Research conducted in my group in the period 2006-2009 has led to a better understanding of the oncogenic mechanisms of the FIP1L1-PDGFRA and NUP214-ABL1 oncogenes. Insights into these mechanisms may help us to design novel strategies to treat leukemia. In addition, we have identified the small molecule inhibitor sorafenib as a potent inhibitor of the FIP1L1-PDGFRA and its T674I imatinib resistant mutant. Sorafenib was originally developed as a BRAF inhibitor, but our work demonstrates that sorafenib can also be used to treat FIP1L1-PDGFRA positive leukemia, demonstrating that new therapies to treat rare leukemias may be simply found by testing drugs that are already in use for the treatment of other diseases. Finally, using genome-wide screening approaches, we have identified the MYB gene as a novel oncogene implicated in the pathogenesis of T-ALL, and we suggest that MYB may represent a novel target for therapy in T-ALL as well as in other cancers.
Sorafenib is sold under the brand name Nexavar and is made by Bayer.
We try to better understand the genetic cause of leukemia, in order to be able to use that information to develop novel treatment strategies.
Molecular analysis of leukemias has identified a large number of specific chromosomal defects and oncogenes. This information is used for diagnostic purposes and for risk stratification, but the translation of current genetic insights into therapeutic applications is limited. The general aim of our projects is to identify novel oncogenic mutations, to study the potential of targeting these deregulated pathways for leukemia therapy, and to study the cooperation of oncogenes during leukemogenesis in order to further improve therapeutic strategies.
We aim to identify novel oncogenic events in leukemia using genome-wide molecular strategies (array CGH, SNP arrays, next-generation sequencing) or through functional screens (RNAi and chemical screens). A special focus will be on signaling pathways that may be involved in the proliferation and survival of the leukemic cells. For modeling purposes in our studies, we use chronic eosinophilic leukemia (CEL) as a model for a genetically ‘simple’ leukemia, and T-cell acute lymphoblastic leukemia (T-ALL) as a model for a genetically ‘complex’ leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive T-cell malignancy that is most common in children and adolescents. Improvement of treatment regimens has led to significant increases in survival, but long-term survival rates for adult T-ALL patients are still below 40%. At least 4 different types of mutations can be identified simultaneously in specific T-ALL cases and cell lines, suggesting that leukemic transformation of developing thymocytes is caused by a multi-step process involving various mutations that affect proliferation/survival, differentiation, cell-cycle control, and stem-cell maintenance. The mutations providing the proliferation and survival advantage of T-ALL cells remain unknown in 70 % of the cases.
Chronic eosinophilic leukemia (CEL) is a clonal myeloproliferative disease characterized by an overproduction of eosinophils in the bone marrow, with subsequent eosinophilia in the peripheral blood and infiltration of eosinophils in tissues. A common cause of CEL is expression of the FIP1L1-PDGFRa protein, a constitutively active tyrosine kinase that provides a proliferative and survival advantage to the leukemic cells. FIP1L1-PDGFRa can be inhibited by the tyrosine kinase inhibitor imatinib, which forms the basis for the current treatment of CEL. Some CEL patients, however, progress towards an imatinib resistant disease, which remains difficult to treat. Some CEL patients lack the FIP1L1-PDGFRA fusion, and the cause of the eosinophilia in these patients remains unknown."
I am curious is the FDA will approve Sorafenib as a tretmeant for CEL in the near future. Results are very promising and would offer a drug path for those who are resistant to Gleevec.
N von Bubnoff, S P Gorantla, R A Engh, T M Oliveira, S Thöne, E Åberg, C Peschel and J Duyster
Myeloproliferation with prominent eosinophilia is associated with rearrangements of PDGFR-A or -B. The most common rearrangement is FIP1L1-PDGFRA (FP). The majority of patients with PDGFR-rearranged myeloproliferation respond to treatment with imatinib. In contrast to BCR–ABL-positive chronic myelogenous leukemia, only few cases of imatinib resistance and mutations of the FP kinase domain have been described so far. We hypothesized that the number of critical residues mediating imatinib resistance in FP in contrast to BCR–ABL might be limited. We performed an established systematic and comprehensive in vitro resistance screen to determine the pattern and frequency of possible TKI resistance mutations in FP. We identified 27 different FP kinase domain mutations including 25 novel variants, which attenuated response to imatinib, nilotinib or sorafenib. However, the majority of these exchanges did not confer complete inhibitor resistance. At clinically achievable drug concentrations, FP/T674I predominated with imatinib, whereas with nilotinib and sorafenib, FP/D842V and the compound mutation T674I+T874I became prevalent. Our results suggest that the PDGFR kinase domain contains a limited number of residues where exchanges critically interfere with binding of and inhibition by available PDGFR kinase inhibitors at achievable concentrations, which might explain the low frequency of imatinib resistance in this patient population. In addition, these findings would help to select the appropriate second-line drug in cases of imatinib-resistant disease and may be translated to other neoplasms driven by activated forms of PDGFR-A or -B.
Study showing the potential of using Nilotinib (Tasignia) as a treatment for those with CEL w/ the FIP1L1/PDGFRA+ clonality.
We developed a xenograft model of human Chronic Eosinophilic Leukemia (CEL) to study disease progression and remission-induction under therapy with tyrosine kinase inhibitors using imatinib and nilotinib as examples. The FIP1L1/PDGFRA+ human CEL cell lineEOL-1 was injected intravenously into scid mice, and MR imaging and FACS analysis of mouse blood samples were performed to monitor disease development and the effects of imatinib and nilotinib. Organ infiltration was analyzed in detail by immunohistochemistry after sacrifice. All animals developed CEL and within one week of therapy, complete remissions were seen with both imatinib and nilotinib, resulting in reduced total tumor volumes by MR-imaging and almost complete disappearance of EOL-1 cells in the peripheral blood and in tissues. The new model system is feasible for the evaluation of new tyrosine kinase inhibitors and our data suggest that nilotinib may be a valuable additional targeted drug active in patients with FIP1L1/PDGFRA+ CEL.