Targeted Therapy in Oncology PDF

TARGETED THERAPY IN ONCOLOGY PROF. DR NEBOJŠA STILINOVIĆ DEPARTMENT OF PHARMACOLOGY, TOXICOLOGY AND CLINICAL PHARMACOLOGY INTRODUCTION ACCORDING TO THE WORLD HEALTH ORGANIZATION (WHO), TUMORS ARE THE SECOND LEADING CAUSE OF DEATH IN THE WORLD. GLOBALLY, ONE IN EVERY 6...

TARGETED THERAPY IN ONCOLOGY PROF. DR NEBOJŠA STILINOVIĆ DEPARTMENT OF PHARMACOLOGY, TOXICOLOGY AND CLINICAL PHARMACOLOGY INTRODUCTION ACCORDING TO THE WORLD HEALTH ORGANIZATION (WHO), TUMORS ARE THE SECOND LEADING CAUSE OF DEATH IN THE WORLD. GLOBALLY, ONE IN EVERY 6 DEATHS IS CAUSED BY A MALIGNANCY. THE NUMBER OF NEW CASES IS EXPECTED TO INCREASE BY ABOUT 70% IN THE NEXT TWO DECADES. THE IMPACT THAT MALIGNANT DISEASES HAVE ON THE GLOBAL ECONOMY IS SIGNIFICANT AND IS CONSTANTLY GROWING. CANCER STATISTICS (WORLD) FIRST PLACE SECOND PLACE Country MEN WOMEN MEN WOMEN (i) (m) (i) (m) (i) (m) (i) (m) USA Prostate Lung Breast Lung Lung Prostate Lung Breast GREAT Prostate Lung Breast Lung Colon Prostate Lung Breast BRITAIN SERBIA Lung Lung Breast Breast Colon Colon Colon Lung Table 1. Frequency and localization of tumors that occurred in the United States, Great Britain and the Republic of Serbia in 2018, (i) incidence, (m) mortality. CANCER STATISTICS (US) From Dipiro JT, Pharmacotherapy: A Pathophysiologic Approach, 10th edition, 2020. ESSENTIAL CHANGES IN THE CANCER CELL PHYSIOLOGY Hanahan & Weinberg, Cell 100:57 (2000) Target for new drugs? EXAMPLES OF ONCOGENES AND TUMOR SUPPRESSOR GENES GENE FUNCTION of gene CANCER TYPE EGFR Epidermal growth factor Breast, colon, receptor glioblastoma HER2 Growth factor receptor Breast, ovaries, prostate BCR-ABL Nonreceptor tyrosine kinase CML p53 Protein for apoptosis Wide range of induction cancers BRCA DNA repair and transcription Breast, ovaries regulation EXAMPLE OF CHANGES IN THE CANCER CELL Philadelphia chromosome: t(9;22) translocation EXAMPLE OF CHANGES IN THE CANCER CELL 9 22 bcr bcr-abl abl Fusion protein with tyrosine kinase activity  WHAT IS TARGETED THERAPY? DRUGS TARGETED AT PATHWAYS, PROCESSES AND PHYSIOLOGY WHICH ARE UNIQUELY DISRUPTED IN CANCER CELLS: RECEPTORS GENES ANGIOGENESIS A “smart” bomb versus a “cluster” bomb. Dr. Nevin Murray  TARGETED VS. CLASSICAL CHEMOTHERAPY If you know the target, and there is only one target you can be very specific. If you don’t really know or it’s a really big target, a larger weapon may be needed.  TARGETED VS. CLASSICAL CHEMOTHERAPY CHRONIC MYELOID LEUKEMIA – DEATH SENTENCE BEFORE IMATINIB ERA. CLASSICAL CHEMOTHERAPY CAN’T STOP DISEASE PROGRESSION? TARGETED THERAPY CAN STOP DISEASE PROGRESSION IN CML. “FROM LEUKEMIA YOU WON’T DIE”, BRIAN DRUKER  TARGETED THERAPY - CLASSES SMALL MOLECULES - MOLECULAR MASS ABOUT 500 DA, ENTER CELLS AND BLOCK DOWNLINK SIGNALING MONOCLONAL ANTIBODIES (MOAB) - MOLECULAR WEIGHT ABOUT 150,000 DA, TARGET EXTRACELLULAR COMPONENTS (EXTRACELLULAR LIGANDS AND RECEPTORS ON THE CELL SURFACE) TARGETED THERAPY SMALL MOLECULES MOAB  TARGETED THERAPY – SMALL MOLECULES (PROTEIN KINASE INHIBITORS) SMALL MOLECULES THAT ACT ON THE INTRACELLULAR RECEPTOR DOMAIN.  