Trevor Lucas

Bio: Trevor Lucas is an academic researcher from Medical University of Vienna. The author has contributed to research in topics: Hearing loss & Stromal cell. The author has an hindex of 19, co-authored 55 publications receiving 1092 citations.

A Rac1/Cdc42 GTPase-specific small molecule inhibitor suppresses growth of primary human prostate cancer xenografts and prolongs survival in mice.

Abstract: Deregulated Rho GTPases Rac1 and Cdc42 have been discovered in various tumors, including prostate and Rac protein expression significantly increases in prostate cancer. The Rac and Cdc42 pathways promote the uncontrolled proliferation, invasion and metastatic properties of human cancer cells. We synthesized the novel compound AZA1 based on structural information of the known Rac1 inhibitor NSC23766. In the current study we investigated the effects of inhibition of these pathways by AZA1 on prostate tumorigenicity by performing preclinical studies using a xenograft mouse model of prostate cancer. In androgen-independent prostate cancer cells, AZA1 inhibited both Rac1 and Cdc42 but not RhoA GTPase activity in a dose-dependent manner and blocked cellular migration and proliferation. Cyclin D1 expression significantly decreased following Rac1/Cdc42 inhibition in prostate cancer cells. AZA1 treatment also down-regulated PAK and AKT activity in prostate cancer cells, associated with induction of the pro-apoptotic function of BAD by suppression of serine-112 phosphorylation. Daily systemic administration of AZA1 for 2 weeks reduced growth of human 22Rv1 prostate tumor xenografts in mice and improved the survival of tumor-bearing animals significantly. These data suggest a role of AZA1 in blocking Rac1/Cdc42-dependent cell cycle progression, cancer cell migration and increase of cancer cell apoptosis involving down-regulation of the AKT and PAK signaling pathway in prostate cancer cells. We therefore propose that a small-molecule inhibitor therapy targeting Rac1/Cdc42 Rho GTPase signaling pathways may be used as a novel treatment for patients with advanced prostate cancer.

The Melanocyte-specific Isoform of the Microphthalmia Transcription Factor Affects the Phenotype of Human Melanoma

Abstract: The microphthalmia transcription factor MITF plays a pivotal role in the development and differentiation of melanocytes. The purpose of this work was to investigate the expression and function of the melanocyte-specific isoform MITF-M in human melanoma. We found that MITF-M is repressed in 8 of 14 established melanoma cell lines tested. Transfection of MITF-M into a melanoma cell line (518A2) lacking the M-isoform and into a permanent cell line established from normal melanocytes (NMel-II) resulted in slower tumor growth in a severe combined immunodeficient-mouse xenotransplantation model. The growth difference between vector control-transfected tumors derived from the NMel-II cell line (mean tumor weight +/- SD, 3.2 g +/- 1.13) and MITF-M (+) transfectants (mean tumor weight +/- SD, 1.1 g +/- 0.49) was significant (P = 0.018). The mean tumor weight of control-transfected 518A2 tumors was 0.99 g +/- 0.22 and of MITF-M (+) transfectants, 0.69 g +/- 0.32. The difference in growth between 518A2 controls and the MITF-M (+) transfectants was clear, however it did not reach statistical significance (P = 0.08). In addition to the growth-inhibitory effects, MITF-M expression led to a change in the histopathological appearance of tumors from epitheloid toward a spindle-cell type in vivo. These results indicate a role for the MITF-M isoform in the in vivo growth control and the phenotype of human melanoma. In conclusion, MITF-M may qualify as a marker capable of identifying subgroups of melanoma patients with different tumor biology and prognosis.

Connexin 26 mutations in cases of sensorineural deafness in eastern Austria.

Abstract: Mutations in the connexin 26 (Cx26) gene (GJB2) are associated with autosomal nonsyndromic sensorineural hearing loss. This study describes mutations in the Cx26 gene in cases of familial and sporadic hearing loss (HL) by gene sequencing and identifies the allelic frequency of the most common mutation leading to HL (35delG) in the population of eastern Austria. For this purpose we have developed and applied a molecular beacon based real-time mutation detection assay. Mutation frequencies in the Cx26 gene of individuals from affected families (14 out of 46) and sporadic cases (11 out of 40) were 30.4% and 27.5%, respectively. In addition to known disease related alterations, a novel mutation 262 G→T (A88S) was also identified. 35delG accounted for almost 77% of all Cx26 mutations detected and displayed an allelic frequency in the normal hearing population of 1.7% (2 out of 120). The high prevalence of the 35delG mutation in eastern Austria would therefore allow screening of individuals and family members with Cx26 dependent deafness by a highly specific and semi-automated method.

Melanoma biology and new targeted therapy

Abstract: Melanoma is a cancer that arises from melanocytes, specialized pigmented cells that are found predominantly in the skin. The incidence of melanoma is rising steadily in western populations--the number of cases worldwide has doubled in the past 20 years. In its early stages malignant melanoma can be cured by surgical resection, but once it has progressed to the metastatic stage it is extremely difficult to treat and does not respond to current therapies. Recent discoveries in cell signalling have provided greater understanding of the biology that underlies melanoma, and these advances are being exploited to provide targeted drugs and new therapeutic approaches.

Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation

Abstract: The microenvironment of solid tumors is characterized by a reactive stroma with an abundance of inflammatory mediators and leukocytes, dysregulated vessels and proteolytic enzymes TAM, major players in the connection between inflammation and cancer, summarize a number of functions (eg, promotion of tumor cell proliferation and angiogenesis, incessant matrix turnover, repression of adaptive immunity), which ultimately have an important impact on disease progression Thus, together with other myeloid-related cells present at the tumor site (Tie2 macrophages and MDSCs), TAM represent an attractive target of novel biological therapies of tumors

Roles of the immune system in cancer: from tumor initiation to metastatic progression.

Abstract: The presence of inflammatory immune cells in human tumors raises a fundamental question in oncology: How do cancer cells avoid the destruction by immune attack? In principle, tumor development can be controlled by cytotoxic innate and adaptive immune cells; however, as the tumor develops from neoplastic tissue to clinically detectable tumors, cancer cells evolve different mechanisms that mimic peripheral immune tolerance in order to avoid tumoricidal attack. Here, we provide an update of recent accomplishments, unifying concepts, and future challenges to study tumor-associated immune cells, with an emphasis on metastatic carcinomas.