Targeted Drugs for Cancer Therapy: Small Molecules and Monoclonal Antibodies

Baldo, Brian A.; Pham, Nghia H.

Specific targeting of tumor cells without inflicting collateral damage on normal healthy cells has been, and remains, a long-standing aim in cancer therapy. Effective targeting of tumor cells without accompanying toxicity has started to be realized with the introduction of signal transduction therapies and monoclonal antibodies (mAbs). Small molecule examples of the former drugs include imatinib (which inhibits both the ABL and BCR-ABL tyrosine kinases); gefitinib and erlotinib; mTOR inhibitors; histone deacetylase inhibitors (HDACIs); all-trans retinoic acid (tRA) and arsenic trioxide that target PML; the synthetic retinoic X receptor agonist bexarotene for T cell lymphoma; some hormone therapies; and proteosome inhibitors including bortezomib and carfilzomib. For most of the tyrosine kinase inhibitors targeting EGFRs, papulopustular rash, hand-foot skin reaction, mucositis, and nail abnormalities are the main adverse events. Retinoic acid syndrome occurs in some patients treated with tRA and/or arsenic trioxide. mTOR inhibitors are associated with a considerable number of adverse events including interstitial lung disease. Myelosuppression is a frequent event with HDACIs, and bortezomib, a proteosome inhibitor, may cause gastrointestinal symptoms, thrombocytopenia, peripheral neuropathy, and adverse cutaneous reactions including Sweet’s syndrome. Of the 85 currently approved mAbs, 34 recognizing 21 different targets are indicated for the treatment of cancers. Seven mAbs are antibody-drug conjugates (ADCs) which effect cell killing by an attached bioactive payload of a potentially lethal toxin, drug, cytokine, or radionuclide. Immune checkpoint inhibitors target inhibitory pathways regulating signaling between T cells and antigen-presenting cells. mAbs may provoke type I immediate hypersensitivities (anaphylaxis, urticaria), types II (rituximab-induced neutropenia) and III hypersensitivities (serum sickness), delayed type IV cutaneous reactions, pulmonary toxicities, and cardiac adverse events. Skin reactions after cetuximab and panitumumab often appear as papulopustular eruptions. Severe infusion reactions provoked by mAbs can resemble anaphylaxis, cytokine-release syndrome (CRS), infusion, and type I allergic reactions, while tumor lysis syndrome, unlike CRS, is easy to distinguish from type I immediate reactions.