New Gefitinib Data - Furthering Understanding of Molecular & Genetic Basis for Anti-Cancer Activity
LONDON, March 31 /PRNewswire/ --
At the 95th annual American Association for Cancer Research (AACR) meeting in Orlando, USA, AstraZeneca Plc (LSE: AZN.L - news - msgs) reported new gefitinib (IRESSA(tm), ZD1839) data exploring mechanisms of drug activity and resistance, as well as new data relating to novel anti-angiogenesis drugs ZD6474 and AZD2171 that have potential in a wide range of tumours.
Furthering scientific understanding of anti-cancer activity and mode of action of gefitinib
The advancement of powerful pharmacogenomic technologies enables scientists to investigate why some patients respond to particular medicines and why some do not. Many factors influence a patient's response to a drug, but identifying and understanding specific genes that may influence response is an important area of research, and may enable drugs to be targeted for specific individuals in the future. New data add to the growing body of evidence about how gefitinib works at a molecular level and shed light on the genetic '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 who demonstrated a near-complete response to gefitinib sustained for 18 months before relapsing. Sequencing of the EGFR gene in the tumour after relapse demonstrated a somatic mutation in the receptor and functional analysis of this mutant is in progress.
- In a preclinical study reported by Benavente et al(2), cells were made resistant to gefitinib or to the EGFR monoclonal antibody (MAb), cetuximab. The results showed cells which were made resistant to the EGFR MAb still responded to gefitinib; conversely cells made resistant to gefitinib did not respond to EGFR MAb.
- Hayama et al(3) reported initial findings from a study aimed at identifying genes which could be important in the onset of gefitinib resistance.
- Changes in biomarkers associated with the decrease in cell growth and survival following gefitinib were reported by Speake(4) at al; these data contribute further to understanding the mode of action of gefitinib.
A large programme of work is ongoing, directed at fully understanding mechanisms of resistance and the implications for optimal treatment sequencing strategies. In addition, several pre-clinical abstracts reported the feasibility of a range of combinations of gefitinib with other agents such as cetuximab, Cox-II inhibitors, TLK286 (Telcyta) and other cytotoxics.
Dr Alan Barge, gefitinib Worldwide Medical Director commented: "The advent of novel, targeted drugs, such as gefitinib, may herald a potential shift in the treatment of cancer, changing it from an acute, lethal disease to a chronic, manageable condition. The complexity and diversity of the signalling-pathways in cancer cells means that sophisticated studies like these will be necessary to fully understand how to select the patients most likely to benefit from drugs like gefitinib."
Encouraging new data in novel anti-angiogenesis agents
ZD6474 and AZD2171 are agents under development by AstraZeneca plc that target the process of angiogenesis through inhibition of vascular endothelial growth factor (VEGF) receptor signalling. Angiogenesis is the growth of blood vessels, which are required for tumour growth, invasion and metastasis. VEGF plays a key role in stimulating the formation and maintaining the viability of new tumour blood vessels. Agents that target angiogenesis are likely to have a very broad spectrum of anti-tumour activity.
ZD6474 is a potent once daily oral inhibitor of vascular endothelial growth factor receptor (VEGFR) signalling that has additional activity against epidermal growth factor receptor (EGFR) signalling. New research presented at AACR included:
- Results of a study assessing ZD6474 effect on lung angiogenesis and metastasis in an orthotopic model of non-small cell lung cancer that closely mimics the patterns of clinical disease. Herbst et al(5) reported that ZD6474 resulted in almost complete suppression of growth, invasion and metastasis of established lung tumours.
- A second study by Nishio et al(6) assessed the antitumour effect in a VEGF-producing primary gastric cancer model, and showed that ZD6474 treatment resulted in tumour regression and reduced tumour dissemination.
This year's meeting of AACR is the first time that data on AZD2171 has been presented. AZD2171 is a once-daily, oral inhibitor of vascular endothelial growth factor receptor (VEGFR) signalling. It is highly potent and selective without activity against EGFR. New data from a range of pre-clinical studies were presented:
- Research evaluated anti-tumour and anti-angiogenic activity in a spontaneous breast carcinoma model. Klinowska et al(7) reported results that showed a significant inhibition in tumour growth even at very low doses (0.75mg/kg/day). In established disease, AZD2171 also restricted tumour growth and at higher doses caused tumour regression.
- Drevs et al(8) presented data which showed that, in a model of kidney cancer, AZD2171 significantly inhibited primary tumour growth, metastatic spread and the development of tumour blood vessels, and had superior potency to 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 tumour model. Results showed significant reduction in tumour vascular permeability and vascular volume demonstrating direct effects of AZD2171 on tumour blood vessels.
ZD6474 is in phase II development, currently being studied in NSCLC, small cell lung cancer and other tumours as a monotherapy or in combination with cytotoxic chemotherapy. AZD2171 is currently in Phase I development and has potential for activity in a wide range of tumours, as well as for combining with other anti-cancer agents.
AstraZeneca has over 20 different anti-cancer projects in research and development including a range of novel targeted products such as anti-proliferatives, anti-angiogenics, vascular targeting and anti-invasive agents. AstraZeneca is also harnessing rational drug design technologies to develop new compounds that offer advantages over current cytotoxic and hormonal 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 |
