Editorial Cite This: ACS Med. Chem. Lett. 2017, 8, 1205−1207
Editorial for Cancer Virtual Issue
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physical carcinogens such as ionizing radiation and ultraviolet light, (2) chemical carcinogens such as tobacco smoke components, asbestos, and arsenic, and (3) infectious agents such as hepatitis, human papilloma virus (HPV), and the Epstein−Barr Virus (EBV).4 Given the impact on human health and well-being, it should come as no surprise that identifying cancer therapies has been and continues to be a major focus of the pharmaceutical industry and the academic community. Early treatments such as mustine, a nitrogen mustard first examined in 1942 as a possible treatment for Hodgkin’s lymphoma,12 and methotrexate, an antifolate drug identified in 1947 as capable of inducing remission in leukemia,13 were the first entries into a wide ranging arsenal of anticancer agents. The success of these two agents led to intense research focused on the identification of additional compounds with similar mechanisms of action. The DNA cross-linking agent mustine was followed by additional alkylating agents such as Cytoxan (cyclophosphamide),14 Carmustine (BiCNU),15 and Platinol AQ (cisplatin),16 while methotrexate inspired the development of other antimetabolites including Folotyn (Pralatrexate),17 Gemzar (Gemcitabine),18 and Xeloda (Capecitabine).19 The National Cancer Act of 197120 led to a substantial increase in federal support for cancer therapy research in the United States. Although the underpinnings of the disease itself were still unclear, new targets and therapies began to emerge. Topoisomerases, enzymes that play a key role in DNA superstructure, became a major focus of anticancer research. These efforts led to the identification of drugs such as Camptosar (Irinotecan)21 and Etopophos (Etoposide).22 Separately, the identification of the mitosis inhibitor Taxol (Paclitaxel)23 in 1971 and its eventual commercialization in 1993 highlighted the difficulties of developing novel therapies for this complex set of diseases. This success was followed by the development of additional Taxol analogs such as Docefrez (Docetaxel)24 and Jevtana (Cabazitaxel),25 as well as non-Taxol mitosis inhibitors such as Ixempra (Ixabepilone).26 By the end of the 20th century, the complexities of cancer pharmacology were becoming clearer and new therapeutic target were identified. A variety of kinases, enzymes responsible for phosphorylation of targeted proteins, for example, were identified as key players in oncogenesis. The intense interest in developing kinase inhibitors for the treatment of cancer led to the identification and commercialization of over 20 FDA approved therapies such as Imatinib (Gleevec),27 Tasigna (Nilotinib),28 Tarceva (Erlotinib),29 and Cotellic (Cobimetinib).30 Histone deacetylase (HDAC) inhibitors, compounds capable of altering gene expression via modulation of chromatin topology, were added to the list of anticancer agents beginning in 2006 with the FDA approval of Zolinza (Vorinostat).31 Further exploration of HDAC inhibitors produced additional FDA approved therapies such as Istodax (Romidepsin)32 and Farydak (Panobinostat). 33 The reapplication of known
ebster’s New World Medical Dictionary defines cancer as “an abnormal growth of cells that tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread) to other areas of the body.”1 This deceptively simple definition masks the complexity of cancer. In reality, there are over 100 different types of cancers, many of which have multiple subcategories.2 The first documented cases of cancer date back to ancient Egypt (∼1600 BCE). Although the term cancer was not used, the Edwin Smith Papyrus, an Egyptian medical text, described eight cases of tumors of the breast that were removed by cauterization. Hippocrates (460−370 BCE), the father of medicine, later coined the Greek terms “carcinoma” and “carcinos” in reference to ulcer forming and non-ulcer forming tumors, while the Roman physician Celsus (28−50 BCE) coined the term “cancer.”3 Our understanding of cancer progression and methods of treatment have improved over the centuries, but this disease remains a major medical issue. According to the World Health Organization,4 cancer is the second leading cause of death globally. In 2012, there were 14 million new cases of cancer reported, and the number of new cases is expected to rise by 70% over the next two decades.5 Over 8.8 million people died from cancer in 2015, and ∼70% of its victims live in low to middle income countries. Current growth rates suggest that the number of cases will rise to 21.7 million and that 13 million cancer deaths will occur in 2030.6 The most common cancer deaths are caused by cancers of the lung (1.69 million deaths), liver (788,000 deaths), colorectal (774,000 deaths), stomach (754,000 deaths), and breast (571,000 deaths). The economic impact of cancer is staggering. In 2010, the global economic cost of cancer was ∼$1.16 trillion, and there is every indication that the costs will continue to rise for the foreseeable future.7 Despite the wide scope of this disease, all cancers share six major features. The ability of tumor cells to undergo