (AML subtype M3)* -Non Cancer: Dermatology, acne treatment. *ADVERSE:* -*Retinoid acid syndrome:* fever, wt gain, respiratory distress, pleural effusions, pulmonary infiltrates, rapidly increased white blood cell -The etiology of retinoic acid syndrome has been attributed to capillary leak syndrome from cytokine release from the differentiating promyelocytes. *PK:* *Route:* Oral

Flutamide

*CLASS:* *Hormone Therapy - non-steroidal antiandrogen drug* *MECHANISM OF ACTION:* -*An antagonist of the androgen receptor (AR)* -Competing with testosterone and its metabolite, dihydrotestosterone (DHT) for binding to ARs in the prostate gland. -Prevents testosterone from stimulating the prostate cancer cells to grow. *INDICATION:* -*Androgen-dependent Prostate Cancer* *ADVERSE:* -Gynecomastia -Mild liver injury -Gastrointestinal side effects *PK:* *Route:* Oral

Abiraterone

*CLASS:* *Hormone Therapy* *MECHANISM OF ACTION:* -An androgen production inhibitor from non-gonadal source -Formulated as the prodrug abiraterone acetate. -*Inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1)*, an enzyme expressed in testicular, adrenal, and prostatic tumor tissues. *Inhibits two sequential reactions:* -Pregnenolone ->17-α-hydroxy Pregnenolone using *17 α-hydroxylase activity* -Form dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its *C17,20 lyase activity* *INDICATION:* -*Castration-resistant (formerly hormone-resistant or hormone-refractory) prostate cancer* -*Androgen-independent prostate cancer* *ADVERSE:* -UTI -Hypokalaemia -Hypertension -Diarrhea -Peripheral edema *PK:* *Route:* Oral w/ food *Metabolism:* -Prodrug Abiraterone acetate is cleaved to release free Abiraterone by plasma esterases in the bloodstream

Leuprolide

*CLASS:* *Hormone Therapy- GnRH and LH-RH analog* *MECHANISM OF ACTION:* -*Acts as an agonist at pituitary GnRH receptors* -Indirectly downregulates the secretion of gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). -Leading to reduction in estradiol and testosterone levels in both sexes. *INDICATION:* -Hormone response cancers: *breast cancer and prostate cancer* -Estrogen-dependent conditions (such as endometriosis or uterine fibroids), to treat precocious puberty, and to control ovarian stimulation in In Vitro Fertilization (IVF) -*Non cancer: chronic adrenal disease* *ADVERSE:* -bone pain -gynecomastia -hematuria -impotence -testicular atrophy *PK:* *Route:* Slow release implant or subcutaneous/IM injection

Raloxifene

*CLASS:* *Hormone Therapy- SERM* *MECHANISM OF ACTION:* -Has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast. *INDICATION:* -*Breast cancer in post-menopausal women* -*Prevention of osteoporosis in post-menopausal women* *ADVERSE:* -Blood clots -Leg swelling/pain -Trouble breathing -Chest pain -Vision changes -Developmental abnormalities such as birth defects *ADVANTAGE:* -*It does not to promote endometrial cancer* -*does not increase the risk of cataracts* *(different from Tamoxifen)* *PK:* *Route:* Oral

Tamoxifen

*CLASS:* *Hormone Therapy- SERMs* (selective estrogen-response modulators) *MECHANISM OF ACTION:* -*An antagonist of the estrogen receptor* -Metabolized into compound (4-hydroxytamoxifen) that also binds to the estrogen receptor but do not activate it. -Preventing estrogen from binding to its receptor. Hence breast cancer cell growth is blocked. *INDICATION:* -*Breast Cancer [nearly all pre-menopausal women with hormone receptor-positive (ER+) breast cancer)* -McCune-Albright syndrome -Infertility -Gynecomastia -Bipolar disorder *ADVERSE:* -*Increase the risk of endometrial cancer* -Blood clots -CNS: reduced cognition -Risk of cataracts *PK:* *Route:* Oral *Metabolism:* -*A prodrug*, having relatively little affinity for its target protein, the estrogen receptor -Metabolized in the liver by the cytochrome P450 isoform CYP2D6 and CYP3A4 into active metabolites which have 30-100 times more affinity with the estrogen receptor than tamoxifen itself

