Selective Inhibitor Of Nuclear Export Compound Research Articles

Highlights of This Issue

Induction of programmed cell death through tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors has shown significant promise in preclinical studies as a therapeutic approach for cancer. However, early attempts at targeting this axis in the clinic have not yielded significant benefit to patients. By driving significantly greater activity, including in models refractory to TRAIL, the novel scaffold offers new hope in targeting this axis for cancer therapy and may provide insights to maximize therapeutic benefits for other members of the TNFR superfamily.The CRM1 receptor mediates the nuclear export of critical proteins that are required for cancer cell proliferation, survival, and drug resistance. Salas Fragomeni and colleagues evaluated the effects of novel inhibitors of CRM1 in melanoma and found that selective inhibitors of nuclear export (SINE) decrease melanoma cell proliferation independent of BRAF mutation status and synergistically enhance the cytotoxic effects of BRAF inhibition in BRAF-mutant melanoma. These SINE compounds also induce complete regression of BRAF V600E tumors when combined with BRAF inhibition. Clinical studies to explore the use of SINE compounds in combination cancer therapy are underway.Antibody-drug conjugates (ADC), potent cytotoxic drugs linked to antibodies via chemical linkers, allow for the targeting of chemotherapy to tumors. Here, Li and colleagues describe the preclinical data for DCDT2980S, an anti-CD22 ADC that targets the potent microtubule inhibitor monomethyl auristatin E to B-cell malignancies. DCDT2980S is active in xenograft models of lymphoma at clinically relevant exposures. Notably, surface expression of CD22 had little correlation to efficacy of DCDT2980S. These data suggest that DCDT2980S could be used to treat a wide variety of B-cell malignancies. DCDT2980S is currently being evaluated in patients.Clear cell carcinoma (CCC) of the ovary is characterized by poor sensitivity to standard chemotherapy; thus, new treatments are critically needed. Hisamatsu and colleagues found that mTORC2 is frequently activated in CCC and that CCC cells are highly sensitive to mTORC2 inhibition. These findings have significant implications for the future design of clinical trials of firstline therapies for CCC. They also discovered that RAD001-mediated mTORC2 activation is involved in the mechanism responsible for RAD001 resistance and that mTORC2 inhibition has profound antitumor effects in RAD001- resistant CCC. Therefore, an mTORC2-targeting therapy represents a novel treatment option for recurrent CCC developing after mTORC1-inhibition.

KPT‐330 inhibitor of CRM1 (XPO1)‐mediated nuclear export has selective anti‐leukaemic activity in preclinical models of T‐cell acute lymphoblastic leukaemia and acute myeloid leukaemia

This study explored the anti-leukaemic efficacy of novel irreversible inhibitors of the major nuclear export receptor, chromosome region maintenance 1 (CRM1, also termed XPO1). We found that these novel CRM1 antagonists, termed SINE (Selective Inhibitors of Nuclear Export), induced rapid apoptosis at low nanomolar concentrations in a panel of 14 human T-cell acute lymphoblastic leukaemia (T-ALL) cell lines representing different molecular subtypes of the disease. To assess in vivo anti-leukaemia cell activity, we engrafted immunodeficient mice intravenously with the human T-ALL MOLT-4 cells, which harbour activating mutations of NOTCH1 and NRAS as well as loss of function of the CDKN2A, PTEN and TP53 tumour suppressors and express a high level of oncogenic transcription factor TAL1. Importantly, we examined the in vivo anti-leukaemic efficacy of the clinical SINE compound KPT-330 against T-ALL and acute myeloid leukaemia (AML) cells. These studies demonstrated striking in vivo activity of KPT-330 against T-ALL and AML cells, with little toxicity to normal murine haematopoietic cells. Taken together, our results show that SINE CRM1 antagonists represent promising 'first-in-class' drugs with a novel mechanism of action and wide therapeutic index, and imply that drugs of this class show promise for the targeted therapy of T-ALL and AML.

