Since researchers developed the first modern cancer treatments in the 20th century, the number of strategies to treat cancer have exploded, now employing everything from small-molecule drugs, monoclonal antibodies, immune proteins, engineered immune cells, and oncolytic virus therapies.
Sorting those therapies into discrete buckets according to their mechanism of action can be helpful for patients to understand the kind of treatment they’re on and the associated side effects. It can also help investigators know what research questions to ask and inform oncologists about what potential interactions and side effects to expect to see in their patients. But the distinction between these therapy groups is not always clear-cut — nor do all experts consistently refer to the same things with the same nomenclature.
For instance, statistician Matthew Maurer, MS, assistant professor of biostatistics and medicine at the Mayo Clinic in Rochester, Minnesota, and his colleagues who are studying a large observational cohort of lymphoma patients, often group individuals within a lymphoma subtype based on the type of therapy they’ve received. Now that the list of therapies is approaching some 150 types, grouping them in this manner is often challenging, he said. “It’s evolved over the years.”
Cancer Therapy Advisor put together a brief guide on the definitions and history of common modern cancer therapies.
In principle, the concept of targeted therapies — agents that kill pathogenic cells but not healthy ones — goes back to around 1900 when the German bacteriologist and Nobel Prize laureate Paul Ehrlich, PhD, was researching ways to kill disease-causing microbes without harming their hosts, which he called “magic bullets” at the time. Toward the end of the 20th century, cancer biologists were pursuing similar approaches driven by a desire to create treatments that were more specific and had fewer unwanted side effects on healthy cells than the then-prevailing chemotherapies.
Around the 1980s, biologists had learned that many growth factors and growth factor receptors exploited by cancer cells are encoded by oncogenes, noted cancer historian Carsten Timmermann, PhD, senior lecturer in the Center for the History of Science, Technology and Medicine at the University of Manchester, UK. When Genentech scientists discovered that the oncogene human epidermal growth factor receptor 2(ERBB2; formerly HER2) was overexpressed in many breast cancer tumors, they developed the monoclonal antibody trastuzumab (Herceptin®), which binds to HER2 receptors and is thereby thought to block signals that encourage cell growth and division.
Other targeted therapies that interrupt cell growth signals on tumor cells include the epidermal growth factor receptor (EGFR)-inhibiting monoclonal antibody cetuximab (Erbitux®), and also small-molecule drugs such as gefitinib (Iressa®), which also targets EGFR, the tyrosine kinase inhibitor imatinib (Gleevec®), and vemurafenib (Zelboraf®) which inhibits the serine/threonine-protein kinase BRAF.
Targeted therapies include antiangiogenesis agents, such as the monoclonal antibody bevacizumab (Avastin®), which slows the growth of new blood vessels by blocking an endothelial growth factor. They also include compounds that tinker with cancer cell survival and death machinery such as venetoclax (Venclexta®), which inhibits the B-cell lymphoma 2 protein, which is part of a critical survival pathway in chronic lymphocytic leukemia (CLL) cells.
The National Cancer Institute (NCI) has defined targeted therapy as treatments that “identify and attack specific types of cancer cells with less harm to normal cells,” a loose definition, as it would, in principle, include chemotherapies, which typically aren’t considered targeted therapies.1 That said, the antimetabolite chemotherapy capecitabine (Xeloda®), developed by Hoffmann-La Roche in the 1990s based on the earlier antimetabolite fluorouracil, was initially called a “targeted therapy” and marketed as such at the time, according to a book on the history of the pharma giant by Dr Timmermann.2
Targeted therapy is “directly killing tumor cells. And it’s typically designed to be specific to them. So it’s different from chemo in the sense that it’s not killing a lot of other cells as well,” explained Kristen Mueller, PhD, the senior director of the scientific program of the Melanoma Research Alliance. Targeted therapies may have knock-on effects on the immune system, but their primary purpose is to kill cancer cells.