Novel classes of drugs identified with antiproliferative effect in thyroid cancer

Zhang L. J Clin Endocrinol Metab. 2011;doi:10.1210/jc.2011-2671.

Quantitative high-throughput drug screening can identify novel agents in different therapeutic categories and drugs with nonclassic chemotherapy mode of action, according to study results published online in the Journal of Clinical Endocrinology & Metabolism.

To identify agents with an anticancer effect in thyroid cancer cell lines, researchers used quantitative high-throughput drug screening to examine the accumulated NIH Chemical Genomics Center’s Pharmaceutical Collection. The quantitative high-throughput drug screening, which contained 2,816 approved drugs and bioactive compounds, used concentration response curve information to identify 244 active compounds in the human papillary thyroid cancer cell line TPC-1, 40 of which had high-confidence activity.

Of the 40 compounds with high-confidence activity — distributed across various therapeutic categories and with different modes of drug action — 16 had efficacy of more than 60% and a 50% inhibitory concentration (IC₅₀) of less than 1.7 mcM. Enrichment analysis of active agents in each drug category indicated that although a small quantity (12%) of antineoplastic drugs showed activity in the thyroid cancer cells, more than 25% of anti-obesity and cardiotonic drugs demonstrated potent activity.

To test whether these drugs had specific anticancer activity, the researchers said they compared the antiproliferative activity of the same drug library in several normal and cancer cell lines and primary culture of chronic lymphocytic leukemia cells from patients. Further analysis demonstrated that many compounds with activity against TPC-1 cells showed no cytotoxicity when tested in normal cells; conversely, many drugs that showed antiproliferative effect in other tested cancer cell types did not express activity in TPC-1 cells.

“The compounds found to have potent activity in our screen represent possible opportunities to repurpose these drugs for the treatment of patients with aggressive recurrent or metastatic thyroid cancer,” Electron Kebebew, MD, of the NCI in Bethesda, Md., and one of the study researchers, said in a press release. “Clinicians can more readily translate these findings into therapy when the drug characteristics are well known. The drugs can then be used in developing clinical trials or, in some cases, for off-label use.”

Disclosure: The researchers report no relevant financial disclosures.

Richard T. Kloos

Given the time and cost to develop new anticancer agents and the absence of thyroid cancer cell lines in the NCI 60 panel frequently used to screen compounds for anti-cancer cell activity, Zhang and colleagues used quantitative high-throughput screening (qHTS) to study 2816 (52%) of the existing FDA-approved drugs and bioactive compounds to identify antiproliferative activity in thyroid cancer cell lines. The goal was to identify compounds not known to have antineoplastic properties that may demonstrate previously unrecognized antithyroid cancer activity with the benefit of already having well-established pharmacokinetic and toxicity profiles. Additionally, this unexpected anticancer activity may lead to new insights into mechanisms of action, or the processes of cancer growth and survival themselves.

In their study, Zhang et al identified 16 agents with greater than 60% efficacy and 50% inhibitory concentrations (IC₅₀) at doses in the nanomolar range. The identified compounds represent a broad range of agents used for a variety of human diseases in the clinic, including cardiotonic and antiobesity agents.

The authors should be commended for taking on a global approach to screening agents for in vitro activity against thyroid cancer cells. The approach has potential to direct future efforts towards compounds offering timely clinical translation. However, enthusiasm for in vitro findings must be tempered with the sobering fact that in vitro screening of anticancer agents often does not predict activity in human clinical trials. This issue is exemplified in thyroid cancer by the multiple compounds that have shown in vitro activity against anaplastic thyroid cancer cells, while survivorship has not been improved for this nearly universally fatal form of the disease in clinical trials. Reasons for this lack of prediction in clinical trials are numerous and include the inability to account for tumor microenvironment and host effects in vitro, the introduction of hepatic first-pass effects in vivo that are not present in cell line experiments, differences in studying cell lines that have been propagated in vitro for long periods of time that may no longer reflect the in vivo biology of a cancer cell, and many others. Thus, while the new compounds with anti-tumor cell activity identified via qHTS may represent an important step in potential drug development for thyroid cancer, investigators must now demonstrate clear mechanisms of action and beneficial activity in relevant animal models before being studied in human clinical trials.

– Richard T. Kloos, MD
Professor, Divisions of Endocrinology and Nuclear Medicine
The Ohio State University College of Medicine
Co-Director, The Ohio State University Thyroid Cancer Unit
Arthur G. James Comprehensive Cancer Center
– Matthew D. Ringel, MD
Professor of Medicine, Divisions of Endocrinology and Oncology
The Ohio State University College of Medicine
Co-Director, The Ohio State University Thyroid Cancer Unit
Arthur G. James Comprehensive Cancer Center

Disclosure: Drs. Kloos and Ringel report no relevant financial disclosures.

Kenneth D. Burman

Dr. Zhang and colleagues have utilized the recently developed system of quantitation of high-throughput screening to rapidly assess 2,816 small molecule compounds for their individual ability to effectively decrease thyroid cancer cell proliferation in vitro. This technique has previously been used in multiple, various systems, for example, to screen for relevant biologic modulators and cytokines. Zhang et al identified 40 compounds that were considered to be highly effective. Surprisingly, the highly effective agents encompassed several different therapeutic groups with only 12% of anticancer agents demonstrating activity, whereas some medications in the antiobesity and cardiotonic therapeutic categories seemed particularly effective. The technique of quantititave high-throughput screening represents a significant advance and adjunct over present models (eg, animal testing, selection of individual specific potentially useful agents) because of its ability to rapidly screen literally thousands of medications and its ability to identify potentially useful agents in medication classifications for which we were previously unaware of their anticancer potential, thus allowing repurposing of these agents. This system, of course, is dependent on the methods and cell culture lines that are utilized and focuses only on antiproliferative effects. This technique has significant implications for all types of cancer. However, agents selected in this manner for potential anticancer activity must undergo further testing in vitro and in vivo models and ultimately in clinical trials to confirm their biologic activity. Nonetheless, this technique and this study will allow identification of agents that have beneficial antiproliferative (and hopefully antineoplastic) effects, including in medication categories for which we were previously unaware of this potential benefit.

– Kenneth D. Burman, MD
Chief, Endocrine Section
Washington Hospital Center
Professor, Department of Medicine
Georgetown University

Disclosure: Dr. Burman reports no relevant financial disclosures.

Investigators at National Cancer Institute and National Human Genome Research Institute collaborated to mine the NIH Pharmaceutical Collection of 2,800 approved and investigational drugs via a high -throughput screen toward discovering agents with antitumor activity in thyroid cancer. In addition to antineoplastic agents, they found a wide range of drugs that displayed antiproliferative activity on thyroid cancer cell lines, including cardiovascular and anti-obesity agents. Their strategy, often called repurposing or repositioning, is based on discovering novel uses for agents already shown to be safe in humans. By avoiding pitfalls of conventional drug development, repurposing offers higher success rates and lower costs. Nonetheless, dose, formulation, FDA and legal concerns can all slow the adaptation of old drugs to new uses.

– Ralph R. Weichselbaum, MD
Chairman, Dept. of Radiation and Cellular Oncology
Director, Ludwig Center for Metastasis Research
The University of Chicago Medical Center
– Stephen Kron, MD, PhD
Professor, Department of Molecular Genetics and Cell Biology
Center for Molecular Oncology
The University of Chicago Medical Center

Disclosure: Drs. Kron and Weichselbaum are co-founders of Oncosenescence.

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