Biomedical subjects

Jean Charles Soria

Publications and source records attributed to Jean Charles Soria.

6 recordsLinked to original sources

PubMed2006

STEAP, a prostate tumor antigen, is a target of human CD8+ T cells.

STEAP is a recently identified protein shown to be particularly overexpressed in prostate cancer and also present in numerous human cancer cell lines from prostate, pancreas, colon, breast, testicular, cervical, bladder and ovarian carcinoma, acute lymphocytic leukemia and Ewing sarcoma. This expression profile renders STEAP an appealing candidate for broad cancer immunotherapy. In order to investigate if STEAP is a tumor antigen that can be targeted by specific CD8(+) T cells, we identified two high affinity HLA-A*0201 restricted peptides (STEAP(86-94) and STEAP(262-270)). These peptides were immunogenic in vivo in HLA-A*0201 transgenic HHD mice. Peptide specific murine CD8 T cells recognized COS-7 cells co-transfected with HHD (HLA-A*0201) and STEAP cDNA constructs and also HLA-A*0201(+) STEAP(+) human tumor cells. Furthermore, STEAP(86-94) and STEAP(262-270) stimulated specific CD8(+) T cells from HLA-A*0201(+) healthy donors, and these peptide specific CD8(+) T cells recognized STEAP positive human tumor cells in an HLA-A*0201-restricted manner. Importantly, STEAP(86-94)-specific T cells were detected and reactive in the peripheral blood mononuclear cells in NSCLC and prostate cancer patients ex vivo. These results show that STEAP can be a target of anti-tumor CD8(+) T cells and that STEAP peptides can be used for a broad-spectrum-tumor immunotherapy.

Amino Acid Sequence↗

PubMed2005

Telomere shortening and telomerase reverse transcriptase expression in preinvasive bronchial lesions.

PURPOSE: Telomerase, a ribonucleoprotein complex whose activity is related to the expression of its catalytic subunit human telomerase reverse transcriptase (hTERT), restores telomere length in tumor cells and enables immortality after p53/Rb inactivation has been achieved. To determine the timing of hTERT derepression during bronchial carcinogenesis and its relationship with telomere shortening and the p53/Rb pathway alterations, we did an immunohistochemical and in situ hybridization study in preinvasive and invasive bronchial lesions. EXPERIMENTAL DESIGN: hTERT, P53, P16, cyclin D1, Bax-to-Bcl2 ratio, and Ki67 immunostainings were done in 106 preneoplastic lesions and in paired lung carcinoma and normal bronchial mucosae. Concomitantly, hTERT mRNA levels and qualitative telomere shortening were assessed by in situ hybridization and fluorescence in situ hybridization, respectively, in a subset of preneoplastic and neoplastic lesions. RESULTS: Telomerase was increasingly expressed from normal epithelium to squamous metaplasia, dysplasia, and carcinoma in situ, and decreased in invasive carcinoma (P < 0.0001), with a direct correlation between protein and mRNA levels of expression (P < 0.0001). hTERT expression was directly correlated with P53, Ki67, and Bcl2-to-Bax ratio, suggesting a coupling between telomerase reactivation, proliferation, and resistance to apoptosis. Telomere signals significantly decreased as early as squamous metaplasia and progressively increased over the spectrum of preneoplastic lesions. CONCLUSIONS: Telomere shortening represents an early genetic abnormality in bronchial carcinogenesis, preceding telomerase expression and p53/Rb inactivation, which predominate in high-grade preinvasive lesions.

Adult↗

PubMed2005

New concepts for phase I trials: evaluating new drugs combined with radiation therapy.

The rationale for delivering concomitant chemoradiation is not only to increase tumor cell kill but also to achieve a synergistic effect of chemotherapy and radiation. Combination of chemotherapy and radiotherapy has yielded encouraging results in patients with locally advanced diseases. Our increased knowledge of cancer at the molecular level has transformed our understanding of tumor radiation resistance. Preclinical models have shown that several biologic agents designed to target specifically these molecular processes are radiosensitizing agents. Many of these agents are in the process of clinical evaluation with radiotherapy. The translation of these findings into the clinical setting will be feasible only if early phase I trials demonstrate their safety when combined with ionizing radiation. The combination of new drugs and radiation might not necessarily be equivalent to the toxicity of the new drug plus the usual toxicity of radiation. The doses and schedule to be explored for the new drug might vary from those assessed for the new drug alone. Inappropriate evaluation of a combination regimen can result in unjustified abandonment of a combination, or adoption of a regimen at toxic dose levels because of poor toxicity monitoring. Beside the 'in field' radiation dose-dependent symptoms, 'outside the field' symptoms that are not dose dependent might be identified. Specific and long-term clinical evaluation will be required to identify potentially harmful interactions. It will be necessary to rethink phase I strategies, toxicity endpoints, and trial designs and concepts in order to fully optimize these regimens.

Antineoplastic Agents↗

PubMed2005

[Oncogenes and thyroid tumors].

Papillary thyroid carcinomas are characterized in 70% of cases by the presence of either a RET/PTC rearrangement, or an activating point mutation of RAS or BRAF genes that induce a constitutive activation of the MAP kinase pathway. Follicular carcinomas are characterized by the presence of a RAS mutation or of a PAX8-PPARgamma rearrangement. Inactivating mutations of the p53 gene are found only in anaplastic thyroid carcinomas.

Adenocarcinoma, Follicular↗

PubMed2005

Generation of diverse mutated tumor antigen-specific cytotoxic T lymphocytes in a lung cancer patient with long survival.

We have identified an antigen recognized on a large cell carcinoma of the lung by tumor-specific cytotoxic T lymphocytes (CTL). The antigenic peptide is encoded by a mutated alpha-actinin-4 gene and presented by human leukocyte antigen (HLA)-A2. Using HLA-A2-peptide tetramers, we have derived from patient peripheral blood lymphocytes (PBL) and autologous tumor infiltrating lymphocytes (TIL) several mutated alpha-actinin-4-specific T cell clones. These clones displayed similar tetramer staining but distinct T cell receptor (TCR) usage and antitumor reactivity. Indeed, TIL clones lysed more efficiently the autologous tumor cells and released higher cytokine levels than PBL clones. Importantly, treatment of cancer cells with interferon-gamma enhanced their susceptibility to PBL clone-mediated lysis correlated with increase in HLA-class I expression. The present findings provide evidence that an immune T cell response took place in a lung cancer patient with favorable clinical evolution and suggest that CTL, recognizing a truly tumor-specific antigen, may contribute to controlling the tumor.

Actinin↗

PubMed2004

Environmental, genetic, and molecular features of prostate cancer.

Prostate cancer is the sixth most common cancer in the world and the third leading cause of cancer in men. The increase in the understanding of prostate carcinogenesis over the past 15 years has helped to define crucial steps in the natural history of the disease, namely initiation and progression to androgen independence. This heterogeneous disease encompasses a range of environmental and familial factors, which provides strong support for the use of chemopreventive strategies. Most patients with advanced prostate cancer are treated with androgen-deprivation therapy, which leads to a striking regression of androgen-responsive cancer cells. A transition from an androgen-responsive to an androgen-unresponsive stage is seen during the clinical course in almost all patients with prostate cancer. This transition also signals a substantial worsening of prognosis. Here, we review the most important findings in prostate carcinogenesis and the molecular anomalies associated with the androgen-refractory stage.

Environmental Exposure↗