Compositions and Methods using RNA Splicing Modulation to Selectively Impair Leukemic Cancer Stem Cells
Splice isoform signatures distinguish normal and malignant progenitor cell agingPro-survival splice isoform switching is a feature of secondary AML LSCSplice isoform biomarkers provide diagnostic and therapeutic targets for AMLSpliceosome modulators impair AML LSC maintenance in humanized pre-clinical models
AML stem cell signatures may enable diagnostic and prognostic assessment of disease risk, patient stratification, and response to therapy. In addition, this technology enables the identification of splice modulating drugs (as validated with FD-895 and 17s-FD-895) as that may disrupt AML leukemia stem cell (LSC) maintenance by promoting intron retention and altering splicing of AML-associated/pro-survival transcripts.
Researchers from UC San Diego used comparative splice isoform profiling of FACS-purified hematopoietic progenitors and whole transcriptome analyses, to identify unique splicing signatures that distinguishes normal human HSC and progenitor cell aging from AML and MDS progenitors. The diagnostic potential is validated by confirmation that a novel pharmacological spliceosome modulatory drug (see FD-895 and 17s-FD-895) disrupted AML leukemia stem cell (LSC) maintenance. Furthermore, normal versus malignant aging splice isoform switching signatures may be exploited in companion diagnostics to evaluate the efficacy of splicing modulators or other LSC-targeted agents.
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State Of Development Pre-clinical studies identified a predictive splice isoform biomarker for sAML and the anti-tumor activity of novel compositions of matter were demonstrated in vitro and in vivo (in a mouse model of AML). Splice modulatory compounds were validated toward this MOA by using a splicing reporter and PCR assays. Intellectual Property Info Worldwide rights available for pending patents available under confidentiality. A published, US patent on composition of matter is described at “Synthetic Anticancer Polyketide Compounds”. Related Materials Kashyap, M.K., et al. Targeting the spliceosome in chronic lymphocytic leukemia with the macrolides FD-895 and pladienolide B. Haematologica (2015). Related Technologies Tech ID/UC Case 27067/2016-033-0 Related Cases 2016-033-0, 2012-262-0
Villa R, Kashyap MK, Kumar D, Kipps TJ, Castro JE, La Clair JJ, Burkart MD. Stabilized cyclopropane analogs of the splicing inhibitor FD-895. J Med Chem 56, 6576-6582 (2013).
Adamia, S., et al. A genome-wide aberrant RNA splicing in patients with acute myeloid leukemia identifies novel potential disease markers and therapeutic targets. Clin Cancer Res 20, 1135-1145 (2014).
Mandel, A.L., Jones, B.D., La Clair, J.J. & Burkart, M.D. A synthetic entry to pladienolide B and FD-895. Bioorg Med Chem Lett 17, 5159-5164 (2007).
Crews LA1, Balaian L2, Delos Santos NP2, Leu HS2, Court AC2, Lazzari E2, Sadarangani A2, Zipeto MA2, La Clair JJ3, Villa R3, Kulidjian A4, Storb R5,Morris SR6, Ball ED7, Burkart MD3, Jamieson CH8. RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML. Cell Stem Cell(16) 30250-30258 (2016)
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