Recent Advancesin Cancer Chemotherapy

Dr. Kunal A. Chitnis1st Year ResidentT.N.M.C., Mumbai12th March 2011

Carcinos means crab

Over 100 different types of cancer & each is classified by the type of cell that is initially affectedSecond leading cause of death worldwide expected to increase five fold in the next 25 years

India:Prevalence 2.5 millionover 8,00,000 new cases & 5,50,000 deaths occur each yearMales: Oral CaFemale: Cervical Ca six persons die every day from cancer in India40- 50% directly or indirectly related to tobacco

A neoplasm, as defined by Willis, "an abnormal mass of tissue, the growth of which exceeds & is uncoordinated with that of the normal tissues, and persists in the same excessive manner after the cessation of the stimuli which evoked the change."

Benign, its microscopic and gross characteristics are considered to be relatively innocent, remain localized, cannot spread to other sites

Malignant, the lesion can invade and destroy adjacent structures and spread to distant sites

The Cell Cycle

Anti-Cancer Chemotherapy

The first efforts…..

Traced back to the observation by Louis Goodman and Alfred Gilman, of the profound lymphoid and myeloid suppression produced by sulfur mustard gas – a chemical warfare agent.

Cytotoxic Drugs

I. Alkylating Agents

MOA:

• Alkylate nucleophilic group of DNA bases (N7 Guanine)

• Abnormal base pairing, cross linking of bases & DNA strand breakage

• Cell cycle non-specific

Common adverse effects:1. Gastrointestinal distress2. Bone marrow supression3. Alopecia4. Secondary Leukamias5. Sterility6. Veno-occlusive disease of liver (↑dose)

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 of cyclophosphamide and ifosfamide

A. Nitrogen Mustards:

Currently used drugs:

Cyclophosphamide, Ifosfamide

Wegener’s granulomatosis, ALL, CLL, HL, NHL, Multiple myeloma (MM), breast, ovary, lung, Wilm’s, cervix, testis

Mechlorethamine Hodgkin’s disease

Melphalan Multiple myeloma, breast, ovary

Chlorambucil CLL, HL, NHL

Drug related side effects:

Cyclophosphamide, Ifosfamide: Hemorrhagic cystitis, SIADH

Newer Agents:

Trofosfamide

• Prodrug of ifosfamide• Orally active• Metastatic soft tissue sarcomas

Prednimustine

• Ester of prednisolone and chlorambucil• Better drug delivery• CLL, NHL, Ca breast• S/E: myelosuppression, fluid retension

Uramustine• Derivative of nitrogen mustard and uracil• Non Hodgkin’s lymphoma

Bendamustine• 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, hypersensitivity

reactions

B. Alkylsulfonates

Currently used: Busulfan → CMLS/E: Pulmonary fibrosis, hyperpigmentation, adrenal insufficiency

Newer drugs:

Mannosulfan• Tried for polycythaemia rubra vera• Lesser S/E • Phase 2

Treosulfan• Evaluated for ovarian cancers• Lesser S/E compared to busulfan

C. Nitrosoureas

• Highly lipid soluble • Cross blood brain barrier

Currently used agents:

Carmustine, Lomustine, Semustine → Brain tumours like gliomas

Streptozocin → pancreatic islet cell carcinoma, malignant carcinoid tumors

A/E: delayed myelosupression, renal failure

Newer Agents:

Fotemustine• Approved for metastasising melanoma

Nimustine• Oligodendroglioma, Glioblastoma Multiforme• Used with cytarabine

Ranimustine• Approved in Japan• CML and polycythemia vera

D. Other Alkylating agents

Currently used:

Procarbazine→ Hodgkin’s, brain tumors

Dacarbazine→ malignant melanoma, hodgkin’s lymphoma

Temozolomide→ malignant gliomas

II. Platinum Compounds

MOA:• 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, ototoxicity

Cisplatin 1st Generation Highly nephrotoxic

Carboplatin 2nd Generation Less nephrotoxic

Oxaliplatin 3rd Generation Cisplatin/ Carboplatin Resistant

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 1995

Triplatin 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

Picoplatin• Retains activity in Cisplatin & Oxaliplatin Resistant cells• Activity by i.v. & oral routes• Phase 3 small cell Lung Ca & Colorectal Ca

Aroplatin• Liposomal oxaliplatin• Incorporated in multilamellar liposomes• Good biodistribution• Well tolerated