TARGETED THERAPY – SMALL MOLECULES (PROTEIN KINASE INHIBITORS) 1. BCR-ABL INHIBITORS 2. mTOR (mammalian target of rapamycin) INHIBITORS 3. EGFR INHIBITORS 4. MULTIKINASE INHIBITORS 5. BRAF (Rapidly Accelerated Fibrosarcoma) INHIBITORS 6. ALK (Anaplastic lymphoma) INHIBITORS 7. PROTEASOME INHIBITORS 8. OTHER SMALL MOLECULE INHIBITORS  SMALL MOLECULES – BCR-ABL INHIBITORS OLDER GENERATION: IMATINIB (FIRST SMALL MOLECULE EVER). NEWER GENERATION: DASATINIB, NILOTINIB, BOSUTINIB. PONATINIB – THE NEWEST? MECHANISM OF ACTION: TK (bcr-abl present in over 95% of HML patients) inhibition (CSF - colony, SCF - stem, PDGF - platelets and other). 2. GEN. Inhibition of wild-type bcr-abl kinase of imatinib resistant cells. INDICATIONS: Ph chromosome positive CML, ALL, sarkomas and gastrointestinal stromal tumors (GISTs).  SMALL MOLECULES – BCR-ABL INHIBITORS 3rd March 2000 5th April 2000 PET IMAGE BEFORE AND AFTER 4-WEEK THERAPY OF GIST WITH IMATINIB Joensuu et al. N Engl J Med. 2001;344:1052-1056.  SMALL MOLECULES – BCR-ABL INHIBITORS SIDE EFFECTS: severe fluid retention with pleural effusion, pericardial effusion and ascites (ABOUT 10% PATIENTS), myelosuppresion, elevation of liver enzymes, muscle cramps, headache and skin problems inhibit tyrosine kinase and lead to hypothyroidism. INTERACTIONS: with CYP inducers and inhibitors, changing of drug concentration in blood can be dangerous!  SMALL MOLECULES – MTOR INHIBITORS SERINE-THREONINE KINASE INHIBITORS TEMSIROLIMUS, EVEROLIMUS MECHANISM OF ACTION: Selective inhibition of mTOR which controls cell division, inhibition of VEGFR; hypoxia induction. This kinase is particularly active in the proliferator. T lymphocytes.  SMALL MOLECULES – MTOR INHIBITORS INDICATIONS: TEMS. – carcinoma of renal cells, lymphoma EVERO. - HER2 positive breast tumor, neuroendocrine tumors, carcinoma of renal cells. Prevention of graft rejection in combination with corticosteroids and cyclosporine. SIDE EFFECTS: FLUID RETENTION, loss of appetite, rash, hyperglycemia, hyperlipidemia, myelosuppression, immunosuppression with infections, RENAL FAILURE  SMALL MOLECULES – EGFR, HER INHIBITORS ERLOTINIB, GEFITINIB, AFATINIB – TYROSINE KINASE INHIBITION FOR EGFR (ATP) = APOPTOSIS INDUCTION. LAPATINIB – TYROSINE KINASE INHIBITION FOR EGFR AND HER1 AND HER2 (ATP) = APOPTOSIS INDUCTION.  SMALL MOLECULES – EGFR, HER INHIBITORS INDICATIONS: ERLOTINIB, GEFITINIB, AFATINIB – first or second line of non-smallcell LUNG CANCER with EGFR activating mutations, pancreatic cancer. LAPATINIB – breast cancer comb. with other antitumor drugs. INSTITUTE OF SREMSKA KAMENICA – TESTING OF MUTATIONS FOR EGFR AND VARIOUS OTHER. SIDE EFFECTS: rash which correlates with clinical benefit of therapy, diarrhea, pulmonary fibrosis, prolongation of QT interval.  