Bicalutamide

*CLASS:* *Hormone Therapy- non-steroidal antiandrogen* *INDICATION:* -*Androgen-dependent Prostate Cancer* *ADVANTAGES:* -*Less side effects compared to Flutamide* (often used instead of Flutamide *PK:* *Route:* Oral

Anastrozole

*CLASS:* *Hormone therapy- non-steroidal aromatase inhibitor* *MECHANISM OF ACTION:* -*Binds reversibly to the aromatase enzyme through competitive inhibition* -Inhibits the conversion of androgens to estrogens in peripheral tissues (extra-gonadal), thus *inhibits the synthesis of estrogen* *INDICATION:* -*Only postmenopausal women with localized ER+ breast cancer* *ADVERSE:* -*Arthralgias (joint pain)* *ADVANTAGES:* -*This class of drugs is more effective than previous drugs such as tamoxifen and crucially, it has fewer side effects"* -bone weakness -dyspnea -peripheral edema -nausea -diarrhea -hot flushes *PK:* *Route:* Oral

Interferon alpha

*CLASS:* *Immunotherapy- Cytokine Therapy* *MECHANISM OF ACTION:* -Interferons (IFNs) are cytokines produced by the immune system. (Involved in anti-viral response, but also have use in the treatment of cancer.) -Three groups of IFNs: *type I (IFNα and IFNβ)*, type II (IFNγ) and the relatively newly discovered type III (IFNλ). -Although both type I and II IFNs promote the anti-tumor effects of the immune system, *only type I IFNs have been shown to be clinically effective in cancer treatment.* -Promotes the anti-tumor effects of the immune system by increasing major histocompatibility complex (MHC) expression and increasing immune effector T and natural killer cells. *INDICATION:* -*hairy-cell leukemia* *ADVERSE:* -malaise, fatigue, fever, "flu-like symptoms", immunosupression *PK:* *Route:* IM or injection under the skin

Interleukin 2

*CLASS:* *Immunotherapy- Cytokine Therapy* *MECHANISM OF ACTION:* -Interleukin-2 (IL-2) is a member of a group of specific immune system signaling cytokines called interleukins (ILs). -ILs send chemical messages between leukocytes -*IL-2 functions in the proliferation of cytotoxic T-cells* as an immune response to an antigen reaching a T-cell receptor on a leukocyte. -These cytotoxic T-cells have the function of destroying infected, diseased, or tumor-characterized cells. -*IL-2 enhances T-cell response against cancerous cells.* (T cells secrete IL2, which is necessary for the proliferation of T cells) *INDICATION:* -Renal cell carcinoma -Melanoma *ADVERSE:* -May lead to capillary leak syndrome, fevers, renal and liver failure *PK:* *Route:* IV or inject under skin

Trastuzumab Herceptin

*CLASS:* *Immunotherapy- Naked monoclonal antibodies* *MECHANISM OF ACTION:* -*A monoclonal antibody against HER2/neu receptor* -*Binds to domain IV of the extracellular segment of the HER2 receptor, blocking EGF (Epidermal growth factor) pathway* *SELECTIVE TOXICITY:* -In cancer cells, the HER2 protein can be expressed up to 100 times more than in normal cells (2 million versus 20,000 per cell). *INDICATION:* -*HER2-positive breast cancer* *ADVERSE:* -Unique toxicity: *Infusion-related reactions*, flu-like symptoms (such as fever, chills and mild pain), nausea and diarrhea -Significant complications: Trastuzumab is *associated with cardiac dysfunction* in 2-7% of cases. As a result, regular cardiac screening is commonly undertaken during the trastuzumab treatment period. [Trastuzumab downregulates neuregulin-1 (NRG-1), which is essential for the activation of cell survival pathways in cardiomyocytes and the maintenance of cardiac function. These are all significant for the function and structure of cardiomyocytes.] *PK:* *Route:* IV