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

Currently used agents:

Methotrexate→ Choriocarcinoma, ALL, Ca breast, head & neck Ca, Ca ovary, bladder

Pemetrexed→ Mesothelioma, NSCL Ca

A/E: bone marrow suppression, mucositis, hepatotoxicity; pulmonary fibrosis (methotrexate), rashes (pemetrexed)

Development of resistance:

• ↓ transport via folate carrier• ↓ formation of polyglutamates• ↑ formation of DHFRase• Altered DHFRase with ↓ affinity

Newer Drugs:

Trimetrexate:• Lipid soluble • Crosses BBB• Bypasses membrane transport system→ transport-deficient MTX-resistant tumour cells• Leiomyosarcoma & Skin Ca

Pralatrexate• Enters cells expressing ↓ folate carrier type 1 (RFC-1)• Relapsed or Refractory Peripheral T-cell lymphoma• FDA approval in September 2009

Raltitrexed• Quinazoline folate analogue • Selectively inhibits thymidylate synthase (TS)• Advanced colorectal cancer

Lometrexol• Inhibits GARFT as well as AICART• Inhibitor of de novo synthesis of purines• Phase 2 clinical trials: NSCL cancer

B. Purine Analogues

MOA:• Purine antimetabolites activated by HGPRTase• Incorporated into DNA & RNA nucleotides• Inhibits various enzymes of purine synthesis

Currently used agents:

6 Mercaptopurine AML

6 Thioguanine AML , ALL

Cladribine Hairy cell leukamia, CLL, NHL

Fludarabine CLL, NHL

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

C. Pyrimidine Analogues

MOA:

Cytarabine activated to arabinoside CTP→ Inhibit DNA polymeraseα/β 5-FU converted to 5-dUMP→ Inhibit Thymidylate synthase Capecitabine prodrug of 5-FU Gemcitabine Phosphorylated to GDP→ Inhibit Ribonucleotide Reducatase GTP→ Inhibit DNA polymerase α/β, incorporated in DNA Azacytidine & DecitabineDNA hypomethylation by inhibiting DNA methyl transferase

Cytarabine AML, ALL,CML in blast crises

5-FU Colorectal Ca, Anal Ca, Breast Ca, Gastro-esophageal Ca, Head & Neck Ca, hepatocellular Ca

Capecitabine Breast Ca, Colorectal Ca, Gastro-esophageal Ca, Hepatocellular Ca, Pancreatic Ca

Gemcitabine Pancreatic Ca, Bladder Ca, NSCL Ca, Ovary Ca, Soft tissue Sarcoma

Azacytidine & Decitabine

Pancreatic Ca, lung Ca, ovarian Ca, Myelodysplasia

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, HCC

Carmofur:• Oral lipophilic derivativeof 5-FU• Managable toxicities (hot flushes, urinary frequency)• Serious toxicity- Leucoencephalopathy• Adjuvant chemotherapy for curatively resected Colorectal Ca

IV. Mitotic Spindle Inhibitors

A. Vinca Alkaloids:

MOA:• Bind to microtubule protein-tubulin • Dissolve the assembly• Chromosomes cannot align along the division plate• Cell division arrests in Metaphase

Currently used Agents:

Vinblastine, Vinorelbine Hodgkin’s, NHL, Breast, Lung, Testis Ca

Vincristine ALL, Neuroblastoma, Wilm’s tumour, Rhabdomyosarcoma, Hodgkin’s, NHL

Adverse Effects:

• Vinblastine & Vinorelbine→ bone marrow depression (leukopenia)• Vincristine→ peripheral neuropathy

Resistance:

• ↑ Expression of mdr-1 gene→ ↑ P-glycoprotein (efflux protein)• Expression of Multidrug Resistant Protein & Breast Ca Related

Protein

Newer Agents:

Vinflunine:• More activity than vinblastine/vinorelbine• No peripheral neuropathy• Use: Advanced bladder Ca, advanced Breast Ca

Vindesine:• ALL, NSCL Ca• S/E local vescicant, myelosuppression, peripheral neuropathy

B. Taxanes

MOA:• Binds to β tubin subunit of micro-tubules• Antagonises its disassembly• Enhancement of tubulin polymerisation• Metaphase arrest

Currently Used agents:

