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ERLOTINIB – A ONE STOP SHOP

Introduction: The HER (EGFR) pathway and Erlotinib

Extracellular and intercellular signaling is a major process in the regulation of the life and death of cells within in any tissue matrix. One of the most well known and significant of these signaling steams is the HER protein family pathway consisting of four distinct receptors. Originally this was solely recognized as HER1 receptor called, due to its ligand association and since it was primarily found in epithelial cells, the “epithelial growth factor receptor”. Abbreviated to the acronym EGFR this receptor has since been found to have a family of 3 other closely related protein receptors, HER 2-4 [1-4]. Unfortunately these were known as ErB2-4 before the relationship with EGFR was determined, since then the entire family has been renamed to the HER family. These receptors consist of an extracellular section (head) with a Trans-membrane section and a cytosolic section (tail). Ligands binding to the extracellular domains initiate a dimerization between receptors which in turn induce conformational changes[5]. These changes expose the tyrosine kinase domains in the tail section of the protein. Auto-phosphorylation activates the protein and this in turn attracts ligand binding, in this way signals are transmitted from the systemic circulation into the cell and activates processes in the nucleus.

Erlotinib: Properties and Availability

The Erlotinib EFGR inhibitor has been approved for use in NSCLC after failure of a previous chemotherapy regime since 2004. In addition it has been approved for use in advanced pancreatic cancer when combined with Gemcitabine for naïve patients since 2005. Erlotinib is synthesized and marketed by Genetech using the trade name Tarceva but it has been also researched under the code OSI-774. The Erlotinib structure is based on a anilinoquinazoline containing two methoxy ether tails and an ethynyl substitution. Erlotinib is a specific inhibitor against EGFR with Erlotinib IC50 of approximately ± 2nM. Erlotinib solubility in water is poor for both the free base form and the Erlotinib HCl salt. Erlotinib is soluble in DMSO and ethanol to a maximal concentration of 200 mg/ml and 10 mg/ml respectively. Erlotinib stability is listed for its powdered form and this can be stored for upwards of 2 years if kept at -20oC or below. Researchers can buy Erlotinib from a variety of Erlotinib suppliers although Erlotinib cost is dependent on the supplier. Erlotinib price of a 1 g vial can range from $96 up to $192 for the free base and $96 up to $560 for the hydrochloride form; researchers are advised to shop very carefully for this product.

Erlotinib: FDA approval

Erlotinib lung cancer: - Erlotinib currently has approval status for three different specifications. As already indicated Erlotinib was approved for use in NSCLC after failure of a previous chemotherapeutic regime. Evidence for this was based on a phase III trial with locally advanced / metastatic NSCLC, which established that erlotinib significantly prolonged overall survival by 50%, when subdivided into EGFR+ and EGFR- the overall survival of the EGFR+ group compared to placebo was ~65%, whereas in the EGFFR- no significant effect was observed [10-12]. In addition to this approval Erlotinib was approved for a 2nd indication as maintenance therapy in 2010 for NSCLC with treatment for individuals who had stable disease after four courses of platinum therapy [13]

Erlotinib pancreatic cancer :   - The third approval for erlotinib came in 2005 with the combination of gemcitabine / Erlotinib in locally advanced or metastatic pancreatic carcinoma. Improvements in overall survival compared to gemcitabine alone were observed and on this basis the treatment was approved [14-20].

Erlotinib: Clinical trials in other Cancers

For Erlotinib breast cancer research:- Significant research has been done in Erlotinib mechanism of action in breast cancer. In combination or as a single therapy the general conclusions were all that patient screening for mutations in the EGFR and VEGFR genes were necessary to improve applicable treatment profiles [21-25]. Erlotinib has been investigation extensively elsewhere with good indications of progress in solid tumors, glioma’s, esophagus carcinoma and colorectal cancer. Over 40 clinical trials for Erlotinib are still ongoing, with 50+ reported in literature.

References

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    9.    Blackhall FH, Rehman S et al. Erlotinib in non-small cell lung cancer: a review. Expert Opin Pharmacother 2005; 6(6):995-1002.

  10.    Fuster LM, Sandler AB. Select clinical trials of erlotinib (OSI-774) in non-small-cell lung cancer with emphasis on phase III outcomes. Clin Lung Cancer 2004; 6 Suppl 1:S24-S29.

  11.    Perez-Soler R. The role of erlotinib (Tarceva, OSI 774) in the treatment of non-small cell lung cancer. Clin Cancer Res 2004; 10(12 Pt 2):4238s-4240s.

  12.    Perez-Soler R. Phase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (OSI-774) in non-small-cell lung cancer. Clin Lung Cancer 2004; 6 Suppl 1:S20-S23.

  13.    Dickson R, Bagust A et al. Erlotinib monotherapy for the maintenance treatment of non-small cell lung cancer after previous platinum-containing chemotherapy: a NICE single technology appraisal. Pharmacoeconomics 2011; 29(12):1051-1062.

  14.    Aranda E, Manzano JL et al. Phase II open-label study of erlotinib in combination with gemcitabine in unresectable and/or metastatic adenocarcinoma of the pancreas: relationship between skin rash and survival (Pantar study). Ann Oncol 2011.

  15.    Blanke CD, Beer TM et al. Phase II study of calcitriol-enhanced docetaxel in patients with previously untreated metastatic or locally advanced pancreatic cancer. Invest New Drugs 2009; 27(4):374-378.

  16.    Duffy A, Kortmansky J et al. A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma. Ann Oncol 2008; 19(1):86-91.

  17.    El-Rayes BF, Philip PA et al. A phase II study of isoflavones, erlotinib, and gemcitabine in advanced pancreatic cancer. Invest New Drugs 2011; 29(4):694-699.

  18.    Feliu J, Borrega P et al. Phase II study of a fixed dose-rate infusion of gemcitabine associated with erlotinib in advanced pancreatic cancer. Cancer Chemother Pharmacol 2011; 67(1):215-221.

  19.    Lipkin S, Lee J et al. Phase IIA trial testing erlotinib as an intervention against intraductal pancreatic mucinous neoplasms. Cancer Prev Res (Phila) 2011; 4(4):512-513.

  20.    Robertson JM, Margolis J et al. Phase I Study of Conformal Radiotherapy and Concurrent Full-Dose Gemcitabine with Erlotinib for Unresected Pancreatic Cancer. Int J Radiat Oncol Biol Phys 2011.

  21.    Britten CD, Finn RS et al. A phase I/II trial of trastuzumab plus erlotinib in metastatic HER2-positive breast cancer: a dual ErbB targeted approach. Clin Breast Cancer 2009; 9(1):16-22.

  22.    Dickler MN, Rugo HS et al. A phase II trial of erlotinib in combination with bevacizumab in patients with metastatic breast cancer. Clin Cancer Res 2008; 14(23):7878-7883.

  23.    Dickler MN, Cobleigh MA et al. Efficacy and safety of erlotinib in patients with locally advanced or metastatic breast cancer. Breast Cancer Res Treat 2009; 115(1):115-121.

  24.    Twelves C, Trigo JM et al. Erlotinib in combination with capecitabine and docetaxel in patients with metastatic breast cancer: a dose-escalation study. Eur J Cancer 2008; 44(3):419-426.

  25.    Wulfkuhle JD, Speer R et al. Multiplexed cell signaling analysis of human breast cancer applications for personalized therapy. J Proteome Res 2008; 7(4):1508-1517.