Recent advances in Cancer Chemotherapy


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  • G1- phase that precedes DNA synthesis, S- DNA synthesis phase, Dna replicates itself, G2 phase following termination of DNA synthesis, MM mitosis cell containing double complement of DNA divides into daughter cells, G0 quiescent state where the cell fails to move forward
  • Ven-occlusive-defibrotide
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  • Progression from one phase of cell cycle to next is controlled by the orderly activation of CDKs; D(G1), E(G1S), A(G2),B(M)….A-2,B-1,D-4,E-2
  • regulating the cell cycle
  • NFkB is in cytosol bound to IkB restricted in cytoso…cannot enter nucleus….in stress signal IkB get ubiquited & degraded by proteosome to release NFkB which enters nucleus………. expression of proliferative & anti-apoptotic molecules ……cytokine secretion………obligate marine bacterium
  • Hydroxyurea…std drug….to reduce risk of thrombosis….vasodilation, tachycardia, palpitations, and congestive heart failure…. vasodilatation andpositive inotropic effects
  • active metabolite rate-limiting enzyme of Ribavirin, mycophenolatemofetil
  • estrogen receptors (ER-), progesterone receptors (PR-), and HER2, also called human epidermal growth factor receptor 2 (HER2-)
  • Malignant tranformation- block in differentiation; epigenetis- control of cell differentiation & proliferation beyond pure genetic alterationsDifferentiating agent
  • Responsive to endothelins; others used in PAH
  • function of genes downstream of retinoid acid response elements (RAREs); mycosis fungoides/Se´zary’s syndrome; activateperoxisomeproliferator activated receptors
  • Modification of the DNA conformationleads to
  • trabectedin-DNA adducts
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  • Human epidermal Receptor
  • HER2 breast Ca
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  • Complement dependentcytotoxicity, antibody dependent cell mediated cytotoxicity; chimeric- constant region human, variable region murine, humanised- only complement detemining region- murine
  • some cells may express tumor antigens, while others do not.
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  • targets cells that overproduce the protein HER2
  • Membrane composed of a
  • Tumor specific antigens
  • MHC 1 domain to Cytotoxin T Cells i.e. CD8+ lymphocytes
  • Telomerase is an enzyme that adds DNA sequence repeats ("TTAGGG" in all vertebrates) to the 3' end of DNA strands in the telomere regions region of repeated nucleotide called telomeres contains non-coding DNA material Telomerase is a reverse transcriptase that carries its own RNA molecule, which is used as a template when it elongates telomeres, which are shortened after each replication cycleTelomerase is a reverse transcriptase that carries its own RNA molecule, which is used as a template when it elongates telomeres, which are shortened after each replication cycle
  • Recent advances in Cancer Chemotherapy

    1. 1. RecentAdvancesin CancerChemotherapyDr. Kunal A. Chitnis1st Year ResidentT.N.M.C., Mumbai12th March 2011
    2. 2. Carcinos means crabOver 100 different types of cancer & each is classified by the typeof cell that is initially affectedSecond leading cause of death worldwideexpected to increase five fold in the next 25 yearsIndia:Prevalence 2.5 millionover 8,00,000 new cases & 5,50,000 deaths occur each yearMales: Oral CaFemale: Cervical Casix persons die every day from cancer in India40- 50% directly or indirectly related to tobacco
    3. 3. A neoplasm, as defined by Willis,"an abnormal mass of tissue, the growth of which exceeds & isuncoordinated with that of the normal tissues, and persists in thesame excessive manner after the cessation of the stimuli whichevoked the change."Benign, its microscopic and gross characteristics are consideredto be relatively innocent, remain localized, cannot spread to othersitesMalignant, the lesion can invade and destroy adjacent structuresand spread to distant sites
    4. 4. The Cell Cycle
    5. 5. Anti-Cancer ChemotherapyThe first efforts…..Traced back to the observation by Louis Goodman andAlfred Gilman, of the profound lymphoid and myeloidsuppression produced by sulfur mustard gas – a chemicalwarfare agent.