Paclitaxel, Docetaxel Ovarian, Breast, Prostate, Bladder, Lung, Head & Neck Ca

A/E: Hypersensitivity reactions, myelosuppression, peripheral neuropathy

Resistance:

• ↑ Expression of mdr-1 gene→ ↑ P-glycoprotein• ↑ Survivin→ anti-apoptotic factor• β tubulin mutations• Upregulation of β tubulin isoforms

Newer Agents:

Nab-Paclitaxel:• Protein bound paclitaxel→ ↓ hypersensitivity reactions

Cabazitaxel:• Poor substrate for P-glycoprotein efflux pump • With Prednisolone→ Hormone refractory metastatic Prostate

Ca previously treated with Docetaxel containing regimen• FDA approved in june 2010• A/E: Myelosuppression, hypersensitivity reactions, diarrhea

Ortataxel:• Blocks its own efflux from gpP-overexpressing cells• Phase 2 • Tried for taxane refractory solid tumours (lung, breast, kidney)

Larotaxel:• Active against taxane-resistant & multidrug-resistant tumors• Crosses the blood brain barrier• Advanced Pancreatic Ca & Advanced bladder Ca with Brain metastasis• Phase 3

Tesetaxel:• Orally available• Eliminates transfusion reactions • ↓ incidence of peripheral neuropathy• Tried in Advanced gastric & advanced breast Ca• Phase 3

C. Epothiolones:

MOA:

• Bind to β tubulin• Stabilise the microtubules• G2M interphase arrest

Advantages:

• Less susceptible to gpP mediated Multi Drug Resistance• Superior cytotoxic potential compared to taxanes

Ixabepilone• With Capecitabine Locally advanced or metastatic Breast Ca not responding to Anthracyclins & Taxanes• Monotherapy Metastatic Breast Ca progressed through treatment with Anthracyclins, Taxanes & Capecitabine• A/E: neutropenia, peripheral neuropathy• Approved in 2007

Sagopilone• Natural product of epothilone B• ↑ effective in stabilizing preformed microtubules• Taxane-resistant settings• Crosses the blood-brain barrier• Use: Gastric cancer , NSCLC

Patupilone• Paclitaxel-resistant cancer cells • Target vasculature of solid tumor→ immature endothelial cells have strong dependence on tubulin in maintaining their shape• Phase 2 trials for solid tumours esp Ovarian Ca

KOS 1584/ 21 Aminoepothiolone• Phase 1 trials

V. Topoisomerase Inhibitors

A. Camtothecins:

MOA:• Inhibit topoisomerase I• ss breaks• Collision of replication fork with ss breaks→ ds DNA break• S phase specific

Currently used Agents

Irinotecan, Topotecan Colon, Lung, Ovary Ca

A/E: • Topotecan→ neutropenia• Irinotecan→ diarrhoea, cholinergic syndrome

Newer Agents:

Belotecan• Use ovarian cancer, small cell lung cancer

B. Antitumor Antibiotics

MOA:• 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

Currently used Agents:

Doxorubicin Breast Ca, HL & NHL, soft tissue sarcoma, Ovarian Ca, Lung Ca, Wilm’s tumor & Neuroblastoma

Daunorubicin AML, ALL

Idarubicin AML, ALL, CML in blast crisis

Epirubicin Breast Ca, Gastro-esophageal Ca

Mitoxantrone Hormone Refractory Prostate Ca, NHL, AML

A/E:Cardiotoxicity, myelosuppression, mucositis, radiation recall syndrome

Newer Drugs:

Aclarubicin• Inhihibits RNA synthesis more strongly than DNA• Cardiotoxicity less• Relapsed/ Resistant AML

Amrubicin:• Marketed in Japan for Small cell Lung Ca• Superficial bladder cancer and lymphoma

Pirarubicin:• More lipophilic derivative • Higher uptake rate of cells & better antitumor efficacy• Lower cardiotoxicity• Breast cancer, acute leukemias and lymphomas• Phase 3

Zorubicin:• Four times less cardiotoxic• Less myelosupression• Acute leukaemias & breast cancer• Phase 3

Valrubicin:• US FDA approved → BCG refractory bladder Ca insitu• Administered intravescically • Systemic absorbtion ↓• A/E: urinary frequency, urgency, dysuria

Pixantrone:• Analogue of mitoxantrone• Less cardiotoxic• Phase 3 • Relapsed or refractory aggressive NHL

