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The Prince and the Pauper. a Tale of Anticancer Targeted Agents

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The Prince and the Pauper. a Tale of Anticancer Targeted Agents Molecular Cancer BioMed Central Review Open Access The prince and the pauper. A tale of anticancer targeted agents Alfonso Dueñas-González*1,3, Patricia García-López1, Luis Alonso Herrera1, Jose Luis Medina-Franco2, Aurora González-Fierro1 and Myrna Candelaria1 Address: 1Unidad de Investigacion Biomédica en Cáncer, Instituto de Investigaciones Biomedicas, UNAM/Instituto Nacional de Cancerologia, Mexico City, Mexico, 2Torrey Pines Institute for Molecular Studies. 5775 Old Dixie Highway, Fort Pierce, Florida 34946, USA and 3Dirección de Investigación, Unidad de Investigacion Biomédica en Cáncer, Av. San Fernando 22, Tlalpan, 14080 México, D.F., México Email: Alfonso Dueñas-González* - [email protected]; Patricia García-López - [email protected]; Luis Alonso Herrera - [email protected]; Jose Luis Medina-Franco - [email protected]; Aurora González- Fierro - [email protected]; Myrna Candelaria - [email protected] * Corresponding author Published: 23 October 2008 Received: 27 June 2008 Accepted: 23 October 2008 Molecular Cancer 2008, 7:82 doi:10.1186/1476-4598-7-82 This article is available from: http://www.molecular-cancer.com/content/7/1/82 © 2008 Dueñas-González et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally- based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public- sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited public-sector resources. If these drug types eventually result in being effective, it follows that they could be much more affordable for patients with cancer; therefore, their contribution in terms of reducing cancer mortality at the global level would be greater. Page 1 of 33 (page number not for citation purposes) Molecular Cancer 2008, 7:82 http://www.molecular-cancer.com/content/7/1/82 Background whereas others have consistently failed in the clinical test- At present, cancer remains a significant health problem ing stage. This picture of the heterogenous results of so- worldwide. According to International Agency for called targeted therapies with respect to their clinical effi- Research on Cancer-World Health Organization (IARC- cacy underscore that while these efforts must continue, WHO) estimates, cancer rates are set to increase at an parallel efforts are strongly required in cancer biology alarming rate, from 10 million new cases globally in 2000 research for improved prediction of the target to be to 15 million in 2020 [1]. Cancer statistics from the U.S. approached that offer the highest treatment benefit prob- show a total of 1,368,030 new cancer cases and 563,700 ability. As previously mentioned, these agents are solely deaths expected; paradoxically, there has been a decrease effective in tumor types dependent on the pathways being or stabilization in mortality rates from cancer, particularly inhibited. It is readily apparent that the majority of solid in major cancers such as lung, colorectal, prostate, and tumors are the result of numerous genetic and epigenetic breast. A recent estimate of trends in 5- and 10-year rela- alterations; hence, inhibiting a single cellular pathway tive survival of cancer patients in the U.S. in 1998–2003 may not result in significant therapeutic activity. Design of from the 1973–2003 Surveillance, Epidemiology, and agents that target a number of pathways will possibly End Results Program data base indicated significant increase the therapeutic effect, but could also increase the improvements in 5- and 10-year relative survival for 14 of risk of treatment-related toxicities [3,4]. 24 assessed common forms of cancer, such as prostate, breast, and colorectal cancer. Improvements in long-term While it is obvious that the vast majority of knowledge on survival were strongest for prostate cancer, non-Hodgkin cancer biology has been generated by investigators from lymphoma, and kidney cancer. In general, these improve- public and non-profit organizations, drug discovery and ments are likely the result of progress in early detection, development is generally carried out within the commer- treatment, or both, depending on tumor type [2]. cial rather than the academic realm, given the extraordi- narily high therapeutic drug discovery-associated costs With regard to cancer treatment with drugs, we are cur- and risks. Thus, it is exceedingly unlikely that any single rently in the interphase of two treatment eras. So-called public-sector research group will successfully see a novel pregenomic therapy names the traditional cancer drugs, chemical "probe" become a "drug". mainly cytotoxic drug types. This tagging stems from the fact that in general terms, pregenomic cancer drugs were Classical drug discovery involves target discovery and val- empirically developed based mainly on their capacity to idation, lead identification by high-throughput screening, inhibit cancer growth in experimental systems regardless and lead optimization by medicinal chemistry. Pre-clini- of their nature and potential mechanism of action. Con- cal follow-up evaluation includes analysis in animal mod- trariwise, post-genomic era-type drugs refer to rationally els of compound efficacy and pharmacology based designed drugs in which the startpoint comprises, (Administration, distribution, metabolism, elimination first, target identification, second, demonstrating that can- [ADME]) and toxicology, specificity, and drug interaction didate drugs inhibit this target, and third, proving that studies. The high-risk/high-reward aspect of drug discov- cancer growth is affected as a consequence of target inhi- ery comprises a greater issue in the commercial realm in bition. terms of new-compound approval and marketability. Therefore, oncological products are subject to the laws of Whereas the scientific basis for development of these drug marketing; hence, the majority of the newer cancer prod- classes is strong, our current level of knowledge on the ucts are simply cost-prohibitive to the vast majority of molecular basis of cancer remains a limitation for this patients worldwide, which has been widely approached design type. To date, successful examples of this newer and reviewed [5-7]. This important issue has led research- drug discovery approach are noteworthy, and just to men- ers at non-profit academic organizations to reflect upon tion a few we site dramatic results with the use of bcr-abl- alternatives for cancer drug development [8,9]. and c-kit-targeting agents on chronic granulocytic leuke- mia and gastrointestinal stromal tumors, the impressive An alternative drug development strategy is the exploita- results of Epidermal growth factor receptor (EGFR) inhib- tion of established drugs that have already been approved itors in a small subset of non-small-cell lung cancer, and for treatment of non-cancerous diseases and whose cancer the efficacy of targeting HER2 by a monoclonal antibody target has already been discovered. This strategy is also in approximately 30% of patients with breast cancer denominated drug repositioning, drug repurposing, or indica- whose tumors overexpress this oncoprotein. There are tion switch. Although traditionally development of these many other examples of these drug classes that are already drugs was unlikely to be pursued by Big Pharma due to commercially available for the treatment of cancer; how- their limited commercial value, biopharmaceutical com- ever, these pharmaceuticals only provide, albeit signifi- panies attempting
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