Progression-free survival was longer and response rates were higher in patients with metastatic renal-cell cancer who received sunitinib than in those receiving interferon alfa (ClinicalTrials.gov numbers, NCT00098657 and NCT00083889 [ClinicalTrials.gov]).

No abstract

SU11248, a multitargeted receptor tyrosine kinase inhibitor of VEGF and PDGF receptors, demonstrates antitumor activity in metastatic RCC as second-line therapy, a setting where no effective systemic therapy is presently recognized. The genetics of RCC and these promising clinical results support the hypothesis that VEGF and PDGF receptor-mediated signaling is an effective therapeutic target in RCC.

clinicaltrials.gov Identifier: NCT00077974.

A B S T R A C T PurposeMost gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor ␣ (PDGFRA) kinases, which are imatinib targets. Sunitinib, which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. We evaluated the impact of primary and secondary kinase genotype on sunitinib activity. Patients and MethodsTumor responses were assessed radiologically in a phase I/II trial of sunitinib in 97 patients with metastatic, imatinib-resistant/intolerant GIST. KIT/PDGFRA mutational status was determined for 78 patients by using tumor specimens obtained before and after prior imatinib therapy. Kinase mutants were biochemically profiled for sunitinib and imatinib sensitivity. ResultsClinical benefit (partial response or stable disease for Ն 6 months) with sunitinib was observed for the three most common primary GIST genotypes: KIT exon 9 (58%), KIT exon 11 (34%), and wild-type KIT/PDGFRA (56%). Progression-free survival (PFS) was significantly longer for patients with primary KIT exon 9 mutations (P ϭ .0005) or with a wild-type genotype (P ϭ .0356) than for those with KIT exon 11 mutations. The same pattern was observed for overall survival (OS). PFS and OS were longer for patients with secondary KIT exon 13 or 14 mutations (which involve the KIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the KIT activation loop). Biochemical profiling studies confirmed the clinical results. ConclusionThe clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.

We have identified a rare (0.05-0.1%) subset of human fetal bone marrow cells that contains muiltipotent hematopoietic precursors. The population of human precursor cells that express In bone marrow (BM), the main blood-forming organ in the developed mammal, cascades of stem-cell divisions give rise to most hematolymphoid cell populations (1-3). Of these, only totipotent hematopoietic stem cells (tHSCs) can reconstitute lethally irradiated animals by giving rise to all blood cells, including progeny HSCs.Isolation of candidate HSCs in the mouse required the development of assays for clonogenic precursors of the T [thyrnic colony-forming unit (CFU-T)], B, and myeloerythroid [splenic CFU (CFU-S)] lineages (4-6); such precursors lack detectable surface markers of the T, B, macrophage, granulocytic, and erythroid lineages [lineage-negative (Lin-)] (7) but express the Sca-1/Ly-6A antigen and low levels of the Thy-1 molecule (7-9). This Thy-11oLin-Sca-1+ population, representing -0.05% of mononucleated BM cells, is the only subset that initiates long-term BM stromal cultures; it is 1000-to 2000-fold enriched in the capacity to save lethally irradiated animals and reconstitute them long term with donorderived cells in all hematolymphoid lineages (7, 9). Independent attempts to isolate tHSCs have utilized other cellular properties (10-13) and demonstrated their activity in vitro or in vivo (14-16). In some studies, long-term reconstitution activity was separable from radioprotective and CFU-S activity (17). For example, the Thy-11OLin-Sca-l+Rh-123Io subset (comprising cells that take up little of the mitochondrial dye rhodamine 123) is enriched for self-renewal and longterm reconstitutive potential compared with its Rh-123 counterpart (18).Most attempts to identify human HSCs have utilized the high proliferative response of such cells in vitro in the presence ofhematopoietic cytokines and have revealed CD34 to be a potent cell surface marker of such progenitors (19,20); in mice, HSCs are not the only such cytokine-responsive cells (21). Several groups have developed human stromal cell-dependent long-term culture systems that have identified progenitors of the myeloerythroid type (22-24). The stromal culture system described here allows single human progenitor cells to differentiate into both the myeloerythroid and B-lymphoid lineages.Experimental in vivo hematopoietic assays are not practi- MATERIALS AND METHODSMonoclonal Antibodies. mAbs were purchased from Becton Dickinson (CD3, or from AMAC (CD35,. mAbs against HLA class I antigens were derived from hybridomas obtained from the American Type Culture Collection. mAbs to human CD34 (Tuk3) and to human Thy-1 (F15 421-5) were obtained from

Sunitinib has antitumor activity in pancreatic neuroendocrine tumors; its activity against carcinoid tumors could not be definitively determined in this nonrandomized study. Randomized trials of sunitinib in patients with neuroendocrine tumors are warranted.

Sunitinib is active in patients with heavily pretreated MBC. Most AEs were of mild-to-moderate severity and manageable with supportive treatment and/or dose modification. Further studies in breast cancer are warranted.