Targeted Therapies

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

Function of Cyclins & Cyclin Dependent Kinases

B. Cyclin Dependent Kinase Inhibitors

• Over-expression of Cyclins & CDK’s in Ca• Inhibitors of cyclindependent kinases (CDKs) restore cell cycle control or induce apoptosis

Seliciclib:• Inhibit CDK2→ G1S check point• Inhibits CDK 7, 9 →inhibits RNA polymerase II dependent transcription→ inhibits anti-apoptotic proteins• NSCL Ca

Alvocidib (Flavopiridol):• Same mechanism• AML, CLL

Bortezomib• Binds to 20S core of 26S

proteosome & reversibly inhibits it

• FDA approved for Multiple Myeloma & Relapsed/Refractory Mantle Cell Lymphoma

• A/E: Thrombocytopenia, neutropenia, peripheral neuropathy

Salinosporamide A • Similar mechanism• Multiple myeloma• Preclinical studies

C. Proteosome Inhibtitors

Anagrelide:• Specific inhibition of thrombopoietin-mediated intracellular signaling• Reversibly disrupts MegaKaryocyte maturation→ post-mitotic phases of MK development• Inhibitory effects→ MK ploidy, size and cytoplasmic maturation• Thrombocythemia, primary/secondary to myeloproliferative

disorders• Oral→ first-pass hepatic metabolism→ active metabolite• A/E: Bone marrow fibrosis- reversible, cardiovascular effects• FDA approved in 2005

D. Phosphodiesterase Inhibitors

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

Drugs:

• Tiazofurin: Phase 3 for CML

• Selenazofurin :Phase 2

• Benzamide riboside: Phase 2

F. PARP Inhibitors:

• PolyADP-Ribose polymerase (PARP) → Base excision repair of ss DNA breaks• Inhibition: accumulation of ss breaks→ collision with DNA replication forks→ ds breaks• Ss break repaired by tumour-suppressor genes BRCA1 and BRCA2→ Homologous Repair • Mutated BRCA1 & 2→ mechanism defective

IniparibPhase 3 triple negative Breast Ca

OlaparibOrally activePhase 2 breast, ovary, colorectal Ca

VeliparibPhase 2 breast Ca, melanoma

G. Histone Deacetylase Inhibitor

Vorinostat• DNA warps around histones→ proteosomes• Acetylation of lysine residues→↑ spatial distance between DNA

& histones→ ↑ transcription activity• Acetyl group deacetylated by Histone Deacetylases (HDACs)• Refractory Cutaneous T-Cell Lymphoma• A/E- thrombocytopenia, QT prolongation

Romidepsin• Similar mechanism• Approved Cutaneous T-Cell Lymphoma & Peripheral T Cell Lymphoma

Other HDAC Inhibitors in pipeline

Phase 3:• Panobinostat

Phase 2:• Belinostat• Mocetinostat

II. Receptor Antagonists:

A. Endothelin Receptor Antagonist (ERA)

• Endothelin receptors are ETA, ETB1, ETB2

• G-Protein coupled receptors• Control vascular tone• ETA Vasocontriction, ETB Vasodilation

Atrasentan• ERA for subtype ETA

• Vasodilation→ ↑ tumor perfusion, ↓ hypoxia• ↑ drug delivery, ↑ sensitivity to drug & radiation• NSCL Ca• Phase 3

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, thyroid hormone receptor & PPAR• Heterodimer binds DNA→ expression of retinoid regulated

genes

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 lymphoma refractory to at least one prior systemic therapy• Gel & oral

C. Miscellaneous

Amsacrine• 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

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

Tyrosine Kinase Inhibitors

Protein kinase phosphorylate proteinsFunctional change of target protein→ change enzyme activity, cellular location or association with other proteins

Tyrosine kinases→ subgroup of protein kinases Phosphorylation of proteins→ Gene trancription &/or DNA synthesisFunctions as "on" or "off" switchMutated, stuck in the "on" position→ unregulated growth of the cell→ Cancer

I. Receptor Tyrosine Kinase Inhibitors

A. Epidermal Growth Factor Receptor Inhibitor/ HER 1 Inhibitor

Geftinib:• Inhibits EGFR tyrosine kinase activity• Blocks ATP binding site• Oral administration• Approved for NSCLC pts. who have failed withstd. chemotherapy • A/E: diarrhoea, pustular/papularrash