    6. 6. Cytotoxic Drugs
    7. 7. I. Alkylating AgentsMOA:• Alkylate nucleophilic group ofDNA bases (N7 Guanine)• Abnormal base pairing, crosslinking of bases & DNA strandbreakage• Cell cycle non-specificCommon adverse effects:1. Gastrointestinal distress2. Bone marrow supression3. Alopecia4. Secondary Leukamias5. Sterility6. Veno-occlusive disease of liver (↑dose)
    8. 8. Mechanism of Resistance development• ↓ Permeation of actively transported drug (mechloethamine,melphalan)• ↑ intracellular concentrations of nucleophilic substances• ↑ activity of DNA repair pathways• ↑ rates of metabolism of the activated forms ofcyclophosphamide and ifosfamide
    9. 9. A. Nitrogen Mustards:Currently used drugs:Cyclophosphamide,IfosfamideWegener’sgranulomatosis, ALL, CLL, HL, NHL, Multiple myeloma(MM), breast, ovary, lung, Wilm’s, cervix, testisMechlorethamine Hodgkin’s diseaseMelphalan Multiple myeloma, breast, ovaryChlorambucil CLL, HL, NHLDrug related side effects: Cyclophosphamide, Ifosfamide: Hemorrhagic cystitis, SIADH
    10. 10. Newer Agents:Trofosfamide• Prodrug of ifosfamide• Orally active• Metastatic soft tissue sarcomasPrednimustine• Ester of prednisolone and chlorambucil• Better drug delivery• CLL, NHL, Ca breast• S/E: myelosuppression, fluid retension
    11. 11. Uramustine• Derivative of nitrogen mustard and uracil• Non Hodgkin’s lymphomaBendamustine• Benzimidazole ring and nitrogen mustard• Inhibits mitotic checkpoints & induces mitosis• Partial cross resistance to other nitrogen mustards• Approved for CLL• Hodgkin’s lymphoma NHL, multiple myeloma, breast Ca• S/E: myelosuppression, nausea, vomiting, hypersensitivityreactions
    12. 12. B. AlkylsulfonatesCurrently used:Busulfan → CMLS/E: Pulmonary fibrosis, hyperpigmentation, adrenal insufficiencyNewer drugs:Mannosulfan• Tried for polycythaemia rubra vera• Lesser S/E• Phase 2Treosulfan• Evaluated for ovarian cancers• Lesser S/E compared to busulfan
    13. 13. C. Nitrosoureas• Highly lipid soluble• Cross blood brain barrierCurrently used agents:Carmustine, Lomustine, Semustine → Brain tumours likegliomasStreptozocin → pancreatic islet cell carcinoma, malignantcarcinoid tumorsA/E: delayed myelosupression, renal failure
    14. 14. Newer Agents:Fotemustine• Approved for metastasising melanomaNimustine• Oligodendroglioma, Glioblastoma Multiforme• Used with cytarabineRanimustine• Approved in Japan• CML and polycythemia vera
    15. 15. D. Other Alkylating agentsCurrently used:Procarbazine→ Hodgkin’s, brain tumorsDacarbazine→ malignant melanoma, hodgkin’s lymphomaTemozolomide→ malignant gliomas
    16. 16. II. Platinum CompoundsMOA:• Use platinum to form dimers of DNA• Intrastrand/ interstrand crosslinks• CCNSCurrently used agents:Testicular Ca, Ovarian Ca, Head and neck Ca, bladder Ca,esophagus & colon CaS/E:N, V, Bone marrow supression, nephrotoxicity,peripheral neuropathy, ototoxicityCisplatin 1st Generation Highly nephrotoxicCarboplatin 2nd Generation Less nephrotoxicOxaliplatin 3rd Generation Cisplatin/ CarboplatinResistant
    17. 17. Newer Drugs:Nedaplatin• 2nd generation analogue of cisplatin• ↑ Sensitivity gynecological tumors:Ovarian, Cervical and Endometrial Ca• ↓ Renal toxicity, nausea & vomiting• Exclusively approved in Japan since 1995Triplatin tetranitrate• Chloride prevents hydrolysis outside the cell• ↓ diarrhoea, vomiting• Cancers with cisplatin resistance• Phase 2 trials: Ovarian Ca, Small cell lung Ca &Gastro-oesophageal adenocarcinomas
    18. 18. Picoplatin• Retains activity in Cisplatin & Oxaliplatin Resistant cells• Activity by i.v. & oral routes• Phase 3 small cell Lung Ca & Colorectal CaAroplatin• Liposomal oxaliplatin• Incorporated in multilamellar liposomes• Good biodistribution• Well tolerated
    19. 19. III. Antimetabolites• Act on S Phase (i.e. dividing) of cell cycle (CCS)A. Antifolates• Tranported intracellularly→ folate transporter• Inhibit DHFrase→ purine synthesis• Inhibit thymidylate synthase→ thymidine synthesis• Intracellular formation of polyglutamate metabolites by FPGS
    20. 20. Currently used agents:Methotrexate→ Choriocarcinoma, ALL, Ca breast,head & neck Ca, Ca ovary, bladderPemetrexed→ Mesothelioma, NSCL CaA/E: bone marrow suppression, mucositis, hepatotoxicity;pulmonary fibrosis (methotrexate), rashes (pemetrexed)