SMALL MOLECULES – MULTIKINASE INHIBITORS SUNITINIB AND SORAFENIB – OLDER GENERATION PAZOPANIB AND AXITINIB – NEWER GENERATION MECHANISM OF ACTION: VARIOUS INTRACELLULAR SIGNALING PATHWAYS = APOPTOSIS, INHIBITION OF ANGIOGENESIS, INHIBITION OF LOCAL AND METASTATIC PROGRESSION. They are more potent than other inhibitors, and the possibility of developing resistance to them is less. INDICATIONS: GISTs, metastatic renal cell carcinoma, neuroendocrine tumors, hepatocellular carcinoma (ABDOMINAL TUMORS). S.E.: severe rash and various skin pr., hypertension, KVS.  SMALL MOLECULES – MULTIKINASE INHIBITORS Normal heart Start: After 1 week of After 2 month of GIST resistant therapy with sunitinib therapy with sunitinib to imatinib MK INHIBITORS ARE GIVEN AS A SECOND LINE, i.e. IF THERE IS RESISTANCE TO A PREVIOUS GROUP OF KINASE INHIBITORS.  SMALL MOLECULES – B-RAF INHIBITORS SERINE-THREONINE KINASE INHIBITORS FOR B-RAF PROTO-ONCOGENE. INHIBITION OF MITOGEN-ACTIVATED PROTEIN KINASE (MAPK), WHICH CONTROLS MITOSIS, DIFFERENTIATION, PROLIFERATION AND APOPTOSIS OF SKIN CELLS. VEMURAFENIB AND DABRAFENIB INHIBIT MUTATED B- RAF KINASE (MOST COMMON MELANOMA CELLS BUT OTHER TUMORS AS WELL) AND CONSEQUENTLY CELL PROLIFERATION.  SMALL MOLECULES – B-RAF INHIBITORS INDICATION: unresectable melanoma with pos. B-RAF mutation. "LAZARUS SYNDROME" - a sudden improvement of seriously ill patients that is not sustainable for a long time, because the disease recurs after a certain period and if a new mutation occurs, the malignant cells become resistant to the action of this group of drugs. However, these drugs significantly improve the quality of the patient's remaining life, although they do not lead to a significant overall prolongation of life. S.E.: rash, itching, papillomas, skin squamous carcinoma (SKIN!), QT prolongation, serious eye complications.  SMALL MOLECULES – ALK INHIBITORS The first representative was CRIZOTINIB, and the newer are: CERITINIB, ALECTINIB and BRIGATINIB. M. A.: inhibition of ALK autophosphorylation and further phosphorylation of proteins involved in intra and intercellular signaling and proliferation processes. IND.: non-small cell bronchial carcinoma with pos. ALK mutation is the only indication. Newer agents may be used as a second line in crizotinib treatment failure. S.E.: generalized edema, pleural and cardiac effusions in a high percentage. Interstitial lung disease, hypertension with bradycardia, pancreatic damage with consequent increase in enzymes and hyperglycaemia are also common.  SMALL MOLECULES – PROTEASOME INHIBITORS THE PROTEASOME IS AN ENZYME COMPLEX THAT IS RESPONSIBLE FOR DEGRADING PROTEINS THAT CONTROL THE CELL CYCLE. INHIBITION OF THE PROTEASOME LEADS TO DEATH OF CANCER CELL. BORTEZOMIB, CARFILZOMIB. INDICATION: MULTIPLE MYELOMA AND SOME OF LYMPHOMAS IN COMBINATION WITH OTHER ANTITUMOR DRUGS. S.E.: asthenia (fatigue, weakness), nausea and diarrhea in 50% of patients, myelosuppression, peripheral neuropathies. Administration every 3rd day to avoid cumulative toxicity!  