Exploiting Signal Transduction Pathways in Acute Myelogenous Leukemia

Abstract

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.

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

“…Rapalogs have demonstrated modest activity in preclinical studies against AML; however, single-agent, early-phase trials in adults did not find activity. [149,150,169,170] Preclinical studies combining rapalogs with cytotoxics and targeted agents, including etoposide, doxorubicin, cytarabine, histone deacetylase inhibitors, and glycolytic inhibitors, are more promising, often showing pronounced combined effects. [171][172][173][174][175][176] Based on these results, combination therapy trials are ongoing in adults, and it is anticipated that studies will begin in children if the adult data are promising.…”

Reduction of phosphoinositide-phospholipase C beta1 methylation predicts the responsiveness to azacitidine in high-risk MDS

“…Indeed, lipid signaling in disease is an emerging field of investigation, several pathways being involved in the molecular mechanisms leading to cancer, such as leukemogenesis (15,16). Nuclear inositide signaling is essential in the control of cell growth and differentiation, and nuclear phosphoinositide-phospholipase (PI-PL)Cbeta1 appears as one of the main players of these signal transduction processes.…”

A Phase I Study of the Mammalian Target of Rapamycin Inhibitor Sirolimus and MEC Chemotherapy in Relapsed and Refractory Acute Myelogenous Leukemia

“…The most extensively studied drugs in this class are the FLT3 inhibitors, for which clinical trials are ongoing (12-16). Use of FLT3 inhibitors has been studied primarily in patients with FLT3 mutations, which are known to confer a (12,15,17,18).Phosphatidylinositol-3′-kinase (PI3K) is a potential novel therapeutic target in AML. The role of PI3K signaling in leukemia has been studied in both murine models and primary human cells.…”

“…The most extensively studied drugs in this class are the FLT3 inhibitors, for which clinical trials are ongoing (12-16). Use of FLT3 inhibitors has been studied primarily in patients with FLT3 mutations, which are known to confer a (12,15,17,18).…”

“…Some of these agents seem to be cytotoxic by themselves (4)(5)(6)(7)(8)(9), whereas others alter the response of AML cells to chemotherapy (10,11). The most extensively studied drugs in this class are the FLT3 inhibitors, for which clinical trials are ongoing (12)(13)(14)(15)(16). Use of FLT3 inhibitors has been studied primarily in patients with FLT3 mutations, which are known to confer a poor prognosis.…”