Erlotinib• Similar mechanism of action• Locally advanced or metastatic NSCL & Pancreatic Ca• A/E: same

B. EGFR/HER1 & HER2/neu Inhibitor

Lapatinib• Inhibits EGFR & HER2/neu Kinase activity• ATP binding pocket• Approved for Trastuzumab Refractory breast Ca with Capecitabine• Small molecule→ Crosses BBB→ Brain mets (Phase 3)• A/E: acneform rash, GERD, diarrhea

Afatinib:• Similar mechanism• Phase 3: NSCL Ca

Neratinib:• Phase 2: Breast Ca

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

C. Multiple Receptors Inhibitor

Sunitinib:• Inhibits multiple tyrosine kinases VEGFR 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 events

Sorafenib• Inhibits multiple tyrosine kinases VEGFR 1, 2 & 3, PDGFR β (angiogenesis); c-KIT, b-RAF (cell proliferation)• Hepatocellular Ca & metastatising RCC• A/E: same

Pazopanib

• Multi-targeted receptor tyrosine kinase inhibitor VEGFR-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

II. Non Receptor Tyrosine Kinase Inhibitors

A. bcr-abl Inhibitor

Has activity against:• bcr-abl Tk→ CML• Mutant c-KIT Tk→ GIST• Mutant PDGFR→ CMML, hypereosinophilia $, dermatofibrosarcoma protuberans

Currently used:• Imatinib

Newer Agents:

Dasatinib:• Binds of open & closed configurations• Approved for CML→ Intolerant/ Resistant to Imatinib

Nilotinib:• ↑Potency & ↑ Efficacy• Long t1/2 17 hrs• Approved for CML→ Intolerant/ Resistant to Imatinib

A/E:• GI distress→ N, V, diarrhoea• Edema & peri-orbital swelling• Nilotinib→ Prolongs QT interval

B. Src tyrosine kinase inhibitor

Bosutinib:

• Inhibits the autophosphorylation of bcr-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

C. Janus Kinase 2 Inhibitors

Lestaurtinib

• JAK enzymes→ signaling of cytokine & growth factor receptors

• JAK/STAT signaling exaggerated in MPNs• Polycythemia vera, essential thrombocythemia & primary

myelofibrosis • Mutant JAK2 activity• Inhibits wild type JAK2 kinase activity→ JAK2/STAT5 signaling in cells• Inhibits proliferation MPD cells• Phase II AML & Myeloproliferative disorders

D. EML4-ALK Fusion Inhibitor

Crizotinib

• Non–small-cell lung cancers→ echinoderm microtubule-associated like-protein 4 anaplastic 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)

E. Fusion Protein Against VEGF

Aflibercept

• Fusion protein: VEGFR1 and VEGFR2 , fused to the constant region of human IgG1

• VEGF → angiogenic factors includes VEGF-A, VEGF-B, and placental 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

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 of

Apoptosis• Chimerisation/ Humanisation→ ↓ immunogenic, ↑ efficient & longer acting

• Limitations

Antigen distribution of malignant cells is highly heterogeneous Tumor blood flow is not always optimal High interstitial pressure within the tumor

mAb Antigen Cancers treated

Rituximab CD20 B Cell Lymphomas

Trastuzumab HER-2 / neu Breast Ca

Gemtuzumab CD33 AML

Alemtuzumab CD52 CLL

Cetuximab EGFR Colorectal, head & neck Ca

Panitumumab EGFR Colorectal Ca

Bevacizumab VEGF Colorectal, breast & NSCL Ca

Ofatumumab CD20 B cell CLL

I. Monoclonal Antibodies

II. Radioimmuno- Conjugated Monoclonal Abs:

• RICs provide targeted delivery of radioactive particles to tumor cells

Currently Approved:

• Developed with Murine mAbs against CD20 conjugated with 131I – (131I – tositumomab) & 90Y – (90Y – ibritumomab tiuxetan)

• Both drugs→ Relapsed lymphoma.

• However, reports of secondary leukemias.

III. Monoclonal Ab- Cytotoxic Conjugate

• Enhances its cytotoxicity & drug delivery

Currently used

Gemtuzumab ozogamicin:mAb against CD33, linked to a semi-synthetic derivative of Calicheamicin, an enediyne antitumor antibiotic.

