Understanding targeted therapies: small molecules, antibodies, vaccines (Proceedings)
Molecular biology and genomic profiling now enable the identification of specific targets within cancer cells. Selectively designing therapies to interfere with those targets allows the treatment to become more 'personalized' as it is based on the targets identified in that patient's tumor cells. This differs from chemotherapy which targets rapidly dividing cells regardless of whether they are normal cells or tumor cells. Theoretically our targeted therapies should have less toxicity as they are designed to interact with specific molecules that are part of the metastatic and neoplastic cascade.
All cell processes (including cell growth, death and differentiation) depend on the action of signaling molecules and pathways. Cancer cells bypass the normal safeguards that keep the above processes in balance. Many of the signaling molecules and pathways have now become targets for anti-tumor drug development.
The best target is one that is present exclusively in tumor cells. However, they rarely exist which is not surprising, given that tumor cells evolve from normal cells. The next best is a target is one that is present in much higher numbers in tumor cells than normal cells, or present in both normal and tumor cells, but the body can replace the normal cells that get destroyed. Bottom line – we can still expect to see some toxicity, but we hope it will be minimized.Targeted therapies include small molecules, antibodies and vaccines. Small molecules easily travel across cell membranes and so can interfere with proteins both intra- and extracellularly. They are designed to interact with a specific area of a target protein, most often a surface cell receptor, and modify its interaction with other molecules. Examples include imitinib (Gleevec), masitinib (Kinavet) and toceranib (Palladia).
Imitinab, masitinib and toceranib have published data indicating efficacy in canine mast cell disease. These are all part of the tyrosine kinase inhibitor family. Mast cell tumors were picked for study because a receptor tyrosine kinase known as c-KIT is critical for the development and growth of canine mast cells and the tyrosine kinase inhibitors (TKI's) can effectively keep this receptor in the off position and prevent it from transmitting a phosphorylation signal. Toceranib also blocks the vascular endothelial growth factor receptor (VEGF-R) and platelet derived growth factor receptor (PDGF-R) and therefore will be expected to have significant antiangiogenic activity and impact a wide variety of tumor types. Mastinib has a narrower spectrum of antiangiogenic activity blocking only PDGF-R.
All of the TKI's will have potential toxicity. As a general rule, the more receptors inhibited the more potential for toxicity, but also the more antineoplastic activity. These drugs will need to be administered continuously and you will juggle toxicities to accomplish this goal in the majority of cases. Most toxicities can be prevented or readily managed with appropriate supportive care or dose modulation/schedule modulation. Life-threatening toxicities are rare, but early recognition of potential problems is critical. Side effects of most include anorexia, lethargy, diarrhea, gastrointestinal bleeding, and vomiting. Agent specific side effects for toceranib include neutropenia and muscle cramping. Imitinib is potentially hepatoxic in the dog. Masitinib has been associated with hypoalbuminemia and protein losing nephropathy.
It is recommend the TKI's be administered with food. H2 blockers or proton pump inhibitors may help prevent GI irritation/ulceration and are especially important in the mast cell tumor cases. Famotidine, omeprazole, sucralfate and misoprostol have all been used effectively and are usually started the same time as the drugs. Anti-nausea drugs may help with anorexia and good options are metoclopramide, ondansetron and maropitant. Diarrhea is often the dose limiting side effect and owners should be warned to report this side effect early and understand that administration of anti-diarrheals may be required throughout the treatment regimen. Treatment options include bismuth sulfate (Pepto-bismol), loperamide (Immodium) and metronidazole. If the clinical signs do not readily resolve, consider a drug holiday with alteration of dose and/or schedule.
We have just begun to scratch the surface of what these drugs can do. Toceranib activity is now well documented in a wide variety of tumors, most likely via anti-angiogenic mechanisms. Tumors in which activity has been noted include canine thyroid carcinomas, apocrine gland anal sac adenocarcinomas, head and neck carcinomas and feline injection site sarcomas. These drugs are just now beginning to be used in combination with other drugs and there is also evidence that they are good radiation sensitizers. It may be many years before we have optimized their use.
Monoclonal antibodies, which are large molecules, work outside the cell by preventing signaling molecules and receptors from interacting with each other. Or they can be designed to deliver radioactive molecules or toxins to cancer cells identified by unique antigens, or trigger an immune response that destroys the cell. With the exception of a monoclonal antibody for canine lymphoma patients that is no longer available, all of the antibodies today are human in origin and would not be expected to have prolonged activity in veterinary patients.
The immune system is usually limited in its ability to fight cancer because the malignant cells evolve from normal cells and the immune system doesn't recognize them as foreign antigens. Some tumors actively suppress the immune system. Therapeutic cancer vaccines are designed to activate the body's immune system to make it recognize and attack cancer cells. The canine therapeutic melanoma vaccine (Oncocept) works by immunizing the patient to tyrosinase, an enzyme that is unique to melanin producing cells. While responses have been noted in cases with bulky disease, there is little doubt that this vaccine will be most effective when added to local control with surgery and/or radiation therapy. Its safety profile is impressive with no side effects noted in most cases. There are literally thousands of cancer vaccines under active development in human medicine, particularly in melanoma patients.