Selinexor (Kpt-330), an Oral, Selective Inhibitor of Nuclear Export (Sine) Shows Anti-Prostate Cancer (Prca) Activity Preclinically &amp; Disease Control in Patients (Pts) with Chemotherapy Refractory, Castrate-Resistant Prostate Cancer (Crpc)

Mahaseth, Hemchandra; Maity, Sankar N.; Gabrail, Nashat; Mahipal, Amit; Gericitano, J.F.; Shacham, Sharon; Rashal, Tami; Klebanov, Boris; Carlson, Robert; Shacham, Eran; Vincent, D.; Kauffman, Michael; Shields, Anthony F.; Mirza, Mansoor Raza; Araujo, John C.

doi:10.1093/annonc/mdu336.6

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“…In line with the pre-clinical animal model results mentioned above, preliminary signals of efficacy were observed particularly with hematological malignancies including AML, CLL, NHL, and MM [ 80 ]-[ 82 ]. For solid malignancies, selinexor also displayed single-agent activity in prostate [ 88 ], ovarian [ 84 ],[ 85 ], cervical [ 84 ], and colorectal [ 83 ],[ 84 ] cancers and showed prolonged disease control in patients with head and neck cancer [ 89 ], as well as sarcoma [ 86 ]. Based on the encouraging results from the Phase I studies, several Phase II studies of selinexor have been initiated in patients with AML, GBM, melanoma, prostate, ovarian, cervical, and endometrial malignancies (a complete list of the on-going clinical trials is available at clinicaltrials.gov).…”

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confidence: 99%

Nucleo-cytoplasmic transport as a therapeutic target of cancer

et al. 2014

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Shuttling of specific proteins out of the nucleus is essential for the regulation of the cell cycle and proliferation of both normal and malignant tissues. Dysregulation of this fundamental process may affect many other important cellular processes such as tumor growth, inflammatory response, cell cycle, and apoptosis. It is known that XPO1 (Exportin-1/Chromosome Region Maintenance 1/CRM1) is the main mediator of nuclear export in many cell types. Nuclear proteins exported to the cytoplasm by XPO1 include the drug targets topoisomerase IIα (topo IIα) and BCR-ABL and tumor suppressor proteins such as Rb, APC, p53, p21, and p27. XPO1 can mediate cell proliferation through several pathways: (i) the sub-cellular localization of NES-containing oncogenes and tumor suppressor proteins, (ii) the control of the mitotic apparatus and chromosome segregation, and (iii) the maintenance of nuclear and chromosomal structures. The XPO1 protein is elevated in ovarian carcinoma, glioma, osteosarcoma, pancreatic and cervical cancer. There is a growing body of research indicating that XPO1 may have an important role as a prognostic marker in solid tumors. Because of this, nuclear export inhibition through XPO1 is a potential target for therapeutic intervention in many cancers. The best understood XPO1 inhibitors are the small molecule nuclear export inhibitors (NEIs; Leptomycin B and derivatives, ratjadones, PKF050-638, valtrate, ACA, CBS9106, selinexor/KPT-330, and verdinexor/KPT-335). Selinexor and verdinexor are orally bioavailable, highly potent, small molecules that are classified as Selective Inhibitors of Nuclear Export (SINE). KPT-330 is the only NEI currently in Phase I/II human clinical trials in hematological and solid cancers. Of all the potential targets in nuclear cytoplasmic transport, the nuclear export receptor XPO1 remains the best understood and most advanced therapeutic target for the treatment of cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0085-1) contains supplementary material, which is available to authorized users.

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confidence: 99%

Nucleo-cytoplasmic transport as a therapeutic target of cancer

et al. 2014

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CRISPR-Cas9 therapeutics in cancer: promising strategies and present challenges

2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Emerging Agents for the Therapy of Advanced Prostate Cancer

2015

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Since 2010, multiple advances have been made in the field of metastatic castration-resistant prostate cancer including regulatory approvals for five new agents including androgen pathway inhibitors (enzalutamide, abiraterone acetate), immunotherapy (sipuleucel-T), cytotoxic chemotherapy (cabazitaxel) and radiopharmaceuticals (radium-223) that have improved overall survival in this patient population. Despite these advances, each therapy has only extended median survival by 3-5 months and data suggest substantial cross-resistance among them. Given these modest increments, there is a major role for the vigorous investigation of new drugs and predictive biomarkers to select suitable patients who will benefit from them. This review describes emerging promising agents and their ongoing clinical development.

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Selinexor (Kpt-330), an Oral, Selective Inhibitor of Nuclear Export (Sine) Shows Anti-Prostate Cancer (Prca) Activity Preclinically & Disease Control in Patients (Pts) with Chemotherapy Refractory, Castrate-Resistant Prostate Cancer (Crpc)

Cited by 3 publications

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Nucleo-cytoplasmic transport as a therapeutic target of cancer

Nucleo-cytoplasmic transport as a therapeutic target of cancer

CRISPR-Cas9 therapeutics in cancer: promising strategies and present challenges

Emerging Agents for the Therapy of Advanced Prostate Cancer

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