Wesam Ahmed

Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice.

STAT5 proteins are constitutively activated in malignant cells from many patients with leukemia, including the myeloproliferative neoplasms (MPNs) chronic myeloid leukemia (CML) and polycythemia vera (PV), but whether STAT5 is essential for the pathogenesis of these diseases is not known. In the present study, we used mice with a conditional null mutation in the Stat5a/b gene locus to determine the requirement for STAT5 in MPNs induced by BCR-ABL1 and JAK2(V617F) in retroviral transplantation models of CML and PV. Loss of one Stat5a/b allele resulted in a decrease in BCR-ABL1-induced CML-like MPN and the appearance of B-cell acute lymphoblastic leukemia, whereas complete deletion of Stat5a/b prevented the development of leukemia in primary recipients. However, BCR-ABL1 was expressed and active in Stat5-null leukemic stem cells, and Stat5 deletion did not prevent progression to lymphoid blast crisis or abolish established B-cell acute lymphoblastic leukemia. JAK2(V617F) failed to induce polycythemia in recipients after deletion of Stat5a/b, although the loss of STAT5 did not prevent the development of myelofibrosis. These results demonstrate that STAT5a/b is essential for the induction of CML-like leukemia by BCR-ABL1 and of polycythemia by JAK2(V617F), and validate STAT5a/b and the genes they regulate as targets for therapy in these MPNs.

Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond

In patients with chronic myeloid leukemia (CML) in chronic phase who have achieved complete molecular remission on imatinib therapy, clinical trials from France and Australia have demonstrated that the majority experience prompt molecular relapse of their leukemia upon discontinuation of the drug, showing that long-term monotherapy with tyrosine kinase inhibitors is not curative in the majority of patients with CML. This has focused attention on strategies to eradicate residual disease in CML that is presumed to arise from malignant Ph+ stem cells, which should result in permanent cure and long-term leukemia-free survival. Here, we review the evidence that targeting CML stem cells will be of clinical benefit and discuss pharmacological and immunological approaches to accomplish this goal. Where possible, we link preclinical studies of CML stem cell biology to emerging results from clinical trials of agents that may target these cells.

Signal transduction in the chronic leukemias: implications for targeted therapies.

The chronic leukemias, including chronic myeloid leukemia (CML), the Philadelphia-negative myeloproliferative neoplasms (MPNs), and chronic lymphocytic leukemia (CLL), have been characterized extensively for abnormalities of cellular signaling pathways. This effort has led to the elucidation of the central role of dysregulated tyrosine kinase signaling in the chronic myeloid neoplasms and of constitutive B-cell receptor signaling in CLL. This, in turn, has stimulated the development of small molecule inhibitors of these signaling pathways for therapy of chronic leukemia. Although the field is still in its infancy, the clinical results with these agents have ranged from encouraging (CLL) to spectacular (CML). In this review, we summarize recent studies that have helped to define the signaling pathways critical to the pathogenesis of the chronic leukemias. We also discuss correlative studies emerging from clinical trials of drugs targeting these pathways.

New tools and novel approaches in treating locally advanced pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is one of the most aggressive malignant tumors and represents the fourth leading cause of cancer-related death. The median survival of locally advanced pancreatic carcinoma is ten to thirteen months. In this years American Society of Clinical Oncology (ASCO) Annual Meeting, several studies were presented with novel approaches towards treating locally advanced pancreatic cancer. Wild et al. (Abstract #4055) explored a novel tool of selective delivery of TNF-alpha intratumoral injection. This approach limited the systemic toxicity, and suggested survival benefit in only the subgroup of patients with locally advanced pancreatic adenocarcinoma with stage T1-T3. Two studies were presented which were designed to assess the use of two novel agents, targeting signaling pathways, in addition to gemcitabine. Van Laethem et al. (Abstract #4050) are testing the MEK inhibitor, BAY 86-9766 in combination with gemcitabine. However, treatment related toxicity is still of concern. In the other study, Evans et al. (Abstract #TPS4134) are testing the combination of dasatinib and gemcitabine. This is a placebo-controlled, randomized, double blind phase II study. However, results are not available. Stereotactic body radiotherapy (SBRT) is an emerging technology with the comparative efficacy of single fraction radiotherapy (as is used in radiosurgery) vs. fractionated SBRT still unknown. Herman et al. (Abstract #4045) examined the role of fractionated SBRT in locally advanced pancreatic cancer. The phase II results showed a median overall survival of 15.9 months, suggesting that SBRT may be an emerging tool in the multi-modality treatment of locally advanced pancreatic cancer.