New Gefitinib Data - Furthering Understanding of Molecular & Genetic Basis for Anti-Cancer Activity

LONDON, April 1 -- PRNewswire/AsiaNet

First Data On Novel Anti-Angiogenesis Drug Also Reported By

AstraZeneca at AACR Meeting

At the 95th annual American Association for Cancer Research (AACR)meeting in Orlando, USA, AstraZeneca Plc reported new gefitinib (IRESSA(tm),ZD1839) data exploring mechanisms of drug activity and resistance, as well asnew data relating to novel anti-angiogenesis drugs ZD6474 and AZD2171 thathave potential in a wide range of tumours.

Furthering scientific understanding of anti-cancer activity and mode ofaction of gefitinib

The advancement of powerful pharmacogenomic technologies enablesscientists to investigate why some patients respond to particular medicinesand why some do not. Many factors influence a patient's response to a drug,but identifying and understanding specific genes that may influence responseis an important area of research, and may enable drugs to be targeted forspecific individuals in the future. New data add to the growing body ofevidence about how gefitinib works at a molecular level and shed light on thegenetic 'fingerprint' associated with gefitinib response:

Carbone et al(1) reported a case of a non-small cell lung cancer (NSCLC) patient with progression following four chemotherapeutic regimens whodemonstrated a near-complete response to gefitinib sustained for 18 monthsbefore relapsing. Sequencing of the EGFR gene in the tumour after relapsedemonstrated a somatic mutation in the receptor and functional analysis ofthis mutant is in progress.

In a preclinical study reported by Benavente et al(2), cells were maderesistant to gefitinib or to the EGFR monoclonal antibody (MAb), cetuximab.The results showed cells which were made resistant to the EGFR MAb stillresponded to gefitinib; conversely cells made resistant to gefitinib did notrespond to EGFR MAb.

Hayama et al(3) reported initial findings from a study aimed atidentifying genes which could be important in the onset of gefitinibresistance.

Changes in biomarkers associated with the decrease in cell growth andsurvival following gefitinib were reported by Speake(4) at al; these datacontribute further to understanding the mode of action of gefitinib.

A large programme of work is ongoing, directed at fully understandingmechanisms of resistance and the implications for optimal treatmentsequencing strategies. In addition, several pre-clinical abstracts reportedthe feasibility of a range of combinations of gefitinib with other agentssuch as cetuximab, Cox-II inhibitors, TLK286 (Telcyta) and other cytotoxics.

Dr Alan Barge, gefitinib Worldwide Medical Director commented: "Theadvent of novel, targeted drugs, such as gefitinib, may herald a potentialshift in the treatment of cancer, changing it from an acute, lethal diseaseto a chronic, manageable condition. The complexity and diversity of thesignalling-pathways in cancer cells means that sophisticated studies likethese will be necessary to fully understand how to select the patients mostlikely to benefit from drugs like gefitinib."

Encouraging new data in novel anti-angiogenesis agents

ZD6474 and AZD2171 are agents under development by AstraZeneca plc thattarget the process of angiogenesis through inhibition of vascular endothelialgrowth factor (VEGF) receptor signalling. Angiogenesis is the growth of bloodvessels, which are required for tumour growth, invasion and metastasis. VEGFplays a key role in stimulating the formation and maintaining the viabilityof new tumour blood vessels. Agents that target angiogenesis are likely tohave a very broad spectrum of anti-tumour activity.

ZD6474 is a potent once daily oral inhibitor of vascular endothelialgrowth factor receptor (VEGFR) signalling that has additional activityagainst epidermal growth factor receptor (EGFR) signalling. New researchpresented at AACR included:

Results of a study assessing ZD6474 effect on lung angiogenesis andmetastasis in an orthotopic model of non-small cell lung cancer that closelymimics the patterns of clinical disease. Herbst et al(5) reported that ZD6474resulted in almost complete suppression of growth, invasion and metastasis ofestablished lung tumours.

A second study by Nishio et al(6) assessed the antitumour effect in aVEGF-producing primary gastric cancer model, and showed that ZD6474 treatmentresulted in tumour regression and reduced tumour dissemination.

This year's meeting of AACR is the first time that data on AZD2171 hasbeen presented. AZD2171 is a once-daily, oral inhibitor of vascularendothelial growth factor receptor (VEGFR) signalling. It is highly potentand selective without activity against EGFR. New data from a range ofpre-clinical studies were presented:

Research evaluated anti-tumour and anti-angiogenic activity in aspontaneous breast carcinoma model. Klinowska et al(7) reported results thatshowed a significant inhibition in tumour growth even at very low doses(0.75mg/kg/day). In established disease, AZD2171 also restricted tumourgrowth and at higher doses caused tumour regression.

