Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A British humorist said, "There is much to be said for failure. It is much more interesting than success." This CCR Focus section is aimed at identifying lessons to be learned from difficulties encountered in recent years during development of anticancer agents. Clearly, we have not found a silver bullet tyrosine kinase inhibitor against solid tumors comparable with imatinib in chronic myelogenous leukemia. Although vemurafenib for B-Raf-mutated melanoma and crizotinib for non-small cell lung cancers with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements were developed rapidly and offer hope for individualized targeted therapies, the development of agents targeting a number of other pathways has been slower and less successful. These agents include drugs for blocking the insulin-like growth factor I/insulin receptor pathways, mitotic kinase inhibitors, and Hsp90 antagonists. Several potentially useful, if not groundbreaking, agents have had setbacks in clinical development, including trastuzumab emtansine, gemtuzumab ozogamicin, and satraplatin. From experience, we have learned the following: (i) not every altered protein or pathway is a valid anticancer target; (ii) drugs must effectively engage the target; (iii) the biology of the systems we use must be very well understood; and (iv) clinical trials must be designed to assess whether the drug reached and impaired the target. It is also important that we improve the drug development enterprise to enhance enrollment, streamline clinical trials, reduce financial risk, and encourage the development of agents for niche indications. Such enormous challenges are offset by potentially tremendous gains in our understanding and treatment of cancer.
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PMID:Drug development: portals of discovery. 2221 3

In early 2000, the term 'targeted therapy' became popular and was used to indicate all types of tyrosine kinase inhibitors (TKI). However, the term targeted therapy had been used much earlier. Targeting tumor metabolism was already considered as targeted therapy, with methotrexate and 5-fluorouracil as the most successful examples. Hormone therapy is another successful type of targeted therapy. Imatinib was the first TKI for the fusion protein BCR-ABL and represented a breakthrough in the treatment of chronic myeloid leukemia. Many other TKIs have been introduced into the clinic, but most were less specific and had multiple targets, and therefore, by definition, not targeted. However, with the introduction of TKIs developed specifically against mutations in the active site of a TK, more truly targeted TKI have been approved, such as new anaplastic lymphoma kinase - echinoderm microtubule-associated protein-like 4 (ALK-EML4) inhibitors and the epidermal growth factor-T790M-targeted osimertinib. This article summarizes the content of the Burger-Kelland award lecture given by the Author in February 2019 during the 40th EORTC-PAMM Group meeting in Verona, Italy and reviews the development of various targeted agents.
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PMID:From 'Targeted Therapy' to Targeted Therapy. 3126 54