limitless reproduction and their ability to invade other tissues (metastasis) are the most well-known features of cancer. They are supported by the remaining four characteristics. They include the ability to induce sustained angiogenesis, which leads to the production of vasculature capable of providing nutrients to a growing tumor, insensitivity to antigrowth signals, independence from the externally produced growth signals, and deactivation of programed cell death mechanisms (apoptosis).8 The pharmacological events that cause normal cells to become cancerous can be traced to both genetics and external factors. Faulty BRCA1 and BRCA2,9 for example, are associated with a dramatic increases in the risk of breast cancer, while the CDKN2A gene is associated with an increased risk of melanoma.10 To date, over 50 genes have been linked to hereditary cancer syndromes (disorders that may predispose an individual toward developing particular types of cancer).11 External factors that contribute to the developments of cancer can be more challenging to elucidate. While an individual’s genome is defined at conception, an individual’s interactions with external forces will vary over time. In general, however, carcinogenic agents can be divided into three categories: (1) © 2017 American Chemical Society
Published: December 14, 2017 1205
DOI: 10.1021/acsmedchemlett.7b00472 ACS Med. Chem. Lett. 2017, 8, 1205−1207
ACS Medicinal Chemistry Letters
Editorial
A review of the five year survival data on a variety of cancers provides a clear picture of the dramatic improvement in patient outcomes that has been at least partially driven by the development of novel therapeutic agents (changes in lifestyle, surgical options, and radiotherapy also contributed to gains in life expectancy). According to the American Cancer Society 2017 annual “Cancer Fact and Figures” report, the five year
compounds has also produced some unexpected results, such as the resurfacing of Thalomid (Thalidomide).34 While this drug is well-known for its removal from the market as a result of its ability to cause birth defects, it recently re-emerged as a novel angiogenesis inhibitor. In 2006, it was approved by the FDA for the treatment of multiple myloma. 1206
DOI: 10.1021/acsmedchemlett.7b00472 ACS Med. Chem. Lett. 2017, 8, 1205−1207
ACS Medicinal Chemistry Letters
Editorial
nitrosourea (BCNU; NSC-409962). Cancer Chemotherapy Reports 1971, 55 (5), 599−606. (16) Wiltshaw, E. Cisplatin in the treatment of cancer: The first metal anti-tumor drug. Platinum Metals Review 1979, 23 (3), 90−8. (17) Zain, J.; O’Connor, O. Pralatrexate: Basic understanding and clinical development. Expert Opin. Pharmacother. 2010, 11 (10), 1705−1714. (18) Guchelaar, H. J.; Richel, D. J.; van Knapen, A. Clinical, toxicological and pharmacological aspects of gemcitabine. Cancer Treat. Rev. 1996, 22 (1), 15−31. (19) Ignoffo, R. J. Capecitabine: A new oral fluoropyrimidine. Cancer Practice 1998, 6 (5), 302−304. (20) Senate Bill 1828: Enacted December 23, 1971 (P.L. 92−218). https://www.cancer.gov/about-nci/legislative/history/nationalcancer-act-1971. (21) Masuda, N.; Kudoh, S.; Fukuoka, M. Irinotecan (CPT-11): pharmacology and clinical applications. Critical reviews in oncology/ hematology 1996, 24 (1), 3−26. (22) Witterland, A. H. I.; Koks, C. H. W.; Beijnen, J. H. Etoposide phosphate, the water soluble prodrug of etoposide. Pharm. World Sci. 1996, 18 (5), 163−170. (23) Slichenmyer, W. J.; Von Hoff, D. D. Taxol: a new and effective anti-cancer drug. Anti-Cancer Drugs 1991, 2 (6), 519−30. (24) Trudeau, M. E. Docetaxel: a review of its pharmacology and clinical activity. Canadian journal of oncology 1996, 6 (1), 443−457. (25) Bouchet, B. P.; Galmarini, C. M. Cabazitaxel, a new taxane with favorable properties. Drugs Today 2010, 46 (10), 735−742. (26) Fornier, M. N. Ixabepilone, first in a new class of antineoplastic agents: the natural epothilones and their analogues. Clin. Breast Cancer 2007, 7 (10), 757−63. (27) Lyseng-Williamson, K.; Jarvis, B. Imatinib. Drugs 2001, 61 (12), 1765−1774. (28) Weisberg, E.; Manley, P.; Mestan, J.; Cowan-Jacob, S.; Ray, A.; Griffin, J. D. AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br. J. Cancer 2006, 94 (12), 1765−1769. (29) Sorbera, L. A.; Castaner, J.; Silvestre, J. S.; Bayes, M. Erlotinib hydrochloride: oncolytic EGF receptor inhibitor. Drugs Future 2002, 27 (10), 923−934. (30) Signorelli, J.; Gandhi, A. S. Cobimetinib: a novel MEK inhibitor for metastatic melanoma. Ann. Pharmacother. 2017, 51 (2), 146−153. (31) Richon, V. M.; Zhou, X.; Rifkind, R. A.; Marks, P. A. Histone deacetylase inhibitors: development of suberoylanilide hydroxamic acid (SAHA) for the treatment of cancers. Blood Cells, Mol., Dis. 2001, 27 (1), 260−264. (32) Bertino, E.M.; Otterson, G. A. Romidepsin: a novel histone deacetylase inhibitor for cancer. Expert Opin. Invest. Drugs 2011, 20 (8), 1151−1158. (33) Atadja, P. Development of the pan-DAC inhibitor panobinostat (LBH589): Successes and challenges. Cancer Lett. 2009, 280 (2), 233−241. (34) Garcia-Sanz, R. Thalidomide in multiple myeloma. Expert Opin. Pharmacother. 2006, 7 (2), 195−213. (35) Cancer Facts and Figures 2017; American Cancer Society: Atlanta, GA, 2017.
