NATICK, Mass., Aug. 1, 2012 /PRNewswire/ -- Karyopharm Therapeutics Inc., a leader in the new field of nuclear transport modulators, announced publication of preclinical models utilizing their proprietary SINE compounds in AML. SINEs specifically and irreversibly inhibit the nuclear transporter exportin 1 (XPO1), more commonly called CRM1 (chromosome region maintenance 1).
CRM1 is the exclusive mediator of the nuclear export of p53, p73, pRb, FOXO, p21, p27, BRACA1, and other tumor suppressor proteins, along with the endogenous inhibitor of Nuclear Factor kB (NF-kB) known as IkB. Cancer cells use nuclear export of these key anti-tumor proteins to functionally inactivate them. Blockade of CRM1 with SINE leads to accumulation and activation of tumor suppressor and chemotherapy resistance proteins in the nucleus, leading to selective tumor cell apoptosis while sparing normal cells.
Romero Garzon, MD, PhD, and colleagues at the Ohio State University published a plenary paper in the journal Blood entitled, "Pre-clinical activity of a novel CRM1 inhibitor in acute myeloid leukemia" (PubMed ID: 22677130). The authors showed that Karyopharm's SINE compounds induced apoptosis at nanomolar levels in AML cell lines and in AML blasts from patients. SINEs reduced the levels of the AML oncoprotein FLT3, and when given orally to mice, prolonged their survival with good tolerability.
In the second paper, Tom Look, MD, and colleagues at the Dana Farber Cancer Institute in Boston published a paper in the journal Leukemia entitled "Anti-leukemic activity of nuclear export inhibitors that spare normal hematopoietic cells" (PubMed ID: 22847027). This paper describes the discovery of the SINE compounds based on the X-ray crystal structure of CRM1 using proprietary in silico screening methods developed by Karyopharm's founder, Chief Scientific Officer and head of research and development, Sharon Shacham, PhD, MBA. The authors show that SINEs induce apoptosis at nanomolar levels in multiple different subtypes of AML. When given orally to mice, SINEs had potent antileukemic effects with negligible toxicity to normal hematopoietic cells, significantly prolonging survival with good tolerability.
Shacham commented, "These publications greatly expand our understanding of the biology of nuclear export and its inhibition by Karyopharm's SINE compounds. We greatly appreciate the extraordinary partnerships that we have developed with researchers at Ohio State and Dana Farber, particularly as these collaborations have helped us to move into human clinical studies with our novel oral SINE KPT-330."
Together with multiple presentations at the American Association of Cancer Research, American Society of Clinical Oncology, American Society of Hematology, and other meetings, Karyopharm and their academic collaborators have demonstrated the activity of SINEs in diverse hematological and solid tumor malignancies. The recent publications in AML provide a strong rationale for investigating the utility of SINEs in patients with this devastating cancer.
KPT-330 oral is currently being evaluated in two Phase 1 studies in patients with advanced hematologic and solid tumor malignancies (clinicaltrials.gov: NCT01607892 and NCT01607905). These studies are being conducted in the United States, Toronto, Canada, and Copenhagen, Denmark. Patients with AML will be eligible to enroll in the advanced hematologic cancer study once the tolerability profile of KPT-330 has been established.
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