Johns Hopkins University

Other

Pharmacia & Upjohn S.p.a.

Fundacio Institut Mar D'investigacions Mediques (imim)

Amgen Inc.

Fundacio Institut Mar D'investigacions Mediques

Bardelli, Alberto

Arena, Sabrina

Alberto Bardelli

Bert Vogelstein

Kenneth W Kinzler

Victor E Velculescu

D Williams Parsons

Saurabh Saha

Carlo Battistini

Paolo Comoglio

Yardena Samuels

Patrizia Giordano

Beatriz Bellosillo Paricio

Alba Dalmases Massegú

Clara Montagut Viladot

Fabio Corradi

Joan Albanell Mestres

Tian-li Wang

Ana Rovira Guerin

Will Parsons

Sabrina Arena

Salvatore Siena

Mauro Moroni

Donald William Parsons

Sabrina De Rosa

Christopher Lengauer

Miriam Martini

Alba Dalmases Massegu

The invention relates to new identified mutations in the epidermal growth factor receptor gene, leading to amino acidic changes which highly correlate with the resistance to a therapy regimen comprising cetuximab. The invention includes peptide sequences and primers to detect the mutations, as well as kits for predicting the response of a subject to a therapy regime comprising cetuximab. In particular, the invention is useful in the therapy regimen applicable to metastasic colorectal cancer.

Method of treating cancer based on identifying mutations in the extracellular domain III of epidermal growth factor receptor gene

Protein kinases are important signaling molecules involved in tumorigenesis. Mutational analysis of the human tyrosine kinase gene family (98 genes) identified somatic alterations in &#x2dc;20% of colorectal cancers, with the majority of mutations occurring in NTRK3, FES, GUCY2F and a previously uncharacterized tyrosine kinase gene called MCCK/MLK4. Most alterations were in conserved residues affecting key regions of the kinase domain. These data represent a paradigm for the unbiased analysis of signal transducing genes in cancer and provide useful targets for therapeutic intervention.

Tyrosine kinome

Given the important role of protein kinases in pathways affecting cellular growth and invasion, we have analyzed 340 serine/threonine kinases for genetic mutations in colorectal cancers. Mutations in eight genes were identified, including three members of the phosphatidylinositol-3-kinase (PI3K) pathway; the alterations in the latter genes each occurred in different tumors and did not overlap with mutations in PIK3CA or other non-serine-threonine kinase (STK) members of the PI3K pathway, suggesting that mutations in any of these genes had equivalent tumorigenic effects. These data demonstrate that the PI3K pathway is a major target for mutational activation in colorectal cancers and provide new opportunities for therapeutic intervention.

P13K pathway mutations in cancer

Protein kinases are important signaling molecules involved in tumorigenesis. Mutational analysis of the human tyrosine kinase gene family (98 genes) identified somatic alterations in &#x2212;20% of colorectal cancers, with the majority of mutations occurring in NTRK3, FES, GUCY2F and a previously uncharacterized tyrosine kinase gene called MCCK/MLK4. Most alterations were in conserved residues affecting key regions of the kinase domain. These data represent a paradigm for the unbiased analysis of signal transducing genes in cancer and provide useful targets for therapeutic intervention.

An in vitro diagnostic method for determining invasive potential of cancer comprising measuring MLK4 gene expression in a cancer cell sample, wherein MLK4 gene overexpression is indicative of an invasive cancer, preferably a colorectal, bladder, breast, gastric, melanoma, lung, ovary or GMB cancer.

MLK4 gene, a new diagnostic and prognostic marker in cancers

Protein kinases are important signaling molecules involved in tumorigenesis. Mutational analysis of the human tyrosine kinase gene family (98 genes) identified somatic alterations in -20% of colorectal cancers, with the majority of mutations occurring in NTRK3, FES, GUCY2F and a previously uncharacterized tyrosine kinase gene called MCCK/MLK4. Most alterations were in conserved residues affecting key regions of the kinase domain. These data represent a paradigm for the unbiased analysis of signal transducing genes in cancer and provide useful targets for therapeutic intervention.

Among the genes identified, in a comparison of the global gene expression profile of metastatic colorectal cancer to that of primary cancers, benign colorectal tumors, and normal colorectal epithelium, the PRL-3 protein tyrosine phosphatase gene was of particular interest. It was expressed at high levels in each of 18 cancer metastases studied but at lower levels in non-metastatic tumors and normal colorectal epithelium. In three of twelve metastases examined, multiple copies of the PRL-3 gene were found within a small amplicon located at chromosome 8q24.3. These data suggest that the PRL-3 gene is important for colorectal cancer metastasis and provides a new therapeutic target for these intractable lesions.

Phosphatase associated with metastasis

Methods of predicting whether an anti-epidermal growth factor receptor ('EGFr')-specific binding agent treatment will be efficacious in treating cancer, and methods of treating patients with anti-EGFr-specific binding agents, are provided.

Epidermal growth factor receptor gene copy number

The present invention relates to peptides and peptidomimetic compounds and pharmaceutical compositions containing them as useful pharmacological agents in the control or treatment of proliferative diseases such as cancer, against tumor growing and/or tumoral metastasis, and psoriasis and in the control or treatment of inflammatory, allergic, autoimmune, viral, and cardiovascular diseases. These new compounds have the unique property to inhibit the recognition of several phosphotyrosine containing motifs within all the cellular receptors and cytosolic transducers by a wide spectrum of SH2 domains contained in cytosolic transducers and other effector proteins laying along different pathways of the signal transduction process and with a particularly high affinity for the SH2 domain of the adaptor transducer Grb2, a key element along the pathway to mitogenesis and motogenesis, this last activity leading to invasiveness and to metastasis. The invention also relates to methods for production of the compounds and methods of treatment employing the compounds.

Peptide antagonists of cellular mitogenesis and motogenesis and their therapeutic use

Growing community of inventors

Turin, Italy

Alberto Bardelli