    21. 21. Development of resistance:• ↓ transport via folate carrier• ↓ formation of polyglutamates• ↑ formation of DHFRase• Altered DHFRase with ↓ affinityNewer Drugs:Trimetrexate:• Lipid soluble• Crosses BBB• Bypasses membrane transport system→transport-deficient MTX-resistant tumour cells• Leiomyosarcoma & Skin Ca
    22. 22. Pralatrexate• Enters cells expressing ↓ folate carrier type 1 (RFC-1)• Relapsed or Refractory Peripheral T-cell lymphoma• FDA approval in September 2009Raltitrexed• Quinazoline folate analogue• Selectively inhibits thymidylate synthase (TS)• Advanced colorectal cancerLometrexol• Inhibits GARFT as well as AICART• Inhibitor of de novo synthesis of purines• Phase 2 clinical trials: NSCL cancer
    23. 23. B. Purine AnaloguesMOA:• Purine antimetabolites activated by HGPRTase• Incorporated into DNA & RNA nucleotides• Inhibits various enzymes of purine synthesisCurrently used agents:6 Mercaptopurine AML6 Thioguanine AML , ALLCladribine Hairy cell leukamia, CLL,NHLFludarabine CLL, NHL
    24. 24. Newer Drugs:Clofarabine:• Paediatric patients for Relapsed or Refractory ALL• S/E: Tumour lysis syndrome, bone marrow suppression,Systemic Inflammatory Response (SIRS)• FDA approved in 2004
    25. 25. C. Pyrimidine AnaloguesMOA: Cytarabineactivated to arabinoside CTP→ Inhibit DNA polymeraseα/β 5-FUconverted to 5-dUMP→ Inhibit Thymidylate synthase Capecitabineprodrug of 5-FU GemcitabinePhosphorylated to GDP→ Inhibit Ribonucleotide ReducataseGTP→ Inhibit DNA polymerase α/β, incorporated in DNA Azacytidine & DecitabineDNA hypomethylation by inhibiting DNA methyl transferase
    26. 26. Cytarabine AML, ALL,CML in blast crises5-FU Colorectal Ca, Anal Ca, Breast Ca,Gastro-esophageal Ca, Head & NeckCa, hepatocellular CaCapecitabine Breast Ca, Colorectal Ca, Gastro-esophageal Ca, Hepatocellular Ca,Pancreatic CaGemcitabine Pancreatic Ca, Bladder Ca, NSCL Ca,Ovary Ca, Soft tissue SarcomaAzacytidine &DecitabinePancreatic Ca, lung Ca, ovarian Ca,Myelodysplasia
    27. 27. Newer Drugs:Tegafur Uracil:• Tegafur is 5-FU prodrug developed in 1967• Had unacceptable CNS toxicity & discontinued• Combination of Tegafur & Uracil (1:4)• Uracil→ Inhibitor of Dihydropyrimidine Dehydrogenase• ↑ levels of 5-FU without toxic levels of Tegafur• Given orally• Approved in Japan for last 15 years• Gastric Ca, Colorectal Ca, HCCCarmofur:• Oral lipophilic derivativeof 5-FU• Managable toxicities (hot flushes, urinary frequency)• Serious toxicity- Leucoencephalopathy• Adjuvant chemotherapy for curatively resectedColorectal Ca
    28. 28. IV. Mitotic Spindle InhibitorsA. Vinca Alkaloids:MOA:• Bind to microtubule protein-tubulin• Dissolve the assembly• Chromosomes cannot align along the division plate• Cell division arrests in MetaphaseCurrently used Agents:Vinblastine, Vinorelbine Hodgkin’s, NHL, Breast, Lung,Testis CaVincristine ALL, Neuroblastoma, Wilm’s tumour,Rhabdomyosarcoma, Hodgkin’s,NHL
    29. 29. Adverse Effects:• Vinblastine & Vinorelbine→ bone marrow depression (leukopenia)• Vincristine→ peripheral neuropathyResistance:• ↑ Expression of mdr-1 gene→ ↑ P-glycoprotein (efflux protein)• Expression of Multidrug Resistant Protein & Breast Ca RelatedProtein
    30. 30. Newer Agents:Vinflunine:• More activity than vinblastine/vinorelbine• No peripheral neuropathy• Use: Advanced bladder Ca, advanced Breast CaVindesine:• ALL, NSCL Ca• S/E local vescicant, myelosuppression, peripheral neuropathy
    31. 31. B. TaxanesMOA:• Binds to β tubin subunit of micro-tubules• Antagonises its disassembly• Enhancement of tubulin polymerisation• Metaphase arrestCurrently Used agents:Paclitaxel, Docetaxel Ovarian, Breast, Prostate, Bladder,Lung, Head & Neck Ca
    32. 32. A/E:Hypersensitivity reactions, myelosuppression, peripheralneuropathyResistance:• ↑ Expression of mdr-1 gene→ ↑ P-glycoprotein• ↑ Survivin→ anti-apoptotic factor• β tubulin mutations• Upregulation of β tubulin isoforms
