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Exploiting Signal Transduction Pathways in Acute Myelogenous Leukemia

  • Acute Leukemia
  • Published:
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Opinion statement

Traditional cytotoxic chemotherapy is effective at temporizing AML in the majority of patients but cures a small minority. Thus, enrollment in clinical trials remains a recommended approach for nearly all patients. While signal transduction inhibition is a promising area to advance AML therapy, no agent as monotherapy has demonstrated obvious clinical benefit over traditional cytotoxic chemotherapy. Tipifarnib is perhaps an exception as it is the only signal transduction inhibitor in AML that reproducibly shows clinical benefit using traditional chemotherapy response criteria. Due to toxicity and low response rates, however, the potential advantages of tipifarnib over either traditional cytotoxic chemotherapy or best supportive care alone await confirmation from phase III studies. Available data suggest that combining signal transduction inhibitors with chemotherapy will improve response rates. Clinical trials to test this hypothesis are ongoing using various agents directed against targets such as FLT3, ras/raf/MAPK, mTOR, KIT, and VEGF, but the optimal approach is yet to be defined. Similarly unclear is the benefit of a potent specific kinase inhibitor versus a broad inhibitor of multiple kinases that could prove relevant to leukemia biology. In general, the incomplete understanding of many signal transduction inhibitors’ true mechanism of action limits our ability to identify pretreatment predictors of response. To this end, the extensive measures applied to correlate the biologic activity of FLT3 inhibitors with clinical responses are noteworthy and provide useful lessons for clinical trial design and drug development both in leukemia and other cancers.

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Acknowledgments

AEP is a Special Fellow in Clinical Research of the Leukemia and Lymphoma Society, a fellow of the University of Pennsylvania Institute for Translational Medicine and Therapeutics, and a sponsored researcher of the Douglass Kroll Leukemia Research Foundation. MC is a Scholar of the Leukemia and Lymphoma Society and supported by National Cancer Institute R01 CA 100885.

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  1. Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA, USA

    Alexander E. Perl MD & Martin Carroll MD

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  1. Alexander E. Perl MD
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  2. Martin Carroll MD
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Correspondence to Alexander E. Perl MD.

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Perl, A.E., Carroll, M. Exploiting Signal Transduction Pathways in Acute Myelogenous Leukemia. Curr. Treat. Options in Oncol. 8, 265–276 (2007). https://doi.org/10.1007/s11864-007-0043-z

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