Reflections on Oncotherapies

Abstract

Reflections on Oncotherapies When I lectured on cancer chemotherapy, I would often start out by saying, "There are many ways to skin a cat." I would explain that by cat I meant a CAncerous Tumor. I would then engage the students by asking them to suggest ways to treat cancers. Before I go into their answers, I want to comment on how I learned this phrase. Growing up in Florida, we used to catch a lot of catfish and skin them in preparation for cooking. When I was preparing for this Note, I decided to look up the origins of "ways to skin a cat." I was surprised to learn that the phrase actually stems from debates in England in 1932 about whether cats should be skinned when still alive or only once dead! 1 I would start the list of answers by giving students the most common answer, surgical removal, and then relate what one of my surgical teachers used to say, "When in doubt, cut it out." The students' additional answers usually ended up (in no specific order) as follows: (1) radiation to destroy the mass or to reduce its size (we called that "zap it"), (2) chemotherapy to halt tumor growth at different stages of cellular division and maturation, (3) cutting off a tumor's blood supply, and (4) harnessing and enhancing the body's own antitumor defenses. We would also discuss issues such as solid versus hematologic cancers and primary versus metastatic lesions. Point 4 above is where much excitement and attention is currently focused. There is a new language and associated sets of acronyms that clinicians have to learn. The public is also exposed to this new vocabulary through television and print advertising. I saw a television ad today for the injectable monoclonal antibody, pembrolizumab *. It is the only immunotherapy approved for solid tumors that have increased levels of microsatellite instability, which is a function of impaired DNA mismatch repair. These tumor cells have numerous DNA repeats that make them vulnerable to mutations. Tumors of the endometrium, distal colon, and gastrointestinal tract are particularly prone to microsatellite instability. An Internet ad I saw focused on the use of pembrolizumab for some forms of melanoma as well as for metastatic non-small-cell lung cancer. Keytruda's product information states that when used for the latter, the tumor material should test "… positive for 'PD-L1' and … not have an abnormal 'EGFR' or 'ALK' gene." 2 Solid tumors with high levels of microsatellite instability are particularly sensitive to PD-1/PD-L1 immunotherapy. Acronyms such as PD-1 must be confusing to the average patient or consumer. For those readers unfamiliar with these terms, let's discuss the PD-1/PD-L1 acronym. PD stands for programmed cell death. Circulating activated T cells (lymphocytes) seek out unhealthy and cancerous cells as part of the body's immune system. PD-1 is a surface receptor on these T cells that keeps them from destroying cells in the body. PD-L1 is a ligand on the surface of cancerous cells and on some normal cells; it is often present in large amounts on some cancer cell...