    33. 33. Newer Agents:Nab-Paclitaxel:• Protein bound paclitaxel→ ↓ hypersensitivity reactionsCabazitaxel:• Poor substrate for P-glycoprotein efflux pump• With Prednisolone→ Hormone refractory metastatic Prostate Capreviously treated with Docetaxel containing regimen• FDA approved in june 2010• A/E: Myelosuppression, hypersensitivity reactions, diarrheaOrtataxel:• Blocks its own efflux from gpP-overexpressing cells• Phase 2• Tried for taxane refractory solid tumours (lung, breast, kidney)
    34. 34. Larotaxel:• Active against taxane-resistant & multidrug-resistant tumors• Crosses the blood brain barrier• Advanced Pancreatic Ca & Advanced bladder Ca withBrain metastasis• Phase 3Tesetaxel:• Orally available• Eliminates transfusion reactions• ↓ incidence of peripheral neuropathy• Tried in Advanced gastric & advanced breast Ca• Phase 3
    35. 35. C. Epothiolones:MOA:• Bind to β tubulin• Stabilise the microtubules• G2M interphase arrestAdvantages:• Less susceptible to gpP mediated Multi Drug Resistance• Superior cytotoxic potential compared to taxanes
    36. 36. Ixabepilone• With CapecitabineLocally advanced or metastatic Breast Ca not responding toAnthracyclins & Taxanes• MonotherapyMetastatic Breast Ca progressed through treatment withAnthracyclins, Taxanes & Capecitabine• A/E: neutropenia, peripheral neuropathy• Approved in 2007Sagopilone• Natural product of epothilone B• ↑ effective in stabilizing preformed microtubules• Taxane-resistant settings• Crosses the blood-brain barrier• Use: Gastric cancer , NSCLC
    37. 37. Patupilone• Paclitaxel-resistant cancer cells• Target vasculature of solid tumor→immature endothelial cells have strong dependence on tubulinin maintaining their shape• Phase 2 trials for solid tumours esp Ovarian CaKOS 1584/ 21 Aminoepothiolone• Phase 1 trials
    38. 38. V. Topoisomerase InhibitorsA. Camtothecins:MOA:• Inhibit topoisomerase I• ss breaks• Collision of replication fork with ss breaks→ ds DNA break• S phase specificCurrently used AgentsIrinotecan, Topotecan Colon, Lung, Ovary Ca
    39. 39. A/E:• Topotecan→ neutropenia• Irinotecan→ diarrhoea, cholinergic syndromeNewer Agents:Belotecan• Use ovarian cancer, small cell lung cancer
    40. 40. B. Antitumor AntibioticsMOA:• Inhibition of topoisomerase II• Binding to DNA through intercalation→blockage of DNA & RNA• Semiquinone & oxygen free radicals• Bind to cell membrane→ alter fluidity & ion transfer
    41. 41. Currently used Agents:Doxorubicin Breast Ca, HL & NHL, soft tissue sarcoma,Ovarian Ca, Lung Ca, Wilm’s tumor &NeuroblastomaDaunorubicin AML, ALLIdarubicin AML, ALL, CML in blast crisisEpirubicin Breast Ca, Gastro-esophageal CaMitoxantrone Hormone Refractory Prostate Ca, NHL, AMLA/E:Cardiotoxicity, myelosuppression, mucositis, radiation recallsyndrome
    42. 42. Newer Drugs:Aclarubicin• Inhihibits RNA synthesis more strongly than DNA• Cardiotoxicity less• Relapsed/ Resistant AMLAmrubicin:• Marketed in Japan for Small cell Lung Ca• Superficial bladder cancer and lymphoma
    43. 43. Pirarubicin:• More lipophilic derivative• Higher uptake rate of cells & better antitumor efficacy• Lower cardiotoxicity• Breast cancer, acute leukemias and lymphomas• Phase 3Zorubicin:• Four times less cardiotoxic• Less myelosupression• Acute leukaemias & breast cancer• Phase 3
    44. 44. Valrubicin:• US FDA approved → BCG refractory bladder Ca insitu• Administered intravescically• Systemic absorbtion ↓• A/E: urinary frequency, urgency, dysuriaPixantrone:• Analogue of mitoxantrone• Less cardiotoxic• Phase 3• Relapsed or refractory aggressive NHL
    45. 45. Targeted Therapies
    46. 46. I. Enzyme Inhibitors:A. Farnesyl-transferase Inhibitors:• Ras proteins→ transduction of cell growth• Ras gene mutation→ constant activation→uncontrolled cell proliferation• 30% of all human cancers• Ras undergoes four steps of modification• Isoprenylation: Farnesyl-tranferase→transferring a farnesyl group• Farnesyl transferase inhibitors (FTIs)• Blockade of signal transduction pathway→cessation of cell growth• Tipifarnib & Lonafarnib
    47. 47. Function of Cyclins & Cyclin Dependent Kinases
    48. 48. B. Cyclin Dependent Kinase Inhibitors• Over-expression of Cyclins & CDK’s in Ca• Inhibitors of cyclindependent kinases (CDKs) restorecell cycle control or induce apoptosisSeliciclib:• Inhibit CDK2→ G1S check point• Inhibits CDK 7, 9 →inhibits RNA polymerase II dependenttranscription→ inhibits anti-apoptotic proteins• NSCL CaAlvocidib (Flavopiridol):• Same mechanism• AML, CLL