Newer Agents

Trastuzumab-maytansinoid• Trastuzumab linked to DM1• Trastuzumab → Ab against Her2 receptors• DM1→ microtubule-depolymerizing agent• Patients with Her2-positive metastatic breast cancer

Gemtuzumab zogamicin• Humanized anti-CD33 monoclonal antibody conjugated with Calicheamicin CD33→ Myeloid lineage• Calicheamicin → enediyne antitumor antibiotic• Binds to the minor groove of DNA→ ds breaks• FDA approval AML

Others in Pipeline:

• Methotrexate (MTX) conjugated with murine monoclonal antibody (aMM46) mouse mammary tumor antigen (MM antigen)

• Paclitaxel-antibody conjugates

• Antibody Linked To Ricin Toxin

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

Solubilisers• Majority anticancer drugs→ poor solubility• Newer agents→ Sorporol 230, Sorporol 120 Ex,

Aceporol 345-T, Riciporol 335

Self-Emulsifying Drug Delivery Formulations (SEDDS)• Enhance oral absorption of poorly soluble drugs

Implantable 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

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

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

Immunoliposomes• Antibodies or ligands are attached to the liposome surface • ↑ binding to specific epitopes/receptors on target cells

Stealth liposomes• Formulated to escape RES• ↑ the circulation time→ Depot preparations • Coat→ Polymers, polyethylene glycols, synthetic phospholipids• Hematological malignancies

Proteins & Amino acids as Carrier system• D-alanine with nitrogen mustard→ good bioavailability• Serum albumin of human, bovine or rat origin

Cyclodextrins• Carbohydrate macrocycles• Form molecular inclusion complexes with hydrophobic molecules• A/E renal toxicity• Eg: melphalan & carmustine

Dendrimers• Repeatedly branched, roughly spherical large molecules• Drug can be coupled to the core or surface of dendrimer• Polyamidoamine→ targeted drug carrier• Eg: Dendrimer platinate→ ↓ toxic than cisplatin

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

Nanotechnology

• Highly targeted therapy with high efficacy & low toxicity.• Transport of drug across BBB.• Deliver anticancer drugs into cells without triggering p- glycoprotein pump• Paclitaxel, Doxorubicin, Dexamethasone 5- FU

Carbon nanotubes

• Well ordered, hollow nanotubes • Single or multiple graphene sheets rolled into a cylinder• Single & multiwalled carbon nanotubes• Consist of fluorescent marker and a monoclonal antibody at non-binding sites• Penetrate cell membranes• Delivery anticancer drug• Eg: doxorubicin

Superparamagnetic nanoparticles• Iron oxide magnetic nanoparticles• Functionalized with recombinant single chain Fv antibody fragments• Target cancer cells• Injected into the tumor and then heated in an alternating magnetic field

Oncolytic Viruses

• Viruses that replicate selectively in tumor cells with defined genetic 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

Cancer Vaccines

• Cancer vaccine contain cancer cells, parts of cells or pure antigens

• ↑ immune response against cancer cells

Autologous• 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 time

Allogeneic • Use cells from a stock of cancer cells• Mixture of cells removed from several patients

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 cancer Prostatic 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 cells that have those antigens on them

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

IV. Telomerase vaccine:

• Loss of telomeric repeats with each cell division cycle→ gradual telomere shortening→ growth arrest Replicative 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

Chemoprevention

• Adjuvant Isotretinoin→ ↓incidence of second primary tumors in pts. treated with local therapy for H & N cancer

• Oropharyngeal premalignant lesions responded to β- carotene, retinol, Vit E, Selenium

• Diets high in calcium, lower colon cancer risk

• Men taking Selenium to prevent skin cancer→ ↓ incidence of prostate cancer.

• Potential of COX- 2 inhibitors to prevent colorectal cancer continues to remain a subject of study

Other Treatment Modalities

1. Hormones

2. Immunomodulators

3. Radioisotopes

4. Complementary System of Medicine

ConclusionThe period from 1980 to the present has seen a remarkable growth in the understanding of many of the cellular and molecular mechanisms underlying malignant transformation of a cell. Given our increasing knowledge about the biology of cancer, it is clear that no single therapy will serve as a panacea & it is most likely that in the near future, agents directed against the molecular events will have to be combined with the existing standard chemotherapies for the desired outcome