SMALL MOLECULES – OTHER RETURN OF FAMOUS THALIDOMIDE – INDICATIONS CHANGE. IMMUNOMODULATORY DRUG TODAY! ITS DERIVATIVES LENALIDOMIDE AND POMALIDOMIDE. MECHANISM: angiogenesis inhibition, direct cytotoxicity, TNF-alpha and other cytokines production inhibition. INDICATIONS: multiple myeloma, myelodisplastic syndrome, second line of immunosuppression in graft versus host disease, leprosy. S.E.: orthostatic hypotension, peripheral neuropathies, rash, CNS toxicity, teratogenic effects.  ADVANTAGES OF SMALL MOLECULES FOR SOME TUMORS REVOLUTIONARY CHANGE – IMATINIB AND CML. MORE COMFORT FOR PATIENT – THERAPY CAN TAKE AT HIS HOME, BECAUSE SMALL MOL. ARE MOSTLY TABLETS AND CAPSULES. THEY PROLONG PROGRESSION-FREE SURVIVAL. LESS SERIOUS SIDE EFFECTS THAN CLASSIC CHEMOTHERAPEUTIC DRUGS, BUT EXPENSIVE! BEYOND THE FUTURE THERAPY – MODERN SCIENCE HAS DISCOVERED GREAT NUMBER OF NEW TARGETS.  TARGETED THERAPY MONOCLONAL ANTIBODIES (MOAB) TARGETED THERAPY – MOAB  TARGETED THERAPY – MOAB MONOCLONAL ANTIBODIES ARE PART OF BIOLOGIC THERAPY (DRUGS), AS CYTOKINES, GROWTH FACTORS AND VACCINES. BIOLOGICAL DRUGS ARE THOSE WHICH ARE MANUFACTURED IN, EXTRACTED FROM OR SEMISYNTHESIZED FROM BIOLOGICAL SOURCES (DIFFERENT TO CLASSIC DRUGS). MoAB ARE SPECIALLY DESIGNED FOR TARGETING OF PATHWAYS WHICH ARE CRITICAL FOR SURVIVAL AND GROWTH OF CANCER CELLS. ON THE OTHER SIDE MINIMIZATION OF SIDE EFFECTS.  TARGETED THERAPY – MOAB GROUPS OF MoAB: NAKED ANTIBODIES (UNCONJUGATED) AND ANTIBODIES CONJUGATED WITH TOXIN, CHEMOTHERAPY DRUG AND RADIOACTIVE PARTICLE (TARGETED RELEASE). NOMENCLATURE: -OMAB MURINE (MOUSE), -UMAB HUMAN, -XIMAB CHIMERIC (MOUSE, HUMAN), -ZUMAB HUMANIZED. GENERAL MECHANISM: COMPLEMENT-DEPENDENT CYTOTOXICITY, ANTIBODY-DEPENDENT CYTOTOXICITY, INHIBITION OF CELL SIGNALING. S.E. DEPEND ON AMOUNT OF FOREIGN COMPONENT – SEE NOMENCLATURE.  TARGETED THERAPY – MOAB INFUSION-RELATED AND HYPERSENSITIVITY REACTIONS, FROM MILD TO SEVERE LIKE CARDIOCIRCULATORY COLLAPSE AND ANAPHYLAXIS. DURING INFUSION CAREFUL MONITORING OR PREMEDICATION WITH ANTIHISTAMINES AND CORTICOSTEROIDS. DURING THERAPY ANTIPRODUCT ANTIBODIES CAN INCREASE CLEARENCE OF THE MoAB. HUMAN MoAB ARE THE BEST (LOGICAL). LESS COMFORT THAN PREVIOUS GROUP (SMALL MOLECULES), THIS IS PARENETERAL THERAPY!  TARGETED THERAPY – MOAB MoAB AND IMMUNOCONJUGATES THAT TARGET CELL SURFACE GLYCOPROTEINS (CD20, CD30 AND CD52; CD – CLUSTER OF DIFFERENTIATION) RITUXIMAB (CD20) – APOPTOSIS INDUCTION IN B LYMPHOCYTES; B-CELL LYMPHOMA, CLL, WEGENER, RHEUMATOID ARTHRITIS. BRENTUXIMAB VEDOTIN (CD30) – CONJUGATE, UPON BINDING ENDOCYTOSIS, DRUG GOES INTO CELL AND ACTS AS INHIBITOR OF MICROTUBULES (DNA REPLICATION). ALEMTUZUMAB (CD52) – APOPTOSIS INDUCTION OF T AND B LYMPHOCYTES, NK CELL, MONOCYTES...  