targeted cancer therapies

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Increased response to growth signals

Evasion of apoptosis

Insensitivity to anti-growth signals

Limitless replication potential

Sustained angiogenesis

Tissue invasion and metastasis

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Aberrant growth factor receptors

Anti-Cancer drugs

Dysregulated intracellular

signalling pathways

Defective DNA repair

& apopto

sis

Tumour

angiogenesi

s

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Achilles’ heel that the therapist can attack

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Targeted cancer therapies

Dr. Pooja Vaidya (Second year Resident)

Guide: Dr. Sandhya KamatProfessorDept. of Pharmacology & Therapeutics

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“Targeted cancer therapies are drugs that interfere with specific molecular structures implicated in tumor growth

and progression”

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Targeting nuclear factors

Targeting cell survival

Targeting angiogenesis

Targeting cellular proliferation

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Primary tools for targeted therapyMonoclonal antibodies

Small synthetic molecules

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ABL – BCR kinase inhibitors

EGFR inhibitors

VEGFR inhibitors

Multi-targeted TK inhibitors

Drugs targeting nuclear receptors

mTOR inhibitors

Other kinase inhibitors

Monoclonal antibodies

Combination therapies


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Monoclonal antibodies

• Block cell surface receptors

• Can carry toxins and radionuclides to the cells of interest thereby enhancing their cytotoxic effects

• Specific for a single receptor

• Long plasma half life

• Intermittent administration

Small molecules• May also exert effect

by entering cells and inhibiting enzymatic functions• May inhibit multiple

enzymatic sites• Half life is 12 – 24

hours• Daily administration

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518 Protein kinases

91 Protein tyrosine kinases (PTKs)

Serine/threonine kinases & others

Eg: TGF-β, RAF, ERK, MEK, Cyclin dependent

kinases59 Receptor PTKs

32 Non receptor PTKsEg. ABL, JAKTrans membrane glycoproteins

Eg: ErB family of receptors, PDGFR


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Imatinib mesylate First molecularly targeted protein kinase inhibitor

to receive FDA approval in 2003 Targets the BCR-ABL tyrosine kinase in a closed or

inactive configuration

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Resistance to Imatinib

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To overcome the resistance to Imatinib

binds to multiple states of kinase including active conformation

targets both ABL & SRC kinases

active against almost all of the clinically relevant mutants, the exception being the T315I mutant

more potent and less toxic than Imatinib

Target the active kinase

conformationTarget substrate

binding site

ON012380Dasatinib & Nilotinib

Effective against all mutants including T315I

Synergises well with Imatinib

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Imatinib, Dasatinib & Nilotinib Additional therapeutic benefits in,

GIST ( kit mutation positive) Chronic myelomonocytic leukemia Hypereosinophilia syndrome Dermatofibrosarcoma protuberans

Dose: Imatinib: 250 – 750mg/day Dasatinib: 100 mg daily (chronic CML) 70 mg BD (advanced CML) Nilotinib: 400 mg twice daily Bioavailability of Nilotinib increases in the presence of

food ADR: Fluid retention & hepatotoxicity

Dasatinib may cause pleural effusions Nilotinib may prolong the QT interval

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EGFR/ ErbB1 inhibitors

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EGFR/ ErbB1 inhibitors

CetuximabPanitumum

ab

Gefitinib Erlotinib

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Gefitinib and Erlotinib Responsive tumors have specific activating mutations

in the EGFR kinase domain which convert EGFR into a strongly oncogenic form that can be an essential tumor survival factor

Act by targeting tumor survival factors Standard dose of Gefitinib is 250 mg daily In 2003, Gefitinib was approved for the third-line

treatment of patients with NSCLC, but, two large trials have failed to demonstrate significant survival benefit

But, Gefitinib continues to be widely used outside the U.S

Both metabolized by CYP3A4

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Erlotinib is approved for, Second-line treatment of patients with locally

advanced or metastatic NSCLC (150 mg daily ) First-line treatment of patients with locally

advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine (100 mg daily )

Food increases bioavailability of Erlotinib to 100%, so should not be taken with food

Concurrent PPI decreases the bioavailability of Erlotinib by 50%

ADR: Diarrhoea , pustular/papular rash Asymptomatic increases in liver transaminases Interstitial lung disease in <2% cases but may have a fatal outcome.

