The role and clinical implications of the endosteal niche and osteoblasts in regulating leukemia.

Osteoblasts are one among the critical components of the endosteal bone marrow (BM) niche. In addition to hematopoietic stem cell fate, their role in leukemogenesis as well as metastasis of a variety of cancers has been demonstrated in various studies. In this regard, endosteal niche can have a dual role as an initiator and protective role against leukemia. Knowledge of growth factors, chemokines and cytokines secreted by osteoblasts as well as their interaction with signaling pathways inform our understanding of the development, prognosis, recurrence and treatment of malignant BM diseases. Clinical progress in targeting the endosteal niche is also discussed.

Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes.

CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31-87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2-24) for the 14-day dosing schedule and 6 (1-24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS.

The hunt for cancer-initiating cells: a history stemming from leukemia.

Conventional cancer therapies are plagued by disease relapses due to incomplete eradication of cancer-initiating cells. Evidence for cancer-initiating cells originally arose from studies in hematology and leukemia. Lessons learned from hematopoietic stem cells laid the bedrock for understanding how leukemic cells self-renew and remain in immature states. Decades later, leukemia-initiating cell techniques are now being applied to the field of solid tumors such as brain, breast, bone, colon, pancreas, lung and prostate cancer, with several cancer-initiating cell efforts led by hematologists. Different isolation techniques enriching for primitive cancer-initiating cells have been developed and are described in this review. Although the concept of cancer-initiating cells arose from studies in normal tissue stem cells, differences exist between neoplastic-initiating clones and their normal counterparts. Several efforts have uncovered aberrant molecular pathways and niche interactions unique to cancer-initiating cells. Efforts to exploit these pathways and interactions could ultimately lead to complete eradication of cancers.