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Gene and protein expression profiles associated with the therapeutic efficacy of egfr-tk inhibitors

Gene and protein expression profiles associated with the therapeutic efficacy of egfr-tk inhibitors description/claims

This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application Ser. No. 60/903,684 filed Feb. 27, 2007, the entirety of which is incorporated herein by reference.

Patients diagnosed with cancer are faced with costly and often painful treatment options. These treatments may be ineffective in a subpopulation of patients, and as a result, these patients endure these treatments without little or no therapeutic benefit. Some patients may react adversely to certain agents causing additional suffering and possibly death.

Ineffective treatment also is problematic because time is a key variable when treating cancer. A treatment provider has a far greater chance of containing and managing the disease if the cancer is diagnosed at an early stage and treated with a therapeutically effective agent. An agent may provide great therapeutic benefits if administered at an early stage of the disease; however, with the passage of time, the same agent may cease to be effective.

Lung cancer is an example of a condition where early diagnosis is key for effective treatment. Most lung cancers fall into one of two categories: small cell lung cancer and non-small cell lung cancer (NSCLC). NSCLC is the most common type of lung cancer. There are three main subgroups of NSCLC: adenocarcinoma, squamous cell carcinoma and large cell undifferentiated carcinoma.

Chemotherapy often is used for treating NSCLC. Erlotinib (TARCEVA®) is a chemotherapeutic agent indicated for second-line therapy of NSCLC after failure of at least one prior chemotherapy regimen and gefitinib (IRESSA®) is indicated for continued treatment of NSCLC after failure of platinum-based and docetaxel chemotherapies. As with many chemotherapeutic agents, administration of these drugs often causes deleterious side effects for the patient, and some patients do not respond well, or respond at all, to the treatment. Some patients thus undergo treatment with erlotinib or gefitinib and suffer the painful side effects only to later realize that the agent has not been therapeutically beneficial to their condition. In addition to the unnecessary suffering, critical time is lost in determining an alternative treatment.

The present invention provides gene and protein expression profiles and methods for using them to identify those patients who are likely to respond to treatment with compounds that inhibit the intracellular phosphorylation of tyrosine kinase (TK) associated with epidermal growth factor receptor (EGFR), including erlotinib and gefitinib (these patients are referred to as “responders”), as well as those patients who are not likely to benefit from such treatment (these patients are referred to as “non-responders”). The present invention allows a treatment provider to identify those patients who are responders to treatment with compounds that inhibit the intracellular phosphorylation of EGFR-associated tyrosine kinase, including erlotinib and gefitinib, and those who are non-responders to such treatment, prior to administration of the agent. Compounds such as erlotinib and gefitinib that inhibit the intracellular phosphorylation of EGFR-associated tyrosine kinase are referred to hereinafter as EGFR-TK inhibitors.

The present invention comprises protein expression profiles, as well as the corresponding gene expression profiles (also referred to as “gene signatures”) that are indicative of the tendency of a patient afflicted with lung cancer, particularly NSCLC, to respond to treatment with an EGFR-TK inhibitor. The protein expression profile comprises at least one, and preferably a plurality, of proteins selected from the group consisting of p70S6K, phospho-p70S6, phospho-S6, phospho-AKT, phospho-mTOR, phospho-pTEN, phospho MEK, phospho MAPK, phospho-IGFR/lnR, EGFR, phospho-EGFR, phospho-HER2/ErbB2, phospho-ER, phospho-AR, AIK, osteopontin, MMP11 and GFAP. This group of proteins is referred to herein as the “EGFR-TK Inhibitor Responder Proteins”. According to the invention, some or all of these proteins are differentially expressed (e.g., up-regulated or down-regulated) in patients who are responders to EGFR-TK inhibitor therapy. Specifically, p70S6K, phospho-S6, phospho-AKT, phospho-mTOR, phospho-pTEN, EGFR, phospho-ER, phospho-AR, AIK, osteopontin, MMP11 and GFAP are up-regulated (over-expressed) and phospho-p70S6, phospho MEK, phospho MAPK, phospho-IGFR/InR, phospho-EGFR and phospho-HER2/ErbB2 are down-regulated (under expressed) in patients who are responders to EGFR-TK inhibitors.