    49. 49. Bortezomib• Binds to 20S core of 26Sproteosome & reversiblyinhibits it• FDA approved for MultipleMyeloma &Relapsed/RefractoryMantle Cell Lymphoma• A/E:Thrombocytopenia, neutropenia, peripheral neuropathySalinosporamide A• Similar mechanism• Multiple myeloma• Preclinical studiesC. Proteosome Inhibtitors
    50. 50. Anagrelide:• Specific inhibition of thrombopoietin-mediatedintracellular signaling• Reversibly disrupts MegaKaryocyte maturation→post-mitotic phases of MK development• Inhibitory effects→ MK ploidy, size and cytoplasmic maturation• Thrombocythemia, primary/secondary to myeloproliferativedisorders• Oral→ first-pass hepatic metabolism→ active metabolite• A/E: Bone marrow fibrosis- reversible, cardiovascular effects• FDA approved in 2005D. PhosphodiesteraseInhibitors
    51. 51. E. IMP Dehydrogenase Inhibitor:• Converted intracellularly into NAD analogue• Inhibits Inosine Monophosphate dehydrogenase (IMPDH):IMP to XMP→ de novo guanylate biosynthesis• Cell proliferation, cell signaling, energy source• Apoptosis→ neoplastic cell lines & activated T lymphocytes
    52. 52. Drugs:• Tiazofurin: Phase 3 for CML• Selenazofurin :Phase 2• Benzamide riboside: Phase 2
    53. 53. F. PARP Inhibitors:• PolyADP-Ribose polymerase (PARP) →Base excision repair of ss DNA breaks• Inhibition: accumulation of ss breaks→ collision with DNAreplication forks→ ds breaks• Ss break repaired by tumour-suppressor genes BRCA1 andBRCA2→ Homologous Repair• Mutated BRCA1 & 2→ mechanism defective
    54. 54. IniparibPhase 3 triple negative Breast CaOlaparibOrally activePhase 2 breast, ovary, colorectal CaVeliparibPhase 2 breast Ca, melanoma
    55. 55. G. Histone Deacetylase InhibitorVorinostat• DNA warps around histones→ proteosomes• Acetylation of lysine residues→↑ spatial distance between DNA &histones→ ↑ transcription activity• Acetyl group deacetylated by Histone Deacetylases (HDACs)• RefractoryCutaneous T-Cell Lymphoma• A/E- thrombocytopenia,QT prolongation
    56. 56. Romidepsin• Similar mechanism• Approved Cutaneous T-Cell Lymphoma &Peripheral T Cell LymphomaOther HDAC Inhibitors in pipelinePhase 3:• PanobinostatPhase 2:• Belinostat• Mocetinostat
    57. 57. II. Receptor Antagonists:A. Endothelin Receptor Antagonist (ERA)• Endothelin receptors are ETA, ETB1, ETB2• G-Protein coupled receptors• Control vascular tone• ETA Vasocontriction, ETB VasodilationAtrasentan• ERA for subtype ETA• Vasodilation→ ↑ tumor perfusion, ↓ hypoxia• ↑ drug delivery, ↑ sensitivity to drug & radiation• NSCL Ca• Phase 3
    58. 58. B. Retinoid Receptor Agonist• Retinoids modulate cell proliferation, differentiation, apoptosis• Retinoid acid receptors (RARs) α,β,Ɣ• Retinoid X receptors (RXR) α,β,Ɣ• RXRs heterodimers with RAR’s, vitamin D receptor, thyroidhormone receptor & PPAR• Heterodimer binds DNA→ expression of retinoid regulatedgenes
    59. 59. Bexarotene• Synthetic retinoid• Specifically binds to RXRs• Anticancer action→ blocks cell cycle progression,induce apoptosis & differentiation, anti-angiogenesis• FDA approved for the Cutaneous T-cell lymphomarefractory to at least one prior systemic therapy• Gel & oral
    60. 60. C. MiscellaneousAmsacrine• Intercalates into DNA of tumor cells→altering major & minor groove proportions→ds DNA breaks• Inhibits topoisomerase II→ S phase and G2 arrest• Acute adult leukemia refractory to conventional treatment
    61. 61. Trabectedin (Yondelis)• Marine tunicate• Binds to minor groove of DNA→alkylates guanine at N2 position→bend DNA towards the major groove→large ternary complexes ds DNA break• Production of superoxide near DNA strand→DNA backbone cleavage• EU- Relapsed Soft tissue sarcomas, Recurrent ovarian Ca
    62. 62. Tyrosine KinaseInhibitors
    63. 63. Protein kinase phosphorylate proteinsFunctional change of target protein→change enzyme activity, cellular location or association with otherproteinsTyrosine kinases→ subgroup of protein kinasesPhosphorylation of proteins→ Gene trancription &/or DNAsynthesisFunctions as "on" or "off" switchMutated, stuck in the "on" position→unregulated growth of the cell→ Cancer