TARGETED THERAPY – MOAB SIDE EFFECTS: RITUXIMAB (CD20) – infusion and hypersensitivity reactions, transient fever, nausea, focal leukoencaphalopathy, skin reactions. BRENTUXIMAB VEDOTIN (CD30) – neutropenia, peripheral neuropathy, infusion reactions, focal leukoencaphalopathy. ALEMTUZUMAB (CD52) – severe infusion reactions, hematologic toxicity, oportunistic infections (Pneumocystis), MONITOR BLOOD COUNT!  TARGETED THERAPY – MOAB MoAB WHICH ACT ON RECEPTORS AND LIGANDS OF GROWTH FACTORS. CETUXIMAB (EGFR) – ANGIOGENESIS INHIBITON, CELL MIGRATION, INHIBITION OF PROLIFERATION AND METASTASIS. IND. metastatic colorectal carcinoma with significant expression of EGFR. S.E. infusion reactions, acne, rash and other more severe skin reactions. TRASTUZUMAB AND PERTUZUMAB (HER2). IND. breast cancer, metastatic stomach carcinoma. S.E. cardiomyopathy, infusion reactions, hypersensitivity reactions, myelosuppression. Loading dose than weekly or every 3rd week to avoid S.E.  TARGETED THERAPY – MOAB MoAB WHICH ACT ON RECEPTORS AND LIGANDS OF GROWTH FACTORS. BEVACIZUMAB – ANTI VEGF ANTIBODY IND.: CANCER BREAST, OVARIES, UTERUS, COLORECTAL ETC. SENILE MACULAR DEG. OFF-LABEL S.E.: BLEEDING LOGICALLY (ANEMIA, WOUND HEALING)  TARGETED THERAPY – MOAB MOAB MODULATING THE EFFECTS OF THE CELLULAR IMMUNE SYSTEM (T LYMPHOCYTES) - “IMMUNOSTIMULATORY ANTIBODIES” IPILIMUMAB (CTLA4) – ACTIVATION OF CYTOTOXIC T LYMPHOCYTES WHICH KILL MALIGNANT CELLS. IND. unresectable or metastatic melanoma and renal cell carcinoma. S.E. IMMUNE-INDUCED DISORDERS: pneumonitis, sarcoidosis, colitis, hepatitis, nephritis, etc. PEMBROLIZUMAB (PD-1). TERMINATION OF T LYMPHOCYTES APOPTOSIS (PD-1 receptor is a negative regulator of T-cell activity). IND. melanoma, non-small cell lung cancer, urothelial carcinomas and refractory Hodgkin's lymphoma. S.E. Same as for ipilimumab.  TARGETED THERAPY – MOAB MoAB FOR OTHER INDICATIONS (OTHER THAN ONCOLOGY) MoAB IN THE THERAPY OF ULCERATIVE COLITIS AND CROHN’S DISEASE: INFLIXIMAB, ADALIMUMAB CERTOLIZUMAB AS TNF-α INHIBITORS AND VEDOLIZUMAB AS BLOCKER OF T LYMPHOCYTE ADHESION. MoAB IN THE THERAPY OF RHEUMATOID ARTHRITIS: ANTI TNF-α + ETANERCEPT AS CONJUGATE. MoAB IN THE THERAPY OF ALLERGIC ASTHMA: OMALIZUMAB AND MANY OTHER.  TARGETED THERAPY – MOAB FOR HIGH INVESTMENTS IN THIS GROUP OF DRUGS (SCIENTIFICALLY AND FINANCIALLY); THE FASTEST GROWING GROUP. SAFE PRESENT BUT ALSO FUTURE OF THIS THERAPY NOT ONLY TUMORS. THE CLOSEST TO SO CALLED PERSONALIZED THERAPY. AGAINST GREAT MINUS – GREAT PRICE. STILL THEY HAVE SERIOUS SIDE EFFECTS.  QUESTIONS WHAT ARE THE BASIC DIFFERENCES BETWEEN CLASSICAL CHEMO AND SMALL MOLECULES? WHAT ARE THE DIFFERENCES BETWEEN SMALL MOLECULES AND MOAB? WHAT ARE THE BASIC GROUPS OF SMALL MOLECULES? WHAT ARE THE BASIC GROUPS OF MOAB? WHAT ARE THE NONONCOLOGICAL INDICATIONS FOR THE USE OF MOAB?  THANK YOU! Unauthorized recording, (audio, video, photography, etc.), reproduction and publishing of this presentation is strictly prohibited. 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