The present invention further comprises gene expression profiles (also referred to as “gene signatures”) that are indicative of the tendency of a patient afflicted with NSCLC to respond to treatment with an EGFR-TK inhibitor. The gene expression profile comprises at least one, and preferably a plurality, of genes that encode the proteins selected from the group consisting of p70S6K, phospho-p70S6, phospho-S6, phospho-AKT, phospho-mTOR, phospho-pTEN, phospho MEK, phospho MAPK, phospho-IGFR/InR, EGFR, phospho-EGFR, phospho-HER2/ErbB2, phospho-ER, phospho-AR, AIK, osteopontin, MMP11 and GFAP. This group of genes is referred to herein as the “EGFR-TK Inhibitor Responder Genes”. According to the invention, some or all of theses genes are differentially expressed (e.g., up-regulated or down-regulated) in patients who are responders to EGFR-TK inhibitor therapy. Specifically, the genes encoding p70S6K, phospho-S6, phospho-AKT, phospho-mTOR, phospho-pTEN, EGFR, phospho-ER, phospho-AR, AIK, osteopontin, MMP11 and GFAP are up-regulated (over-expressed) and the genes encoding phospho-p70S6, phospho MEK, phospho MAPK, phospho-IGFR/lnR, phospho-EGFR and phospho-HER2/ErbB2 are down-regulated (under expressed) in patients who are responders to EGFR-TK inhibitors.

The present invention further comprises a method of determining if a patient is a responder or non-responder to treatment with an EGFR-TK inhibitor. The method comprises obtaining a tumor sample from the patient, determining the protein and/or gene expression profile of the sample, and determining from the gene expression profile whether at least one protein selected from the to EGFR-TK inhibitor Responder Proteins and/or the EGFR-TK Inhibitor Responder Genes is over- or under-expressed in the sample. From this information, the treatment provider can ascertain whether the patient is likely to benefit from to EGFR-TK inhibitor therapy.

The present invention further comprises an assay for determining the protein and/or gene expression profile in a patient's sample, and instructions for using the assay.

The present invention provides gene and protein expression profiles (GPEPs), and their use for predicting a patient's responsiveness to a cancer treatment. More specifically, the present gene and protein expression profiles are indicative of whether a patient afflicted with non small cell lung cancer (NSCLC) is a responder or a non-responder to treatment with a compound which is an EGFR-TK inhibitor, in particular, erlotinib (TARCEVA®) or gefitinib (IRESSA®).

Erlotinib and gefitinib are chemotherapeutic agents which belong to the group of medicines called antineoplastics. These compounds act by inhibiting the intracellular phoshorylation of tyrosine kinase associated with transmembrane cell surface receptors, including EGFR, a receptor expressed on the cell surface of normal cells and cancer cells. These compounds interfere with the growth of cancer cells, which are eventually destroyed.

Significant improvements in the outcomes of NSCLC in some patients treated with erlotinib or gefitinib have been reported. However, the growth of normal cells often is affected by these medicines, causing unwanted and/or unpleasant effects. These other effects may include: diarrhea, rash, acne, dry skin, nausea (feeling sick) and vomiting, loss of appetite and weight loss, asthenia and pruritis and abdominal pain. The present invention provides biomarkers that are associated with those patients that have benefited from treatment with erlotinib and/or gefitinib. The present invention thus enables the treatment provider to determine in advance those NSCLC patients likely to benefit from treatment with erlotinib or gefitinib, and to consider alternative treatment options for non-responders.

In one embodiment, the present invention provides protein expression profiles that are indicative of whether a patient is likely to be a responder or non-responder to EGFR-TK inhibitor therapy. The proteins comprising the expression profile disclosed herein are selected from the group consisting of p70S6K, phospho-p70S6, phospho-S6, phospho-AKT, phospho-mTOR, phospho-pTEN, phospho MEK, phospho MAPK, phospho-IGFR/InR, EGFR, phospho-EGFR, phospho-HER2/ErbB2, phospho-ER, phospho-AR, AIK, osteopontin, MMP11 and GFAP. This group of proteins is referred to herein as the “EGFR-TK Inhibitor Responder Proteins”. According to the invention, some or all of these proteins are differentially expressed (e.g., up-regulated or down-regulated) in patients who are responders to EGFR-TK inhibitor therapy. Specifically, p70S6K, phospho-S6, phospho-AKT, phospho-mTOR, phospho-pTEN, EGFR, phospho-ER, phospho-AR, AIK, osteopontin, MMP11 and GFAP are up-regulated (over-expressed) and phospho-p70S6, phospho MEK, phospho MAPK, phospho-IGFR/InR, phospho-EGFR and phospho-HER2/ErbB2 are down-regulated (under expressed) in patients who are responders to EGFR-TK inhibitors.

Table 1 identifies the EGFR-TK inhibitor Responder Proteins, and indicates whether expression of these proteins is up- or down-regulated in patients that are responders to therapy with an EGFR-TK inhibitor.

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