Laurence Hurley

PMID: 17041088;Abstract:

To address the increased need to understand the similarities and differences in targeting Aurora A or Aurora B for the treatment of cancer, we systematically evaluated the relative importance of Aurora A and/or Aurora B as molecular targets using antisense oligonucleotides. It was found that perturbations in Aurora A and Aurora B signaling result in growth arrest and a apoptosis preferentially in cancer cells. The biological fingerprints of Aurora A and Aurora B inhibition were compared and contrasted in efforts to identify the superior therapeutic target. Due to the different biological responses, we conclude that each Aurora kinase should be treated as autonomous drug targets, which can be targeted independently or in combination. We observed no advantages to targeting both kinases simultaneously and feel that an Aurora A-targeted therapy may have some beneficial consequences over an Aurora B -targeted therapy, such as mitotic arrest and the rapid induction of apoptosis. Copyright © 2006 American Association for Cancer Research.

PMID: 19509249;PMCID: PMC3693733;Abstract:

We recently demonstrated the antitumor efficacy of orally administered α-tocopheryloxyacetic acid (α-TEA), a redox silent and nonhydrolyzable derivative of naturally occurring vitamin E. In order to move α-TEA closer to the clinic to benefit patients with breast cancer, the present study had two goals. First, to determine the minimal effective treatment dose; and second, to test the efficacy of dietary administration of α-TEA in the clinically relevant MMTV-PyMT mouse model of spontaneous breast cancer that more closely resembles human disease. The minimal effective dose of α-TEA was evaluated in the transplantable 4T1 tumor model and we show a dose-dependent decrease of primary tumor growth and reduction of metastatic spread to the lung. Six-week-old MMTV-PyMT mice were treated with oral α-TEA for 9 weeks, with no apparent signs of drug toxicity. The α-TEA treatment delayed tumor development and significantly slowed tumor progression, resulting in a 6-fold reduction of the average cumulative tumor size. In addition, oral α-TEA caused an 80% reduction in spontaneous metastases. In situ analysis of tumor tissue identified apoptosis as an important mechanism of α-TEA-mediated tumor suppression in addition to inhibition of tumor cell proliferation. This study shows, for the first time, the ability of orally administered α-TEA to delay tumor onset and to inhibit the progression and metastatic spread of a clinically relevant model of spontaneous breast cancer. Our finding of the high efficacy in this tumor model highlights the translational potential of oral α-TEA therapy. Copyright © 2009 American Association for Cancer Research.

PMID: 10857992;Abstract:

Telomeres and telomerase have been subjects to a tremendous attention from scientists and oncologists during the past 5 years. This interest has been motivated by the potential of telomerase as a tumor marker for the diagnosis and the prognosis of cancer. The possible use of telomerase or telomeres as new targets for anticancer drugs also triggered investigations. The expression of telomerase was found in overall 85% of cancers. Telomerase is early expressed during oncogenesis with a gradient indicating that a high level of telomerase expression could be associated with a bad prognosis. Therefore, drugs targeting telomerase and telomeres might be useful in many human tumors with little restrictions regarding the tumor type or on the stage of the disease. Moreover, since telomerase is not or slightly expressed in normal cells, it has been postulated that drugs targeting telomerase would induce low toxicity. The race for the discovery of telomerase inhibitors has started while the identification of the components controlling telomerase, telomeres, cell survival, senescence, and apoptosis was still in progress. The recent identification of components regulating telomere length and telomerase expression (TRF1, TRF2, and tankyrase) opened a variety of new opportunities to control telomerase/telomere interactions. Meanwhile, a proof of principle was provided that changing telomere interactions with telomere binding proteins by chemical or biological means can induce cancer cell death. Interestingly, recent data challenge the old paradigm which suggested that a long exposure to telomerase and telomere inhibitors is necessary to induce anticancer effects. In this paper, we review the most recent information concerning the regulation of telomere length and telomerase expression, with emphasis on mechanisms that might translate into new drug discovery.

Recent advances in telomerase inhibition have been achieved by using antisense oligonucleotides and ribozymes to target the telomerase mRNA or the telomerase RNA template. Also, small molecules are potent catalytic inhibitors of telomerase. However, therapeutic regimes incorporating these agents will be challenging to implement in the clinic because of their delayed effectiveness. Drugs that directly bind to the telomeres and stabilize secondary DNA structures such as G-quadruplexes are also potent inhibitors of telomerase and disrupt telomere structure. These G-quadruplex-interactive drugs could feasibly be used in synergy with more conventional cytotoxic agents to bring about more immediate responses in cancer cells that are less dependent upon telomere length. Recently, an emerging possible novel use of G-quadruplex-interactive drugs employs their ability to target G-quadruplexes in promoter regions of genes (such as c-MYC), which then serves to repress the production of the human telomerase reverse transcriptase protein.