Gefitinib and Erlotinib

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Resistance to Gefitinib and Erlotinib

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Cetuximab & PanitumumabCetuximab: recombinant chimeric human/mouse IgG1 antibodyPanitumumab: recombinant, fully humanized IgG2 antibodyBind to extracellular domain of EGFR, blocking cell growth and survival signals

CetuximabPanitumum

ab

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Cetuximab is FDA approved for, locally or regionally advanced HNSCC EGFR-positive metastatic colorectal cancerSingle loading dose of 400 mg/m2 I.V. followed by weekly doses of 250 mg/m2

Panitumumab FDA approved as, First-line therapy in combination with FOLFOX in

patients with wild-type KRAS mCRCBased on improved OS of 4.4 months in phase 3 PRIME study Dose: 6 mg/kg intravenously given once every 2 weeks

ADR: Acne form rash, headache, and diarrhoea Cardiopulmonary arrest, interstitial lung disease, and hypomagnesemia

Cetuximab & Panitumumab

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ErbB2 or HER 2/neu inhibitors

First mab approved for solid tumor

Currently approved for HER2/neu-overexpressing metastatic breast cancer, in combination with paclitaxel as initial treatment or as monotherapy following chemotherapy relapse

Most serious toxicity is cardiac failure

Trastuzumab

Lapatinib

Blocks both ErbB1 and ErbB2

Inhibits the truncated form of HER2 that lacks the trastuzumab binding domain

FDA-approved for HER2-amplified, trastuzumab-refractory breast cancer, with capecitabine

Crosses the BBB ADR: Diarrhoea, rash

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Targeting angiogenesisJudah Folkman: opened the field of anti-angiogenesis therapyJain: proposed an additional mechanism,

Capillary permeability and tumor interstitial pressure

Inhibition of blood flow and drug delivery within the tumor

Targeting primary angiogenic factor would normalize interstitial pressure & improve blood flow

Enhance the ability of chemotherapeutic agents to reach the tumor

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VEGF inhibitorsBevacizum

ab

SunitinibSorafenib

Aflibercept

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Bevacizumab FDA approved for,

mCRC with combination chemotherapy First-Line Treatment of NSCLC in combination with

carboplatin and paclitaxel Metastatic RCC in combination with interferon-

alpha As a single agent following prior therapy for GBM Recurrent, or metastatic cervical cancer in

combination with paclitaxel

Doses vary reflecting the designs of approval directed trials

Plasma t1/2: 4 weeks ADR: Risk of bleeding, hypertension, proteinuria,

arterial thromboembolic event, GI perforation

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Sunitinib and Sorafenib Multi-targeted tyrosine kinase inhibitor

Targets tyrosine kinase domain on the VEGFR-2, FLT3, PDGFR-α, PDGFR- β , RET, CSF-1R, and c-KIT

Sunitinib approved for treatment of advanced renal-cell carcinoma and Imatinib resistant GIST50 mg once a day for 4 weeks followed by 2 weeks off treatmentMetabolized by CYP3A4 and t1/2 is 80 - 110 hours

Sorafenib is the only drug currently approved for treatment of hepatocellular carcinomaAlso approved in metastatic renal-cell cancer400 mg twice daily without treatment breaksMetabolized by CYP3A4 and t1/2 is 20 - 27 hours

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RapamycinTemsirolimusEverolimus

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PI3K/PKB(Akt) /MTOR inhibitors

FDA approved Temsirolimus and Everolimus for Renal cancer

Dose: Temsirolimus 25 mg/week IV Everolimus 10 mg/day oral Administered in the fasting state at least 1 hour before

a meal Also, implicated in,

Hepatocellular cancer Mantle cell lymphoma Endometrial cancer

Metabolized by CYP3A4 Toxicity: maculopapular rash, mucositis, anemia, and

fatigue

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Mitogen-activated protein kinase (MAPK) pathway

PD325901AZD6244 (II)GSK1120212

(I)

PLX4032 (III)GSK2118436

(I)

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Other kinase inhibitors Drug Target Disease Clinical

trial stageOther potential

indicationsCrizotinib (PF02341

066)

ALK Lung cancer (EML4-ALK fusion)

Phase 3 Anaplastic lymphoma,neuroblastoma,Inflammatory myofibroblasticsarcoma

Vandetanib,

Sorafenib,Motesanib

RET Thyroid cancer

Phase 3

Midostaur

inAC220

FLT - 3 FLT mutant Acute myeloid leukaemia

Phase 3 FLT mutant ALL

INCB018424

TG101348

JAK-2 Myelofibrosis

Phase 3Phase 2

Polycythemia veraEssential thrombocytosis

AxitinibTivozanibPazopanib

VEGFR Renal cancer

Phase 3 Hepatocellular carcinoma

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Targeting nuclear factors: Bortezomib NF-κB: tumor survival factor in hypoxic environment

and during chemotherapy Blocks ubiquitin proteasomal protein degradation

pathway, thereby preventing the transcriptional activity of NF-κB and down regulating survival responses

