Evolution of Cancer Pharmacological Treatments at the Turn of the Third Millennium

Abstract

The medical history of cancer began millennia ago. Historical findings of patients with cancer date back to ancient Egyptian and Greek civilizations, where this disease was predominantly treated with radical surgery and cautery that were often ineffective, leading to the death of patients. Over the centuries, important discoveries allowed to identify the biological and pathological features of tumors, without however contributing to the development of effective therapeutic approaches until the end of the 1800s, when the discovery of X-rays and their use for the treatment of tumors provided the first modern therapeutic approach in medical oncology. However, a real breakthrough took place after the Second World War, with the discovery of cytotoxic antitumor drugs and the birth of chemotherapy for the treatment of various hematological and solid tumors. Starting from this epochal turning point, there has been an exponential growth of studies concerning the use of new drugs for cancer treatment. The second fundamental breakthrough in the field of oncology and pharmacology took place at the beginning of the '80s, thanks to molecular and cellular biology studies that allowed the development of specific drugs for some molecular targets involved in neoplastic processes, giving rise to targeted therapy. Both chemotherapy and target therapy have significantly improved the survival and quality of life of cancer patients inducing sometimes complete tumor remission. Subsequently, at the turn of the third millennium, thanks to genetic engineering studies, there was a further advancement of clinical oncology and pharmacology with the introduction of monoclonal antibodies and immune checkpoint inhibitors for the treatment of advanced or metastatic tumors, for which no effective treatment was available before. Today, cancer research is always aimed at the study and development of new therapeutic approaches for cancer treatment. Currently, several researchers are focused on the development of cell therapies, anti-tumor vaccines, and new biotechnological drugs that have already shown promising results in preclinical studies, therefore, in the near future, we will certainly assist to a new revolution in the field of medical oncology.

Keywords: antineoplastic drugs; cancer; cell therapy; chemotherapy; targeted therapy.

Figure 1

Cancer incidence and mortality from 1975 to 2015. (A) In the last 40 years, from 1975 to 2015, there has been a general increase in incidence rates for several cancers as a consequence of the demographic increase. Thanks to cancer prevention and screening strategies the number of many types of cancer has decreased. In particular, for cervix uteri and stomach cancers, a decrease in incidence rates was observed, while the incidence rates for esophagus, bladder, lung and colon remained unchanged. Finally, an increase in incidence rates was recorded for hepatic carcinoma, for breast cancer, NHL and above all for melanoma, whose incidence has increased radically in recent years; (B) Cancer mortality rates have globally decreased thanks to the development of targeted therapy and immunotherapy. In particular, in the last 40 years there has been a decrease in mortality rates for prostate, breast, colon, bladder, and especially for cervix uteri and stomach cancers. Almost unaltered mortality rates are observed for melanoma, pancreatic and esophageal cancers for which really effective pharmacological treatments are not yet available. An increase in mortality was observed for hepatic carcinoma while lung cancer and NHL showed a variable trend over the years with a slight increase in mortality rates from 1975 to 1995, and a general decrease in mortality rates recorded above all in the last 20 years.

Figure 2

Timeline of epochal turning points in modern oncology. After the development of radiotherapy in the early 1900, the modern oncology began with the discovery of the first chemotherapeutic drugs around 1940. Subsequently a breakthrough in the field of medical oncology occurred with the development of targeted therapy in 1980, which determined an improvement in the effectiveness of cancer treatments. The last epochal turn took place in 2010 with the introduction of immune checkpoints inhibitors for the treatment of advanced and metastatic tumors.

Figure 3

Molecular targets of targeted therapy. Targeted therapy for cancer treatment is based on tyrosine and serine/threonine protein kinase inhibitors and monoclonal antibodies. Protein kinase inhibitors are divided into EGFR inhibitors, VEGFR inhibitors, BCR/ABL inhibitors, ALK/EML4 inhibitors, RAF inhibitors, MEK inhibitors, and mTOR inhibitors. Monoclonal antibodies are directed toward extracellular growth factors or extracellular receptor tyrosine kinase. Figure 3 has been adapted and enriched by taking a cue from two published papers by Massimo Libra, co-author of the present review (Russo et al., ; Leonardi et al., 2018). For the general structure of Figure 3 and the name of drugs, the information contained in the book “Farmacologia: Principi di base e applicazioni terapeutiche” was taken into account (Rossi et al., 2016). ABL, Abelson murine leukemia viral oncogene homolog; AKT, protein kinase B; ALK, anaplastic lymphoma kinase; BAD, Bcl-2-associated death promoter; BCR, breakpoint cluster region; EGFR, epidermal growth factor receptor; EML4, echinoderm microtubule-associated protein-like 4; ERK, extracellular signal–regulated kinases; MEK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; RAF, rapidly accelerated fibrosarcoma kinase; RAS, RAS proto-oncogene GTPase; RTK, receptor tyrosine kinase; S6K, S6 kinase; src, proto-oncogene tyrosine-protein kinase Src; VEGFR, vascular endothelial growth factor receptor.