    64. 64. I. Receptor Tyrosine Kinase InhibitorsA. Epidermal Growth Factor Receptor Inhibitor/HER 1 InhibitorGeftinib:• Inhibits EGFR tyrosinekinase activity• Blocks ATP binding site• Oral administration• Approved for NSCLC pts.who have failed withstd. chemotherapy• A/E: diarrhoea, pustular/papularrash
    65. 65. Erlotinib• Similar mechanism of action• Locally advanced or metastatic NSCL & Pancreatic Ca• A/E: same
    66. 66. B. EGFR/HER1 & HER2/neu InhibitorLapatinib• Inhibits EGFR & HER2/neuKinase activity• ATP binding pocket• Approved for TrastuzumabRefractory breast Ca withCapecitabine• Small molecule→ Crosses BBB→Brain mets (Phase 3)• A/E: acneform rash, GERD,diarrhea
    67. 67. Afatinib:• Similar mechanism• Phase 3: NSCL CaNeratinib:• Phase 2: Breast Ca
    68. 68. Angiogenesis of Tumour• Angiogenesis→ essential property of Ca• Angiogenic factors→ VEGF, FGF, TGFβ & PDGF• Turn on angiogenic switch→ tumor growth & mets• Leaky capillaries→ ↑ permeability→ ↑ interstitial pressure•↓ drug delivery, ↓ oxygenation• Anti-angiogenic factors antagonise these actions
    69. 69. C. Multiple Receptors InhibitorSunitinib:• Inhibits multiple tyrosine kinasesVEGFR 2, FLT3, PDGFR α & β (angiogenesis)RET, CSF1-R & c-KIT (cell proliferation)• Metastatising RCC & GIST resistant to Imatinib• A/E: hypertension, proteinuria, arterial thrombotic eventsSorafenib• Inhibits multiple tyrosine kinasesVEGFR 1, 2 & 3, PDGFR β (angiogenesis);c-KIT, b-RAF (cell proliferation)• Hepatocellular Ca & metastatising RCC• A/E: same
    70. 70. Pazopanib• Multi-targeted receptor tyrosine kinase inhibitorVEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit• Blocks tumour growth & inhibits angiogenesis• FDA approved for renal cell carcinoma• Long t1/2 30 hrs• A/E: hair colour changes, hypertension, hepatotoxicity
    71. 71. II. Non Receptor Tyrosine KinaseInhibitorsA. bcr-abl InhibitorHas activity against:• bcr-abl Tk→ CML• Mutant c-KIT Tk→ GIST• Mutant PDGFR→ CMML,hypereosinophilia $,dermatofibrosarcoma protuberansCurrently used:• Imatinib
    72. 72. Newer Agents:Dasatinib:• Binds of open & closed configurations• Approved for CML→ Intolerant/ Resistant to ImatinibNilotinib:• ↑Potency & ↑ Efficacy• Long t1/2 17 hrs• Approved for CML→ Intolerant/ Resistant to ImatinibA/E:• GI distress→ N, V, diarrhoea• Edema & peri-orbital swelling• Nilotinib→ Prolongs QT interval
    73. 73. B. Src tyrosine kinase inhibitorBosutinib:• Inhibits the autophosphorylation ofbcr-abl & Src kinases• Src→ Transmit integrin dependent signals for cell proliferation• 30 times more potent → inhibition of bcr-abl• Against imatinib-resistant mutants of bcr-abl• Resistant CML failed first-line imatinib and second-line dasatinib
    74. 74. C. Janus Kinase 2 InhibitorsLestaurtinib• JAK enzymes→ signaling of cytokine & growth factor receptors• JAK/STAT signaling exaggerated in MPNs• Polycythemia vera, essential thrombocythemia & primarymyelofibrosis• Mutant JAK2 activity• Inhibits wild type JAK2 kinase activity→JAK2/STAT5 signaling in cells• Inhibits proliferation MPD cells• Phase II AML & Myeloproliferative disorders
    75. 75. D. EML4-ALK Fusion InhibitorCrizotinib• Non–small-cell lung cancers→echinoderm microtubule-associated like-protein 4anaplastic lymphoma kinase (EML4-ALK) fusion gene• Protein product→ kinase activity• Inhibits anaplastic lymphoma kinase (ALK) tyrosine kinase• Competes with ATP for kinase domain• Modulation of the growth, migration & invasion of malignant cells• Phase 3→ ALK-positive NSCLC (non smokers)
    76. 76. E. Fusion Protein Against VEGFAflibercept• Fusion protein: VEGFR1 and VEGFR2 , fused to the constantregion of human IgG1• VEGF → angiogenic factors includes VEGF-A, VEGF-B, andplacental growth factor (PIGF)• PIGF→ important regulator of angiogenesis• Binds to VEGF & PIGF in bloodstream & extravascular space• VEGF Trap• Inhibits Angiogenesis• Phase 3 Prostate & Colorectal Ca