Drevs et al(8) presented data which showed that, in a model of kidneycancer, AZD2171 significantly inhibited primary tumour growth, metastaticspread and the development of tumour blood vessels, and had superior potencyto all other VEGF inhibitors previously tested in this model.

An additional study by Bradley et al(9) reported the impact of AZD2171 on VEGF-dependent vascular permeability in tumours in an human colon tumourmodel. Results showed significant reduction in tumour vascular permeabilityand vascular volume demonstrating direct effects of AZD2171 on tumour bloodvessels.

ZD6474 is in phase II development, currently being studied in NSCLC,small cell lung cancer and other tumours as a monotherapy or in combinationwith cytotoxic chemotherapy. AZD2171 is currently in Phase I development andhas potential for activity in a wide range of tumours, as well as forcombining with other anti-cancer agents.

AstraZeneca has over 20 different anti-cancer projects in research anddevelopment including a range of novel targeted products such asanti-proliferatives, anti-angiogenics, vascular targeting and anti-invasiveagents. AstraZeneca is also harnessing rational drug design technologies todevelop new compounds that offer advantages over current cytotoxic andhormonal treatment options.

Notes to Editors:

IRESSA(tm) is a trademark of the AstraZeneca group of companies.

For further information on the Epidermal Growth Factor Receptor and its

potential role in cancer treatment, please visit www.EGFR-INFO.com

For further information on gefitinib and lung cancer, please visit

www.iressa.com

For further press information regarding gefitinib and other AstraZeneca

cancer therapies, please visit www.astrazenecapressoffice.com

References:

1. Ohm et al. Acquired EGFr TKI resistance associated with mutation of

EGFr. Abstract Number 2464. 95th AACR, March 2004

2. Benavente et al. Establishment of acquired resistance to epidermal

growth factor receptor (EGFR) inhibitors in human tumor cells.

Abstract Number 5333. 95th AACR, March 2004

3. Hayama H, et al. Cloning of candidate genes related to gefitinib

resistance. Abstract Number 4548. 95th AACR, March 2004

4. Speake et al. The characterisation of the downstream biomarkers for

erbB2 and EGFR inhibitors. Abstract Number 4653. 95th AACR, March 2004

5. Herbst R, et al. ZD6474, a small molecule targeting VEGF

and EGF receptor signaling, inhibits lung angiogenesis and metastasis

and improves survival in an orthotopic model of non-small cell lung

cancer. Abstract Number 4551. 95th AACR, March 2004

6. Nishio K, et al. Antitumor effect of ZD6474 in a VEGF-producing

primary gastric cancer model. Abstract Number 4537. 95th AACR, March 2004

7. Klinowska T, et al. AZD2171, a highly potent inhibitor of VEGF

receptor tyrosine kinase activity, inhibits the growth of spontaneous

mammary tumours in the MMTV-neu transgenic mouse. Abstract Number 4540.

95th AACR, March 2004

8. Drevs J, et al. Effect of AZD2171, a highly potent VEGF receptor

tyrosine kinase inhibitor, on primary tumour growth, metastasis and

vessel density in murine renal cell carcinoma. Abstract Number 4554.

95th AACR, March 2004

9. Bradley D, et al. The VEGF signalling inhibitors ZD6474 and AZD2171

compromise hemodynamic parameters in an SW620 human colon tumour model:

an analysis using perfusion-permeability dynamic contrast-enhanced

magnetic resonance imaging (pp-DCE-MRI). Abstract Number 4552. 95th

AACR, March 2004

For further information, please contact:

Lee Tomkins,

IRESSA(tm) - Global PR,

Tel: +44 (0) 1625 232685,

Mobile: +44 (0) 7796 314697,

[email protected];

Lynn Grant,

Development Compounds - Global PR,

Tel: +44 (0) 1625 517406,

Mobile: +44 (0) 7715 484917,

[email protected];

Louise Marland,

IRESSA(tm) - Global PR,

Tel: +44 (0) 1625 510782,

Mobile: +44 (0) 7900 607794,

[email protected]

SOURCE: AstraZeneca

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New Gefitinib Data - Furthering Understanding of Molecular & Genetic Basis for Anti-Cancer Activity

ข่าวAstraZeneca+First Dataวันนี้

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