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Overview of New and Emerging Therapies in Cancer Treatment

Explore the history and advancements in cancer therapy, including targeted therapies, immunotherapy, and emerging treatments. Learn about chemotherapy, hormonal therapy, gene therapy, and the hallmarks of cancer. Discover FDA-approved targeted therapies and apoptosis inducers.

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Overview of New and Emerging Therapies in Cancer Treatment

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  1. Overview of New and Emerging Therapies in Cancer Treatment Minhee Kang, PharmD, BCOP, BCPS MedStar Washington Hospital Center

  2. Disclosure • Dr. Kang has nothing to disclose

  3. Objectives • Review the history of cancer therapy development • Recognize the use of targeted therapies • Describe the use of immunotherapy • Identify emerging therapies

  4. Radiation Surgery Chemotherapy Targeted therapy Cancer Treatment Hormonal therapy Immunotherapy Gene therapy

  5. Hallmarks of cancer • Sustaining proliferative signaling • Resisting cell death • Inducing angiogenesis • Enabling replicative immortality • Evading growth suppressors • Activating invasion and metastasis • Genome instability and mutation • Tumor promoting inflammation • Regulating cellular energetics • Avoiding immune destruction

  6. Chemotherapy

  7. Chemotherapy • Drug therapy to slow or stop the growth of rapidly dividing cancer cells in the body.  • Newly approved chemotherapy in recent years • Eribulin (Halaven) for breast cancer and liposarcoma • Trifluridine/tipiracil (Lonsurf) for colorectal cancer (CRC) and gastric and gastroesophageal junction (GEJ) adenocarcinoma • Daunorubicin/cytarabine (Vyxeos) for acute myeloid leukemia (AML) • Calaspargasepegol-mknl (Asparlas) for acute lymphoblastic leukemia (ALL)

  8. Hormone therapy • Slow or stop the growth of hormone-sensitive tumors • Prevent body from producing the hormones or by interfering with the action of the hormones • Breast cancer • Prostate cancer • Enzalutamide (Xtandi) • Apalutamide (Erleada)

  9. Targeted therapy

  10. Targeted therapy • Molecules targeting specific enzymes, growth factor receptors, and signal transducers • Interfere oncogenic cellular processes • Block signal transduction • Antiangiogenesis • Promote cell death (apoptosis) or inactivity (senescence)

  11. Two main types of targeted therapy • Small molecules: attack targets inside and outside of the cell, as well as targets within the same family or class of protein kinases • Monoclonal antibodies • Bind to their molecular target, mostly membrane bound receptors • Prevent ligand binding • Stimulate immune system to kill the targeted cell, such as complement-mediated cytotoxicity, immune modulation, antibody dependent cellular cytotoxicity

  12. Biologic target • Membrane bound receptor kinases: epidermal growth factor receptor (EGFR), human epidermal receptor-2 (HER2), insulin-like growth factor receptor (IGFR) • Intracellular signaling kinases • Epigenetic abnormalities: DNA methyltransferase, histone deacetylase (HDAC) • Genetic mutation: BRCA1 and BRCA2 • Tumor vasculature and microenvironment: angiogenesis with vascular endothelial growth factor (VEGF) inhibitors and VEGFR inhibitors, integrins, hypoxia inducible factors (HIF)

  13. Membrane bound receptor kinases inhibitor

  14. Membrane bound receptor kinases inhibitor (cont.)

  15. Intracellular signaling kinases inhibitor • Src /PI3k/AKT/mTOR pathway inhibitors • Mitogen-activated protein kinase (MAPK) pathway inhibitors • Sonic hedgehog pathway inhibitors

  16. Signaling pathway: Srckinase pathway Jiao Q et al. Mol Cancer.2018;17(1);36

  17. Epigenetic abnormalities • DNA methyltransferase • Histone deacetylase (HDAC) inhibitors • HDAC regulates the acetylation of target protein • Decrease expression of oncogenes such as BCR-ABL • Stop cell cycle • Induce apoptosis • Stop angiogenesis and cell motility

  18. Histone deacetylase (HDAC) inhibitors • Vorinostat (Zolinza) for cutaneous T cell lymphoma (CTCL) • Romidepsin (Istodax) for CTCL • Panobinostat (Farydak) for multiple myeloma

  19. Genetic mutation • DNA repair gene mutation • BRCA mutation: poly ADP ribose polymerase (PARP) inhibitors • Gain of function mutation • Isocitrate dehydrogenase (IDH) mutation: IDH1/2 inhibitors

  20. PARP inhibitors Iqbal S, Rattu MA, Shah N US Pharm. 2018;9(43): HS-10-HS16

  21. Angiogenesis inhibitors • Block the growth of new blood vessels to tumors (a process called tumor angiogenesis) • Inhibit tumor growth and restrain metastasis • Vascular endothelial growth factor (VEGF) is commonly expressed in many solid tumors • VEGF inhibitors • VEGF receptor (VEGFR) inhibitors

  22. Signal transduction and angiogenesis Feng X et al. US Pharm. 2015;35(7)(Oncology suppl):4-9

  23. FDA approved targeted therapy

  24. FDA approved targeted therapy

  25. FDA approved targeted therapy

  26. FDA approved targeted therapy

  27. FDA approved targeted therapy

  28. FDA approved targeted therapy

  29. Apoptosis inducers • Apoptosis is one method the body uses to get rid of unneeded or abnormal cells, but cancer cells have strategies to avoid apoptosis. • Apoptosis inducers can get around these strategies to cause the death of cancer cells. • Target: Bcl2, PI3k, NFkB, proteasome • Bcl2 inhibitor: venetoclax • Proteasome inhibitors