Bevacizumab

*CLASS:* *Immunotherapy- Naked monoclonal antibodies* *MECHANISM OF ACTION:* -*Binds to and prevents VEGF-A from interacting with VEGF receptors* -Leads to inhibition of VEGF signaling; inhibits tumor vasculature. -This inhibits tumor growth and reduced tumor size *INDICATION:* -*Colorectal cancer* *ADVERSE:* -Acute toxicity: Hypertension, infusion reaction -Delayed toxicity: *Arterial thromboembolic events (transient ischemic attack, stroke, angina, and myocardial infarction)*, gastrointestinal perforations, wound healing complications, proteinuria *PK:* *Route:* IV

Rituximab

*CLASS:* *Immunotherapy- Naked monoclonal antibodies* *MECHANISM OF ACTION:* -A chimeric *monoclonal antibody against the protein CD20* -Binds to CD20. (CD20 is widely expressed on B cells, from early pre-B cells to later in differentiation). -Sticks to one side of cancerous B cells, forming a cap and drawing proteins over to that side (asymmetric protein cluster). -The cap enhances the effectiveness of natural killer (NK) cells in destroying these diseased cells. (When an NK cell latched onto the cap, it had an 80% success rate at killing the B cell). [Ab binding all the CD20 to form a large patch that can be killed by the NK cells] *INDICATION:* -*Hematological cancers: leukemias and lymphomas, including Hodgkin's lymphoma.* -*Autoimmune diseases: rheumatoid arthritis.* -*Anti-rejection treatment for organ transplants* *ADVERSE:* -*Severe infusion reaction*, cardiac arrest, cytokine release syndrome, immune toxicity, pulmonary toxicity, bowel obstruction and perforation. *PK:* *Route:* IV

Cetuximab

*CLASS:* *Immunotherapy- Naked monoclonal antibodies* *MECHANISM OF ACTION:* -A chimeric monoclonal antibody *against the extracellular domain of the EGFR* -Binds to EGFR and inhibits downstream EGFR signaling; enhances response to chemotherapy and radiotherapy. *INDICATION:* -*Its efficacy is restricted to only those patients whose tumors express wild-type KRAS* -Colorectal cancer -Head and neck cancer (used in combination with radiotherapy) -Non-small cell lung cancer *ADVERSE:* -Acute toxicity: Infusion reaction -Delayed toxicity: Skin rash, hypomagnesemia, fatigue, interstitial lung disease *PK:* *Route:* IV

Ipilumimab

*CLASS:* *Immunotherapy- Naked monoclonal antibodies* *MECHANISM OF ACTION:* -A human *antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4)* -Binds and activates the immune system by targeting CTLA-4 (CTLA-4 is a protein receptor that downregulates the immune system) -Cancer cell antigens (antigens that are produced by cancer cells), can be recognized by dendritic cells, which present the antigens to CTLs (cytotoxic T lymphocytes). -CTLA-4 inhibits the CTLs activation -*Ipilimumab blocks the CTLA-4 inhibitory signal, and allows the CTLs to destroy the cancer cells* *INDICATION:* -*Melanoma* *ADVERSE:* -Immune related side effects such as: fever, colitis, rash *PK:* *Route:* IV

T-DM1 (Trastuzumab Emtansine)

*CLASS:* *Immunotherapy- conjugated monoclonal antibodies* *MECHANISM OF ACTION:* -links HER2 antibody to cytotoxic cross-linking agent -Targets the HER2 protein, attached to a chemo drug called DM1 (DM1: Derivative of Maytansine, a microtubule destablizing agent) Same as Trastumuzab, except for carrying a chemo drug DM1 *INDICATION:* -*Advanced HER2 positive breast cancer* *ADVERSE:* -Fever, chills, weakness, headache, nausea, vomiting, diarrhea, rashes *PK:* *Route:* IV