FDA approved as initial therapy for Multiple Myeloma and as

therapy for MM after relapse from other drugs for relapsed or refractory mantle cell lymphoma Dose: 1.3 mg/m2 I.V. bolus on days 1, 4, 8, and 11 of

every 21-day cycle with a 10-day rest period per cycle

Plasma t1/2: 5.5 hours Toxicity: Pancytopenia, fatigue, peripheral

neuropathy, hypotension

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Targeted Anticancer Therapies Using Antibodies

Monoclonal antibodies have become a major strategy in clinical oncology

Specifically bind to primary and metastatic cancer cells with high affinity

Antitumor effects by complement mediated cytolysis and antibody-

dependent cell-mediated cytotoxicity (naked antibodies)

By the focused delivery of radiation or cellular toxins (conjugated antibodies)

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Targeted Anticancer Therapies Using Antibodies

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Generic name

Target; Format

Indication EU approv

al

US approv

alRituximab CD20; Chimeric

IgG1NHL 1998 1997

Trastuzumab

HER2; Humanized IgG1

Breast cancer 2000 1998

Gemtuzumab

ozogamicin

CD33; Humanized IgG4

AMLNA

2000 ##

Alemtuzumab

CD52; Humanized IgG1

CLLMultiple sclerosis

2001 ##

2013

2001 ##2014

Ibritumumab tiuxetan

CD20; Murine IgG1

NHL 2004 2002

Tositumomab- I131

CD20; Murine IgG2a

NHL NA 2003 ##

Approved Monoclonal antibodies

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Approved Monoclonal antibodies Generic name

Target; Format Indication

EU appro

val

US appro

valCetuximab EGFR; Chimeric IgG1 Colorectal

cancer 2004 2004

Bevacizumab

VEGF; Humanized IgG1

Colorectal cancer

2005 2004

Panitumumab

EGFR; Human IgG2 Colorectal cancer

2007 2006

Ofatumumab

CD20; Human IgG1 CLL 2010 2009

Ipilimumab CTLA-4; Human IgG1 Metastatic

melanoma

2011 2011

Brentuximab

vedotin

CD30; Chimeric IgG1; Immunoconjugate

Hodgkin lymphom

a

2012 2011

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Approved Monoclonal antibodies Generic name

Target; Format Indication

EU approv

al

US approv

al

Pertuzumab HER2; humanized IgG1

Breast Cancer

2013 2012

Ado-trastuzumab emtansine

HER2; humanized IgG1; Immunoconjugate

Breast cancer

2013 2013

Obinutuzumab

CD20; Humanized IgG1; Glycoengineered

CLL 2014 2013

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Monoclonal antibodies in review

Generic name

Target; Format

Indication

EU approv

al

US appro

valRamucirumab VEGFR2;

Human IgG1Gastric cancer

Pending 2014

Pembrolizumab PD1; Humanized IgG4

Melanoma In review

2014

Nivolumab PD1; Human IgG4

Melanoma In review

2014

Blinatumomab CD19, CD3 ALL In review

2014

Necitumumab EGFR; Human IgG1

NSCLC In review

In review

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Target and drug evaluationTarget

validationAppropriate preclinical models

Desired target is known to be expressed Target is important for cell/ tumour survival

In - vitro screening In - vivo models

a cancer cell line /genetically engineered cell line

Lead compound tested for target inhibition

Confirmed by biochemical studies

Xenograft model in immunocompromised miceOrthotopic grafts: metastatic cancer

Transgenic models

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Combination therapies

To target the cancer stem cells Eg: Interferon + Imatinib for CML To target several different pathways that

affect tumor growth Eg: Erlotinib and Bevacizumab in RCC Targeted inhibition can sensitize cancers

to chemotherapy and radiotherapy Eg: Trastuzumab + chemotherapy in breast cancer

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Take home message… Molecularly targeted therapy is a new way of

approaching cancer treatment Involves rational selection of drugs which target

specific processes in cancer cells that make them different from normal cells

A number of targeted therapies are currently available and many others are in development

Targeted therapies are frequently effective but there are side effects to the treatments, and development of resistance

Targeted therapies are increasingly being used in combination with other targeted therapies or with other treatment modalities

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The Future Is Now: Pharmacogenomics and Personalized

Medicine Personalized treatment using genomic or

proteomic techniques To determine the most susceptible molecular

targets in a specific patient To predict the likelihood that a patient will respond to a specific chemotherapy regimen To predict the risk of toxic side effects

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targeted cancer therapies

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