  30. Venetoclax (Venclexta) • Selective and orally bioavailable small-molecule inhibitor of BCL-2, an antiapoptotic protein. • BCL-2proto-oncogene encodes a mitochondrial protein that blocks programmed cell death (PD) • Known to be present in lymphoid malignancies • High expression of BCL-2 associated with lower complete response (CR) rate after intensive chemotherapy • Indication: CLL/SLL, AML

  31. Proteasome inhibitors • Proteasome pathway • Degradation of intracellular proteins • Maintenance of protein homeostasis • Clearance of misfolded/unfolded and cytotoxic proteins • Proteins degraded by the proteasome include mediators of cell-cycle progression and apoptosis • Proteasome inhibitors: inhibit proliferation and induce apoptosis in multiple myeloma cell lines • Bortezomib, carfilzomib, ixazomib

  32. Monoclonal antibody

  33. Monoclonal antibody SLAM7: signaling lymphocytic activation molecule family member 7

  34. Antibody drug conjugates (ADC) • Antibody + toxic substance that kill cancer cells • Gemtuzumabozogamicin (Mylotarg) • Anti- CD33 antibody fragment linked to the antitumor agent calicheamicin • Inidcation: CD-33 positive AML • Inotuzumabozogamicin (Besponsa) • Anti- CD22 antibody fragment linked to the antitumor agent calicheamicin • Indication: adults with relapsed or refractory B-cell precursor ALL

  35. Antibody drug conjugates (ADC) • Moxetumomabpaudotox-tdfk (Lumoxiti) • Anti-CD22 antibody + protein toxin PE38 • Indication: HCL • Ado-trastuzumab emtansine (T-DM1) • Monoclonal antibody trastuzumab + the cytotoxic agent emtansine, which inhibits cell proliferation by blocking the formation of microtubules. • Indication: HER2-positive breast cancer • Brentuximabvedotin (Adcetris) • Anti-CD30 antibody + microtubule disrupting agent, MMAE • Indication: HL, anaplastic large cell lymphoma

  36. Application

  37. Targeted therapy in breast cancer • Hormonal therapy • HER2/neu inhibitor • CDK4/6 inhibitor • Poly ADP-ribose polymerase (PARP) inhibitor • Immunotherapy

  38. Targeted therapy in breast cancer Clinical trial PARP inhibitors Olaparib, talazoparib Pernas S et al. TherAdv Med Oncol, 2018(10):1-15

  39. Targeted therapy in AML • Targets • Cell surface epitopes: CD33, CD123, NGK2D • Activated kinases: FLT3, KIT • Other gain-of-function mutations: mutant RAS, IDH1/2 • Spliceosome inhibition: U2AF1, SF3B1 • CD 33 targeting monoclonal antibody: gemtuzumabozogamicin • FLT3 inhibitor: midostaurin, gilteritinib • IDH1 IDH2 inhibitors: enasidenib, ivosidenib

  40. Side effects of targeted therapies • Skin problems: acneiform rash, dry skin, nail changes, hair depigmentation • GI perforation • Diarrhea • Hepatitis, elevated liver enzymes • Interstitial lung disease • Problems with blood clotting or wound healing • High blood pressure

  41. Limitation of targeted therapies • Resistance • Mutation in target • Develop a new pathway to achieve tumor growth that dose not depend on the target • Overcome resistance • Two different targeted therapies combination • Combination with chemotherapy: i.e. trastuzumab + docetaxel

  42. Immunotherapy

  43. Immunotherapies • The 5th modalities of cancer treatment after surgery, radiation, chemotherapy and targeted therapy • Stimulate one’s own immune system to fight cancer, activating immune cells or getting them to recognize cancer cells as different from normal cells

  44. Cancer Immunotherapy approaches http://www.media.jkstudios.tv/3d-animation-cgi/2d-3d-medical-animation-cancer-immunotherapy_009.jpg

  45. Immune checkpoints • Immune checkpoints reduce inappropriate responses to self-antigens • Protect self from inflammation and autoimmunity • Prevents allergy and/or hypersensitivity • Pregnancy • Gastrointestinal microbiome (commensal organisms)

  46. Immune checkpoint inhibitors Clinicaloptions.com

  47. CTLA-4 Blockade • CTLA-4 ligation on activated T-cells down regulates T-cell response • Blocking CTLA -4 ligation • Enhancement of T- cell activity • Inhibition or elimination of Treg activity • Iplimumab (Yervoy)

  48. PD-1/PDL-1 Blockade • Induce and enhance T-cell activation, expansion, and effector function • Enhance antitumor responses by diminishing the number and/or suppressive activity of Tregs that have infiltrated the tumor • Enhance natural killer (NK) cell activity in the tumors • Enhance antibody production on PD-1 positive B-cell

  49. Immune checkpoint inhibitors

  50. Immune check point inhibitors FDA approval in multiple cancer treatment (March 2019) • Head and neck squamous cell carcinoma • Hodgkin lymphoma • Hepatocellular carcinoma • Gastric/gastroesophageal junctional cancer • Melanoma • Merkel cell carcinoma • Cutaneous squamous cell carcinoma • MMR-deficient solid tumors • Primary mediastinal B cell lymphoma • Non small cell lung cancer • Small cell lung cancer • Renal cell carcinoma • Urothelial carcinoma • MSI-high colorectal cancer • Cervical cancer clinicaloptions.com

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