Results of a Phase I Dose Escalation Study of the Novel, Oral CRM1 Selective Inhibitor of Nuclear Export (SINE) KPT-335 in Dogs with Spontaneous Non-Hodgkin's Lymphomas (NHL)

AbstractAbstract 161 Introduction.Nuclear-cytoplasmic transport is highly regulated by karyopherin proteins – importins and exportins – through the nuclear pore complex. Of the seven known exportins, most tumor suppressor proteins (TSP) and IkB, the inhibitor of NF-kB, are transported out of the nucleus exclusively by exportin 1 (XPO1), more commonly called CRM1. SINE compounds bind irreversibly CRM1/XPO1, forcing the nuclear retention and activation of TSP and IkB, leading to selective tumor cell death. In vitro, SINEs demonstrate potent cytotoxic activity against tumor cells at nanomolar concentrations with minimal effects on normal cells in vitro. KPT-335 and related SINEs show oral bioavailability, good tolerability, and potent activity in multiple mouse xenograft models. Hematologic cancers are particularly vulnerable to SINE induced apoptosis, and effects on normal tissues are minimal at antitumor doses. Methods.Cytotoxicity was assessed in vitro with MTT and apoptosis assays. In order to evaluate the therapeutic potential of SINE in a spontaneous, large animal malignancy with many similarities to human disease including NF-kB activation, dogs with relapsed or newly diagnosed NHL were treated with KPT-335 in this dose escalation study. The primary objective was to evaluate the adverse events (AEs) and to establish the maximum tolerated dose (MTD) of KPT-335 orally in capsules. The secondary objectives were to determine the optimal dosing regimen, correlate pharmacodynamic markers and drug levels, and provide evidence of biological activity. We report the interim results defining the MTD and AEs of KPT-335 in dogs with NHL.All dogs had progressive disease (PD) on entry into the trial. Dogs with newly diagnosed or relapsed NHL, metastatic osteosarcoma (OSA), melanoma (MEL) and mast cell tumor (MCT) were eligible with preference given to NHL. The initial KPT-335 dose was 1 mg/kg (equivalent to 20mg/m2) orally with food on a Monday/Thursday schedule. At least 3 dogs were included in each cohort, and dose was escalated by 0.25mg/kg increments. CBC, serum chemistries, clotting times, drug peak plasma level and response to therapy were assessed at each weekly visit. Tumor samples will be obtained before and after treatment in an expansion cohort once the optimal dosing regimen has been determined. Results.Three structurally related SINE compounds including KPT-335 showed potent cytotoxicity of primary and immortalized canine B cell lymphomas in vitro (EC50<100 nM). The Phase 1 dose escalation study with KPT-335 oral included doses of 1mg/kg twice weekly and continued up to 2mg/kg (Table 1). Doses up to 1.75mg/kg were very well tolerated for over 3 months. At 1.75mg/kg, mild to moderate anorexia, weight loss and alkaline phosphatase elevation (possibly related to prednisone use) were observed. DLTs occurred at 2mg/kg including anorexia and vomiting without diarrhea. Laboratory parameters showed minimal or no changes at doses below the DLT.PatientDiseaseKPT-335 DoseResponseWeeks on Drug1MCT1 mg/kgPD42NHL″SD103NHL″PD44NHL1.25 mg/kgPR115NHL″SD136NHL″SD107NHL1.5 mg/kgSD28NHL″N/A19NHL″SD810OSA″PD311NHL″PR712NHL1.75 mg/kgSD713NHL″SD514NHL″SD215MCT2 mg/kgSD216NHL″SD217NHL″SD3 Discussion.Oral KPT-335 shows single agent disease stabilization and tumor reduction in dogs with NHL, the majority of who have diffuse large B cell lymphoma (DLBCL) relapsed after chemotherapy (typically CHOP). The activation of TSP and the neutralization of NF-kB activity by nuclear localization of IkB may contribute to the antitumor activity of SINE in canine NHL. AEs associated with drug administration include primarily anorexia, with vomiting at the DLT dose; diarrhea and significant laboratory changes were not observed. These observations are consistent with the effects of SINEs in other animal species. Conclusion.The novel SINE KPT-335 exhibits single agent biological activity with good tolerability in a relevant spontaneous large animal model of newly diagnosed and chemotherapy refractory cancer. The MTD and no adverse effect level of KPT-335 given by mouth twice weekly to dogs with NHL are ∼1.75 and 1.25 mg/kg, respectively, with anorexia, weight loss and vomiting as DLTs. Additional cohorts at doses of ≥1.25mg/kg given with increased frequency are being enrolled. These data are directly relevant to the development of oral KPT-330, a related SINE, currently in Phase 1 human clinical trials. Disclosures:Shacham:Karyopharm Therapeutics: Employment. Barnard:Karyopharm: Research Funding. Kisseberth:Karyopharm: Research Funding. Ito:Karyopharm: Research Funding. Jensen:Karyopharm: Research Funding. Borgotti:Karyopharm: Research Funding. Henson:Karyopharm: Research Funding. Wilson:Karyopharm: Research Funding. McCauley:Karyopharm Therapeutics Inc: Employment. Modiano:Karyopharm: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment. London:Karyopharm: Research Funding.