    77. 77. Monoclonal Antibodies• Cancer cells express a variety of Antigens• Target for Monoclonal Antibodies• Specific Ab’s against specific Ag’s expressed by specific cells• Mechanism of killing: ADCC, CDC & Direct Induction ofApoptosis• Chimerisation/ Humanisation→↓ immunogenic, ↑ efficient & longer acting
    78. 78. • Limitations Antigen distribution of malignant cells is highly heterogeneous Tumor blood flow is not always optimal High interstitial pressure within the tumor
    79. 79. mAb Antigen Cancers treatedRituximab CD20 B Cell LymphomasTrastuzumab HER-2 / neu Breast CaGemtuzumab CD33 AMLAlemtuzumab CD52 CLLCetuximab EGFR Colorectal, head & neck CaPanitumumab EGFR Colorectal CaBevacizumab VEGF Colorectal, breast & NSCL CaOfatumumab CD20 B cell CLLI. Monoclonal Antibodies
    80. 80. II. Radioimmuno- Conjugated Monoclonal Abs:• RICs provide targeted delivery of radioactive particles to tumorcellsCurrently Approved:• Developed with Murine mAbs against CD20 conjugated with131I – (131I – tositumomab) & 90Y – (90Y – ibritumomab tiuxetan)• Both drugs→ Relapsed lymphoma.• However, reports of secondary leukemias.
    81. 81. III. Monoclonal Ab- Cytotoxic Conjugate• Enhances its cytotoxicity & drug deliveryCurrently usedGemtuzumab ozogamicin:mAb against CD33, linked to a semi-synthetic derivative ofCalicheamicin, an enediyne antitumor antibiotic.Newer AgentsTrastuzumab-maytansinoid• Trastuzumab linked to DM1• Trastuzumab → Ab against Her2 receptors• DM1→ microtubule-depolymerizing agent• Patients with Her2-positive metastatic breast cancer
    82. 82. Gemtuzumab zogamicin• Humanized anti-CD33 monoclonal antibody conjugated withCalicheamicinCD33→ Myeloid lineage• Calicheamicin → enediyne antitumor antibiotic• Binds to the minor groove of DNA→ ds breaks• FDA approval AMLOthers in Pipeline:• Methotrexate (MTX) conjugated with murine monoclonalantibody (aMM46) mouse mammary tumor antigen (MMantigen)• Paclitaxel-antibody conjugates• Antibody Linked To Ricin Toxin
    83. 83. Newer Drug Carrier Systems• Enhance delivery of anticancer drug to tumour tissue• Minimize its distribution & toxicity in healthy tissue• Effective chemotherapy requires directed action of drug• Undirected distribution→ ↓ therapeutic effectiveness↑ S/E & toxicities
    84. 84. Solubilisers• Majority anticancer drugs→ poor solubility• Newer agents→ Sorporol 230, Sorporol 120 Ex,Aceporol 345-T, Riciporol 335Self-Emulsifying Drug Delivery Formulations (SEDDS)• Enhance oral absorption of poorly soluble drugsImplantable Carmustine wafer• Gliadel→ adjunct to surgery & radiation• Newly diagnosed high grade malignant glioma• Recurrent Glioblastoma multiforme• Biodegradable polymer• Dissolves over several weeks• Releases drug directly to the area of resection• Avoiding systemic toxicity
    85. 85. Polymer Drug Conjugates• Polymer backbone linked with drug & targeting ligand• Improved pharmacokinetic profile→improved organ specific & tumor specific delivery• Leak through disorganized vasculature→accumulates in tumor• Eg: Daunorubicin,Doxorubicin
    86. 86. PEGylation• Covalent attachment of polyethylene glycol polymer chains• ↓ immunogenicity, ↑ circulating half life & ↑ tumor targeting.• Eg: Pegasparginase (PEGylated L- Aspargine; Oncaspar)Liposomes• Spherical vesicle• Phospholipid & cholesterol bilayer• Envelope for active drug particles• Protects drug, ↓ S/E, ↑ duration of action• Drug released intracellularly• A/E: localised in RES→↓ targetted delivery & RES impairment• Eg: Paclitaxel, teniposide, adriamycin
    87. 87. Immunoliposomes• Antibodies or ligands are attached to the liposome surface• ↑ binding to specific epitopes/receptors on target cellsStealth liposomes• Formulated to escape RES• ↑ the circulation time→ Depot preparations• Coat→ Polymers, polyethylene glycols, synthetic phospholipids• Hematological malignancies
    88. 88. Proteins & Amino acids as Carrier system• D-alanine with nitrogen mustard→ good bioavailability• Serum albumin of human, bovine or rat originCyclodextrins• Carbohydrate macrocycles• Form molecular inclusion complexeswith hydrophobic molecules• A/E renal toxicity• Eg: melphalan & carmustineDendrimers• Repeatedly branched,roughly spherical large molecules• Drug can be coupled tothe core or surface of dendrimer• Polyamidoamine→ targeted drug carrier• Eg: Dendrimer platinate→ ↓ toxic than cisplatin
