Lapatinib (Tykerb)

• Inhibitor of intracellular tyrosine kinase domains of EGFR and HER-2

• Indicated in combination with Capecitabine in advanced / metastatic breast Ca overexpressing HER-2 after Tx with anthracycline, taxane and Trastuzumab

• Toxicity – GI toxicity, cardiac, pulmonary, hepatotoxicity

• Interactions – hepatically metabolised

Tykerb Mechanism of Action

PI3K

AKT

SURVIVAL

Ras

Raf

MEK1/2

ERK1/2 (MAPK)

PROLIFERATION

ErbB1 ErbB2

Cell SurfaceReceptors

TYKERB

works inside the cell targeting both receptors:

ErbB1 and ErbB2

Xia Xia et al. et al. OncogeneOncogene 2002;21:62552002;21:6255--63; Moy 63; Moy et al.et al. The OncologistThe Oncologist 2006;11:10472006;11:1047--11--57;57;RusnakRusnak et al. et al. Mol Cancer Mol Cancer TherTher 2001;1:852001;1:85--94; Tykerb Approved Product Information94; Tykerb Approved Product Information

Lapatinib (Tykerb)

• Inhibitor of intracellular tyrosine kinase domains of EGFR and HER-2

• Indicated in combination with Capecitabine in advanced / metastatic breast Ca overexpressing HER-2 after Tx with anthracycline, taxane and Trastuzumab

• Toxicity – GI toxicity, cardiac, pulmonary, hepatotoxicity

• Interactions – hepatically metabolised

Some more ‘Ibs’!

• Sunitinib (Sutent) – Advanced Renal Cell Ca & GI Stromal Tumours – **Adverse effects**

• Sorafenib (Nexavar) – Advanced Renal Cell Ca & Hepatocellular Ca

• Dasatinib (Sprycel) – CML & Ph+ ALL• Nilotinib (Tasigna) - CML

Temsirolimus (Torisel)

• Inhibitor of rapamycin (mTOR) kinase• mTOR is an intracellular serine-threonine

kinase, which lies at the hub of critical intersecting signalling pathways, and is a vital regulator of protein synthesis

• Inhibition of mTOR reduces synthesis of specific proteins which results in decreased tumour cell growth and proliferation and inhibition of angiogenesis.

mTOR Pathway

Temsirolimus (Torisel)• Indicated in advanced renal cell Ca

– Median survival - Torisel vs Interferon 10.9mths vs 7.3mths

• Not on the PBS• Toxicity – hypersensitivity (antihistamine

premed), hyperglycaemia, hyperlipidaemia, immunosuppression, impaired wound healing, renal failure, interstitial pneumonitis, etc., etc.!!

• Interactions – Sunitinib, CYP 3A4 inducers / inhibitors, ACE inhibitors

Bortozemib (Velcade)

• Reversible inhibitor of 26S proteosome• 26S Proteosome – large enzyme complex

– part of the ubiquitin-proteosome pathway • Inhibition of proteosome disrupts the

targeted proteolysis of ubiquinated proteins, interfering with various intracellular signalling pathways and resulting in cell death

X

X

X

Velcade

Bortozemib (Velcade)

• Indicated for the treatment of multiple myeloma patients who have received at least one prior therapy, and who have progressive disease

• PBS Indication – monotherapy or in combination with corticosteroid and/or cyclophosphamide, of progressive multiple myeloma, in patients who have failed one prior therapy.

Bortozemib (Velcade)

• Toxicity – fatigue, GI toxicity, haematological (esp thrombocytopenia), neurotoxicity (peripheral sensory or mixed sensorimotor neuropathy)

• Interactions: nil known but metabolised by 3A4 and 2C19 isoenzymes therefore caution advised with enzyme inducers / inhibitors, drugs associated with peripheral neuropathy

The Future?

• HDAC inhibitors• VDAs• More Ibs and Abs!

Histone Deacetylase Inhibitors• Deacetylases (DACs) are enzymes that can

regulate transcription and other cellular processes by the removal of acetyl groups from target proteins

• First major target for DACs are the histones – the core proteins in chromatin around which DNA is wrapped

• Second target is the non-histone proteins including transcription factors and other proteins which have been shown to modulate cancer cell growth and survival pathways

Histone p53 α-tubulin HSP90HIF-1α

DACs are Implicated in Multiple Hallmarks of Cancer

DAC depicts individual deacetylases, e.g. HDAC1, HDAC4, HDAC6

DACDAC DAC DAC

DAC

Tumor

suppressor

gene activity

Loss of

tumor

suppressor

function

Microtubule depolymerization/

aggresome

formation

VEGF OncoproteinsDownstream effects

Cell-cycle arrest

Apoptosis

Cell motility and Invasion

Cell proliferation and survival

Angiogenesis

Tumor effects

Proteins modulated

by DACs

DACDACDACDACDAC

Histone p53 α-tubulin HSP90HIF-1α

Pan-DAC Inhibition Interferes with the Multiple Hallmarks of Cancer

DAC depicts individual deacetylases, e.g. HDAC1, HDAC4, HDAC6

Cell-cycle arrest

Apoptosis

Cell motility and Invasion

Cell proliferation and survival

Angiogenesis

Tumor effects

Tumor

suppressor

gene activity

Loss of

tumor

suppressor

function

Microtubule depolymerization/

aggresome

formation

VEGF OncoproteinsDownstream effects

DACInhibitor

Proteins modulated

by DACs

Vascular Disrupting Agents• Tumour-VDAs in clinical development target

established blood vessels within the tumour, causing disruption of tumour vasculature, inhibition of tumour blood flow and tumour necrosis

• Anti-angiogenic agents predominantly inhibit neo-vascularization and are mainly cytostatic, showing activity mostly at the tumour periphery.

• VDAs however cause necrosis at the tumour core

• Several VDAs currently in phase I and phase II clinical trials

Br J Cancer 2007;96(8):1159-1165 Vascular Disrupting Agents in Clinical Development

Hands up cancer cell you are

surrounded by our agents

Help Help

The side effects

Help help I’m a good guy

Don’t hurt me

Got you!

Whoops sorry you’re on our side-

you all look the same