survival rates for breast cancer (91%), melanoma (93%), prostate cancer (99%), testicular cancer (97%), and Hodgkin’s lymphoma (89%) have reached levels that would be viewed as impossible when mustine and methotrexate where first discovered. Unfortunately, there are many cancers that remain difficult to treat. The five year survival rates for cancer of the lung (19%), pancreas (9%), liver (18%), ovaries (46%), and brain (35%) remain unacceptably low.35 Clearly, the need for additional anticancer agents remains high, and the research community has continued to push the boundaries of science in an effort to help patients in need. The following collection of patent highlights (see http://pubs.acs.org/page/amclct/vi/ cancer-patents) represents a small fraction of the massive effort to develop the next generation of cancer therapies.
Benjamin E. Blass*
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Temple University School of Pharmacy, Moulder Center for Drug Discovery Research, Philadelphia, Pennsylvania 19140, United States
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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REFERENCES
(1) Webster’s New World Medical Dictionary, third ed.; Houghton Mifflin Harcourt: Boston, MA, 2014. (2) Hanahan, D.; Weinberg, R. A. The hallmarks of cancer. Cell 2000, 100, 57−70. (3) The American Cancer Society. The history of cancer. https:// www.cancer.org/cancer/cancer-basics/history-of-cancer.html. (4) World Health Organization. Cancer Fact Sheet. http://www.who. int/mediacentre/factsheets/fs297/en/. (5) Soerjomataram, I.; Ervik, M.; Dikshit, R.; Eser, S.; Mathers, C. GLOBOCAN 2012 v1.0. Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11; International Agency for Research on Cancer: Lyon, France, 2013. (6) American Cancer Society. The Global Cancer Burden. https:// www.cancer.org/health-care-professionals/our-global-health-work/ global-cancer-burden.html. (7) Stewart, B. W.; Wild, C. P. World Cancer Report 2014; International Agency for Research on Cancer: Lyon, France, 2014. (8) Hanahan, D.; Weinberg, R. A. The hallmarks of cancer. Cell 2000, 100, 57−70. (9) O’Donovan, P. J.; Livingston, D. M. BRCA1 and BRCA2: breast/ ovarian cancer susceptibility gene products and participants in DNA double-strand break repair. Carcinogenesis 2010, 31 (6), 961−967. (10) Aoude, L. G.; Wadt, K. A.; Pritchard, A. L.; Hayward, N. K. Genetics of familial melanoma: 20 years after CDKN2A. Pigm. Cell Melanoma Res. 2015, 28 (2), 148−160. (11) Lindor, N. M.; McMaster, M. L.; Lindor, C. J.; Greene, M. H. Concise Handbook of Familial Cancer Susceptibility Syndromes. J. Natl. Cancer Inst. Monogr. 2008, 38, 3−93. (12) Gilman, A. The initial clinical trial of nitrogen mustard. Am. J. Surg. 1963, 105, 574−578. (13) Farber, S.; Diamond, L. K.; Mercer, R. D.; Sylvester, R. F., Jr; Wolff, J. A. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (Aminopterin). N. Engl. J. Med. 1948, 238, 787−793. (14) Carter, S. K.; Livingston, R. B. Cyclophosphamide in solid tumors. Cancer Treat. Rev. 1975, 2 (4), 295−322. (15) Marsh, J. C.; DeConti, R. C.; Hubbard, S. P. Treatment of Hodgkin’s disease and other cancers with 1,3-bis(2-chloroethyl)-11207
DOI: 10.1021/acsmedchemlett.7b00472 ACS Med. Chem. Lett. 2017, 8, 1205−1207
