mTOR kinase inhibitors are far more useful than rapamycin at suppressing proliferation of standard and transformed cell lines. mTOR kinase inhibitors are extra cytotoxic than rapamycin in models of Ph+ BALL and have some cytotoxic activity in solid tumors, potentially supplying an extra advantage within the setting of cancer therapy. Several mTOR kinase inhibitors have entered clinical trials, and are getting tested in patients with strong tumors and hematological malignancies. Optimizing the therapeutic success of those agents in leukemia will probably be aided by further study in preclinical models. MLN0128 is actually a highly potent, orally active mTOR kinase inhibitor at present in phase I clinical trials . MLN0128 displays antitumor and antimetastatic activity in prostate cancer models and shows strong synergy together with the tyrosine kinase inhibitor lapatinib in breast cancer xenografts .
In this Zosuquidar structure study we evaluated MLN0128 in models of BALL, an aggressive malignancy which is the most prevalent leukemia in kids . Current induction therapies for adult BALL rely primarily on variations of standard chemotherapy followed post remission by allogeneic hematopoetic stem cell transplantation , with BCRABLspecific TKIs added to the regimen for Ph + disease. Additional therapies are necessary to supplement present pre and postremission therapeutic regimens and in situations of relapsed disease. Utilizing each murine BCRABL+ transformed cultures and main patientderived specimens, we show that MLN0128 suppresses development and survival of BALL cells and enhances the efficacy of dasatinib. We also show for the first time that nonPh BALL specimens are sensitive to mTOR kinase inhibitors in vitro and in vivo.
Notably, MLN0128 therapy in vivo has cytostatic effects on Ph+ and nonPh BALL xenografts although sparing regular hematopoietic cell proliferation in the spleen and bone marrow. General the results help further exploration of mTOR kinase inhibitors as therapeutic selections in mixture with current treatments for BALL or as single agents to limit disease progression. We synthesized MLN0128 mercaptopurine and PP242 as previously described . We obtained imatinib, dasatinib, and rapamycin from LC Laboratories. PI103 was synthesized as described in patent # WO 2001083456. Antibodies as well as other flow cytometry reagents have been obtained from Cell Signaling, Invitrogen, eBioscience and Biolegend. We obtained SUPB15 cells from ATCC. Generation and propagation of p190 cells have already been previously described .
Nalm6 and Blin1 cell lines were kindly provided by Dr. David Rawlings . Mice All mice were kept in distinct pathogenfree animal facilities in the University of California, Irvine, and procedures had been authorized by the Institutional Animal Care and Use Committee. We used 8weekold female BALB/cJ mice as recipients of mouse p190 BCRABL transformed BM as has been previously described .