The Leukemia & Lymphoma Society - Fighting Blood Cancers
6 Replies Latest reply: Mar 12, 2012 2:20 PM by ETauntonMA RSS

Potential Treatment for CEL - FIP1L1-PDGFRA positive w/ Gleevec resistance

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http://www.ncbi.nlm.nih.gov/pubmed/20726440

Abstract

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.

http://www.nexavar-us.com/scripts/pages/en/index.php

http://www.nexavar.com/scripts/pages/en/index.php

  • Re: Potential Treatment for CEL - FIP1L1-PDGFRA positive w/ Gleevec resistance
    ETauntonMA Registered Users
    Currently Being Moderated
  • Re: Potential Treatment for CEL - FIP1L1-PDGFRA positive w/ Gleevec resistance
    ETauntonMA Registered Users
    Currently Being Moderated
  • Re: Potential Treatment for CEL - FIP1L1-PDGFRA positive w/ Gleevec resistance
    ETauntonMA Registered Users
    Currently Being Moderated

    http://www.vib.be/en/research/scientists/Pages/Jan-Cools-Lab.aspx

     

    "Research focus

    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."

  • Re: Potential Treatment for CEL - FIP1L1-PDGFRA positive w/ Gleevec resistance
    ETauntonMA Registered Users
    Currently Being Moderated

    The low frequency of clinical resistance to PDGFR  inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be  related to the limited repertoire of possible PDGFRA kinase domain  mutations in vitro

    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.

     

     

    Link

    http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2010476a.html

     

    • Re: Potential Treatment for CEL - FIP1L1-PDGFRA positive w/ Gleevec resistance
      ETauntonMA Registered Users
      Currently Being Moderated

      Study showing the potential of using Nilotinib (Tasignia) as a treatment for those with CEL w/ the FIP1L1/PDGFRA+ clonality.

       

      http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0030567

       

      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.

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