University of Arkansas

Yale University

Synthon Biopharmaceuticals B.v.

Alessandro D Santin

Timothy J O'Brien

Martin J Cannon

Peter Johannes Goedings

John Beard

Kazushi Shigemasa

Paul L Hermonat

Kristina L Bondurant

Yong Liu

Michael Mane

Fabrizio Comper

Groesbeck P Parham

Maurizio Chiriva-Internati

The invention includes a method of determining whether a mammal's cancerous tumor is associated with a hypermutator phenotype (i.e., harboring a large number of mutations) for the DNA Polymerase epsilon (POLE) gene as compared to normal cells. The invention further includes a method of selecting patients harboring an immunogenic tumor that is responsive to immunotherapy.

Methods of identifying patients responsive to immunotherapeutic strategies

The present invention relates to duocarmycin-containing antibody-drug conjugates (ADCs) for use in the treatment of human solid tumors expressing HER2, wherein the human solid tumor expressing HER2 is endometrial cancer, in particular uterine serous carcinoma (USC). In particular, the present invention relates to duocarmycin-containing ADCs for use in the treatment of endometrial cancer, notably USC, with HER2 IHC 2&#x2212; or 1+ and HER2 FISH negative tumor tissue status.

Duocarmycin ADCs for use in treatment of endometrial cancer

The invention discloses high levels of receptors forenterotoxin (CPE) have been found in ovarian cancer and uterine cancer tissue samples. In addition, successful in vivo treatment of a mouse model of ovarian cancer with intraperitoneal injection of CPE is disclosed. High levels of Ep-CAM protein is also disclosed in ovarian cancer tissue samples. Thus, the invention provides a method of treating ovarian cancer and uterine cancer by administering CPE. The invention also provides a method of treating cancer in a mammal involving intraperitoneal administration of CPE, where at least some cancerous cells are located in or adjacent to the peritoneal cavity of the mammal. The invention also provides a method of treating ovarian cancer involving administering an anti-Ep-CAM antibody. The invention also provides a method of treating cancers expressing claudin-3 or claudin-4 by administering an antibody against claudin-3 and/or an antibody against claudin-4. The invention also provides a method of protecting a mammal from CPE toxicity involving administering a protective agent that binds to claudin-3 and/or claudin-4 and inhibits CPE binding to claudin-3 and/or claudin-4.

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Provided herein are methods for treating ovarian serous papillary carcinoma by deliveringenterotoxins to ovarian tumor cells overexpressing claudin 3 or claudin 4 protein or by inhibiting the expression and function of tumor-associated calcium signal transducer 1 (TROP-1/Ep-CAM) gene or gene product. Also provided is a method of detecting ovarian serous papillary carcinoma by examining a tumor sample from the individual for gene or gene product expression levels within a group of genes and performing statistical analysis to determine those genes or gene products which are down-regulated compared to those in a normal individual.

Gene expression profiling in primary ovarian serous papillary tumors and normal ovarian epithelium

The present invention discloses the protease stratum corneum chymotrytic enzyme (SCCE) is specifically over-expressed in ovarian and other malignancies. A number of SCCE peptides can induce immune responses to SCCE, thereby demonstrating the potential of these peptides in monitoring and the development of immunotherapies for ovarian and other malignancies.

Immunotherapeutic methods targeted toward stratum corneum chymotryptic enzyme

TADG-12 and CA125 are two proteins expressed with high specificity in ovarian cancer tumors. They thus would be potential antigens for immunotherapy in ovarian cancer. The invention is based on the discovery of peptides in TADG-12 and CA125 that can be used to induce an autologous T cell response that lyses ovarian cancer cells expressing TADG-12 or CA125. The peptides are contacted with dendritic cells in vitro to generate peptide-loaded dendritic cells. The peptide-loaded dendritic cells are contacted with T cells in vitro to amplify CD8+ T cells that recognize the peptide. At least one CA125 peptide and at least one TADG-12 peptide were found that amplified CD8+ T cells, even from cancer patients, that lysed autologous CA125-expressing or TADG-12-expressing tumor cells. The peptide-loaded dendritic cells can be administered to a cancer patient to amplify CD8+ T cells in vivo that attack the cancer cells. Alternatively, autologous CD8+ T cells can be amplified ex vivo and then infused into the cancer patient.

Target CA125 peptides for cancer immunotherapy

The present invention discloses the protease stratum corneum chymotryptic enzyme (SCCE) is specifically over-expressed in ovarian and other malignancies. A number of SCCE peptides can induce immune responses to SCCE, thereby demonstrating the potential of these peptides in monitoring and the development of immunotherapies for ovarian and other malignancies.

Methods for the early diagnosis of ovarian cancer

The disclosed nucleic acid primer sets, used in combination with quantitative amplification (PCR) of tissue cDNA, can indicate the presence of specific proteases in a tissue sample. Specifically, the present invention relates to expression of hepsin protease. The detected proteases are themselves specifically over-expressed in certain cancers, and the presence of their genetic precursors may serve for early detection of associated ovarian and other malignancies, and for the design of interactive therapies for cancer treatment.

Gene expression profiling and hierarchal clustering analysis readily distinguish normal ovarian epithelial cells from primary ovarian serous papillary carcinomas. Laminin, tumor-associated calcium signal transducer 1 and 2 (TROP-1/Ep-CAM; TROP-2), claudin 3, claudin 4, ladinin 1, S100A2, SERPIN2 (PAI-2), CD24, lipocalin 2, osteopontin, kallikrein 6 (protease M), kallikrein 10, matriptase and stratifin were found among the most highly overexpressed genes in ovarian serous papillary carcinomas, whereas transforming growth factor beta receptor III, platelet-derived growth factor receptor alpha, SEMACAP3, ras homolog gene family, member I (ARHI), thrombospondin 2 and disabled-2/differentially expressed in ovarian carcinoma 2 (Dab2/DOC2) were significantly down-regulated. Therapeutic strategy targeting TROP-1/Ep-CAM by monoclonal chimeric/humanized antibodies may be beneficial in patients harboring chemotherapy-resistant ovarian serous papillary carcinomas.

The present invention discloses the protease hepsin is specifically over-expressed in ovarian and other malignancies. A number of hepsin peptides can induce immune responses to hepsin, thereby demonstrating the potential of these peptides in monitoring and the development of immunotherapies for ovarian and other malignancies. There is also provided a hepsin protein variant that is useful as a marker for ovarian cancer cells, prostate cancer cells or kidney cancer cells.

Oligonucleotide microarrays were used to profile and compare gene expression patterns between uterine serous papillary carcinoma and ovarian serous papillary carcinoma or normal endometrial epithelial cells. mRNA fingerprints readily distinguish the more biologically aggressive and chemotherapy resistant USPC from OSPC or NEC. Plasminogen activator inhibitor is the most highly up-regulated gene in OSPC relative to USPC, whereas the c-erbB2 gene product (HER-2/neu) is strikingly overexpressed in USPC relative to OSPC and may therefore represent a novel diagnostic and therapeutic marker for this highly aggressive subset of endometrial tumors.

Growing community of inventors

Little Rock, AR, United States of America

Alessandro D Santin