Pembrolizumab

*CLASS:* *PD 1 Inhibitors* *MECHANISM OF ACTION:* -PD-1L present on the surface of some tumor cells -PD-1 present on T-cells -PD-1L/PD-1interaction blocks action of T-cell on tumor cell -PD-1 inhibition results in T-cell activation against tumor cell -*Tumor cells can inhibit the body's immune response by binding proteins, such as PD-1 (explained above) on the surface of T cells. Antibody therapies that block this binding reactivate the immune response* *INDICATION:* *Melanoma* *ADVERSE:* -Largely T-cell mediated: such as flu-like symptoms, diarrhea, pneumonitis, etc.

Differences between targeted therapies and classical chemotherapy

*Classical Chemotherapy* -Act on all rapidly dividing normal and cancerous cells -Identified because they kill cells -Cytotoxic (they kill cells) -Waste due to insufficient rx or excessive rx *Targeted Cancer Therapies:* -Act on specific molecular targets that are associated with cancer -Deliberately chosen or designed to interact with their target -Cytostatic (they block tumor cell proliferation) -Currently the focus of much anticancer drug development -Improved effectiveness when compared to some generic therapy

Continuous tx with cancer chemotherapy

- Slow cycling (multiple myeloma)

2 mTOR Complexes

-*mTORC-1 is rapamycin-sensitive* -*mTORC-2 is rapamycin-insensitive*

DNA methyltransferase (DNMT)

-A family of enzymes that catalyze the transfer of a methyl group to DNA. -*DNMT is often found highly active to silence the tumor suppressor genes in cancer*

Intermittent Dosing for cancer chemotherapy

-Chemotherapy is ften given in large doses intermittently (every 2-3 weeks) rather than small doses continuously. *ADVERSE:* -Allows time for cancer cell regrowth and development of resistance *ADVANTAGES: -Allows partial recovery of normal cells (for example, bone marrow). -May give time for non-dividing cells to leave G0 thus making them more susceptible to subsequent chemotherapy

Combination Therapy Goal

-Maximize cell killing efficacy -Minimize resistance -Minimize toxicity to patient

Type of target therapy

1. Chemical inhibitors -signal transduction inhibitors -gene expression modulator -apoptosis inducer -angiogenesis inhibitor 2. Hormone therapies 3. Immunotherapies 4. Toxin delivery molecules 5. Gene therapy

Rationale for combination therapy

1. To reach the maximal cell kill 2. Choose drugs with *single agent activity* against the cancer 3. Choose drugs with *different mechanisms* to: -Affect heterogeneous population of malignant cells -Increase effectiveness and to decrease resistance to therapy 4. Choose drugs with *non-overlapping toxicities* to increase tolerability of therapy 5. Choose drugs are *synergistic* with each other 6. Choose drugs can be given in its *full dosage.* 7. Add *adjuvants* to treat adverse effects (rescue)

Cancer therapy limitations

1. Toxicity -Many drugs have dose-limiting toxicity (too high of a dosage will kill a lot of normal cells) 2."Total cell kill" -Chemotherapy generally follows first-order kinetics -A constant fraction of cells are killed with each dose *making it difficult to achieve total cell kill* (killing 99.99% of a tumor with 1012 cells still leaves 108 malignant cells) 3. Resistance 4.Tumor progression - Development of heterogeneity of malignant cells (tumor can evolve and make it difficult to treat)

Combination Therapy Example

CHOP -Cyclophosphamide -Hydroxydaunorubicin -Oncovin (trade name for vincristine) -Prednisone (not required)

Targeted cancer therapy goal

Deprive cell of proliferation signals or environmental factors

Targeted cancer therapy

Drugs or other substances that block the growth and spread of cancer by interfering with specific molecules *("molecular targets")* that are involved in the growth, progression, and spread of cancer -Sometimes called "molecularly targeted drugs," "molecularly targeted therapies," "precision medicines," or similar names.