    89. 89. Antibody Dependent Enzyme Prodrug Therapy (ADEPT)• Initial→ Antibody Enzyme Conjugate against tumor• f/b prodrug• Activated at tumor site by the enzyme• Eg: Etoposide, taxol, camptothecin
    90. 90. Nanotechnology• Highly targeted therapy with high efficacy & low toxicity.• Transport of drug across BBB.• Deliver anticancer drugs into cellswithout triggering p- glycoprotein pump• Paclitaxel, Doxorubicin, Dexamethasone 5- FU
    91. 91. Carbon nanotubes• Well ordered, hollow nanotubes• Single or multiple graphene sheetsrolled into a cylinder• Single & multiwalled carbon nanotubes• Consist of fluorescent marker anda monoclonal antibody at non-binding sites• Penetrate cell membranes• Delivery anticancer drug• Eg: doxorubicin
    92. 92. Superparamagnetic nanoparticles• Iron oxide magnetic nanoparticles• Functionalized with recombinant single chain Fv antibodyfragments• Target cancer cells• Injected into the tumor and then heated in an alternatingmagnetic field
    93. 93. Oncolytic Viruses• Viruses that replicate selectively in tumor cells with definedgenetic lesions, causing cell death• Include adenoviruses & RSV• Designed to replicate in tumor cells that lack functional p53• Lysis→ Release inflammatory mediators (GM-CSF & TSA)→Dendritic cells→ Immune response throughout the body
    94. 94. Cancer Vaccines• Cancer vaccine contain cancer cells, parts of cells or pure antigens• ↑ immune response against cancer cellsAutologous• Made from killed tumor cells taken from the same person• Whom they will later be used• Limitations:Expensive to create a new, unique vaccine for each patient.Cells tend to mutate over timeAllogeneic• Use cells from a stock of cancer cells• Mixture of cells removed from several patients
    95. 95. I. Antigen vaccines• Specific for specific cancer• Boost immune system by using one antigen (or a few)• Antigens are usually proteins orpieces of proteins called peptides• Eg: CDK-4 & β-catenin→ Melanoma• Prostate cancer vaccine, Sipuleucel-T (Provenge®)Recently been approved → Advanced prostate cancerProstatic acid phosphatase (PAP).II. Dendritic cell vaccines• Dendritic cells→ special antigen-presenting cells• Break down cancer cells & present to T cells• Exposed to cancer cells or cancer antigens• Develop cancer antigens on their surface• Help immune system recognize and destroy cancer cellsthat have those antigens on them
    96. 96. III. DNA vaccines:• Cells can be injected with bits of DNA• Code for Cancer cell protein antigens• Done by DNA vectors→ plasmids• Integrated into cells• Skeletal muscle cells & adipose cells• Altered cells would then make the antigen on an ongoing basis• Keep the immune response strong
    97. 97. IV. Telomerase vaccine:• Loss of telomeric repeats with each cell division cycle→gradual telomere shortening→ growth arrestReplicative senescence• Telomerase→ Reverse transciptase → elongates telomeres• >90% human cancers express high levels of telomerase• In vitro studies, inhibition of this telomerase→leads to tumor cell apoptosis• Phase I clinical studies
    98. 98. Chemoprevention• Adjuvant Isotretinoin→ ↓incidence of second primary tumors inpts. treated with local therapy for H & N cancer• Oropharyngeal premalignant lesions responded toβ- carotene, retinol, Vit E, Selenium• Diets high in calcium, lower colon cancer risk• Men taking Selenium to prevent skin cancer→ ↓ incidence ofprostate cancer.• Potential of COX- 2 inhibitors to prevent colorectal cancercontinues to remain a subject of study
    99. 99. Other Treatment Modalities1. Hormones2. Immunomodulators3. Radioisotopes4. Complementary System of Medicine
    100. 100. ConclusionThe period from 1980 to the present has seen a remarkablegrowth in the understanding of many of the cellular andmolecular mechanisms underlying malignant transformation ofa cell.Given our increasing knowledge about the biology of cancer,it is clear that no single therapy will serve as a panacea & it ismost likely that in the near future, agents directed against themolecular events will have to be combined with the existingstandard chemotherapies for the desired outcome