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Biotech / Medical : Millennium Pharmaceuticals, Inc. (MLNM) -- Ignore unavailable to you. Want to Upgrade?

To: Icebrg who wrote (1993)	12/31/2003 12:54:50 PM
From: Icebrg	Read Replies (2) \| Respond to of 3044

FLT3: The Most Popular Current Target [From Medscape's ASH reporting. To me the prospects for MLN-518 seem relatively limited unless use can be found for the molecule outside AML] The most discussed, studied, and utilized novel therapeutic target in AML is undoubtedly the transmembrane type II tyrosine kinase FLT3. Blasts from approximately 30% of AML patients harbor a mutation in this gene, which encodes for a protein capable of transforming factor-dependent cell lines and inducing a murine myeloproliferative syndrome. These data suggest that this molecule may play a critical role in the pathophysiology of AML. Seven percent of patients express a point mutation in the activating loop, while 23% express an internal tandem duplication, a repeat of 3-60 amino acids in the juxtamembrane region; each of these is associated with a relatively poor prognosis. There are several agents in clinical development that are capable of inhibiting the kinase activity of this activated enzyme. Results of a phase 1 study of MLN518 in 40 patients with advanced AML, with either wild type or mutant FLT3 were reported.[11] A maximally tolerated dose, 525 mg orally twice daily, was identified for eventual phase 2 testing in patients with an FLT3 internal tandem duplication (ITD) mutation. Higher doses were intolerable due to generalized fatigue. Three of 5 patients who happened to have an ITD mutation and were treated at 1 of the 2 highest dose levels exhibited a reduction in peripheral blood blasts. Another FLT3 inhibitor, CEP701, inhibits FLT3 with an IC90 of 10-20 nM. It is highly protein bound, and, similar to MLN518, also inhibits other kinases. PKC 412, a third FLT3 inhibitor, which also inhibits c-kit, vascular endothelial growth factor receptor (VEGFR), and protein kinase C, was associated with responses in mutant FLT3 patients and a more modest level of response in AML patients with wild-type FLT3.[12] It stands to reason that FLT3 inhibitors will need to be used in combination with known active agents, such as chemotherapy, and/or with drugs targeted against other leukemogenic pathways. Important preclinical work was reported by Levis and colleagues from Johns Hopkins.[13] They treated leukemic cells harboring an activating mutation with CEP701 with and without chemotherapy drugs in vitro at various doses and schedules. If CEP701 was given before chemotherapy, the killing effect was antagonistic, possibly because the FLT3 inhibitor induces cell cycle arrest, thereby rendering the cells insensitive to the S-phase specific agents cytarabine and etoposide. On the other hand, if CEP701 was given simultaneously or after chemotherapy, there was a synergistic effect on killing. Similar results were reported by investigators at Oregon Health Sciences University[14] who showed that chemotherapy and another FLT3 inhibitor, MLN518, synergistically killed cell lines made factor-independent due to an FLT3 ITD. Although investigators in the United Kingdom were unable to confirm these effects with primary AML blasts, it is possible that the culture conditions were not amenable to similar conclusions compared with those obtained with the cell lines. A phase 3 trial of mitoxantrone/etoposide/cytarabine with or without subsequent use of CEP701 in patients with relapsed AML whose blasts are shown to have an ITD is about to start. One could also envision combining an FLT3 inhibitor, thereby interrupting proliferation, along with a drug that will aid impaired transcription, which is a second potential "hit" leading to AML. For example, preclinical studies[15] showed that the histone deacetylase inhibitor LAQ824 (which promotes transcription) was synergistically effective against cultured AML cells, particularly those harboring an activating mutation, when used in combination with PKC412. Another approach is to use an antibody to directly target the FLT3 proto-oncogene in AML, since this protein is expressed in 70% of AML cases. Investigators synthesized fully human antibodies that block FLT3 ligand binding to the receptor,[16] thereby preventing FLT3-mediated downstream signaling in cell lines with either a wild type or mutationally activated FLT3 receptor. These agents may work in part via antibody-dependent cell cytotoxicity.[17] Administration of this antibody to mice bearing either wild type or mutant FLT3-based leukemias resulted in improved survival. [For the full article giving a wider perspective on where research and developent is standing with regard to the treatment options for AML: Acute Myeloid Leukemia: New Genes and Nascent Novel Combinations medscape.com ]