selinexor and Neoplasm-Metastasis

Selinexor is an oral Selective Inhibitor of Nuclear Export compound that specifically blocks Chromosomal Region Maintenance protein 1.. To evaluate the safety and tolerability of escalating doses of selinexor plus 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) in metastatic colorectal cancer (mCRC) patients.. In this multicenter phase I trial, mCRC patients, eligible for oxaliplatin-based treatment, were enrolled to receive oral selinexor on days 1, 3, and 8 plus mFOLFOX6 every two weeks. Primary endpoint was the maximum tolerated dose. Secondary endpoints were toxicity, overall response rate, progression free survival, and overall survival.. Overall, 10 patients were enrolled, who had prior treatment with oxaliplatin (6/10), irinotecan (8/10), bevacizumab (6/10) or anti-EGFR therapy (5/10). Four consecutive patients received 40 mg selinexor plus mFOLFOX6. All four experienced dose-limiting toxicities and withdrew from the study after a median of two cycles. Thus, this dose level was regarded as toxic and no further patients were evaluated at this dose. Six patients were enrolled with 20 mg selinexor plus mFOLFOX6. Despite better tolerability, four patients withdrew (patient wish) after the first cycle and only two patients continued until disease progression. Most commonly reported treatment emergent adverse events were nausea (80%), diarrhea (70%), vomiting (60%), fatigue (60%), anorexia (40%), and impaired vision (40%). Due to the short treatment exposure, no relevant clinical activity was observed.. In patients with metastatic colorectal cancer, selinexor on this dose schedule plus mFOLFOX6 was not tolerable. Other dosing schedules or combinations may be evaluated. Clinical trial identifier NCT02384850.

Topics: Active Transport, Cell Nucleus; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Hydrazines; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Prognosis; Survival Rate; Triazoles

Single-agent selinexor has limited activity in heavily pretreated patients with metastatic triple-negative breast cancer.Selinexor 60 mg by mouth twice weekly was generally well tolerated with a side-effect profile consistent with previous clinical trials.Future studies of selinexor in this population should focus on combination approaches and a biomarker-driven strategy to identify patients most likely to benefit.. This phase II trial evaluated the safety, pharmacodynamics, and efficacy of selinexor (KPT-330), an oral selective inhibitor of nuclear export (SINE) in patients with advanced triple-negative breast cancer (TNBC).. This phase II trial was designed to enroll 30 patients with metastatic TNBC. Selinexor was given at 60 mg orally twice weekly on days 1 and 3 of each week, three of each 4-week cycle. The primary objective of this study was to determine the clinical benefit rate (CBR), defined as complete response + partial response + stable disease (SD) ≥12 weeks.. Ten patients with a median age of 60 years (range 44-71 years) were enrolled between July 2015 and January 2016. The median number of prior chemotherapy lines was 2 (range 1-5). A planned interim analysis for the first stage per protocol was performed. Three patients had SD and seven had progressive disease. On the basis of these results and predefined stoppage rules, the study was halted.. Selinexor was fairly well tolerated in patients with advanced TNBC but did not result in objective responses. However, clinical benefit rate was 30%, and further investigation of selinexor in this patient population should focus on combination therapies.

Topics: Adult; Aged; Antineoplastic Agents; Female; Follow-Up Studies; Humans; Hydrazines; Middle Aged; Neoplasm Metastasis; Prognosis; Survival Rate; Triazoles; Triple Negative Breast Neoplasms

Identifying therapeutic targets in rare cancers remains challenging due to the paucity of established models to perform preclinical studies. As a proof-of-concept, we developed a patient-derived cancer cell line, CLF-PED-015-T, from a paediatric patient with a rare undifferentiated sarcoma. Here, we confirm that this cell line recapitulates the histology and harbours the majority of the somatic genetic alterations found in a metastatic lesion isolated at first relapse. We then perform pooled CRISPR-Cas9 and RNAi loss-of-function screens and a small-molecule screen focused on druggable cancer targets. Integrating these three complementary and orthogonal methods, we identify CDK4 and XPO1 as potential therapeutic targets in this cancer, which has no known alterations in these genes. These observations establish an approach that integrates new patient-derived models, functional genomics and chemical screens to facilitate the discovery of targets in rare cancers.

Topics: A549 Cells; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle; Cell Line, Tumor; CRISPR-Cas Systems; Cyclin-Dependent Kinase 4; Doxorubicin; Drug Screening Assays, Antitumor; Exome; Exportin 1 Protein; Female; Genomics; Humans; Hydrazines; Karyopherins; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Transplantation; Piperazines; Pyridines; Rare Diseases; Receptors, Cytoplasmic and Nuclear; RNA Interference; Sarcoma; Sequence Analysis, RNA; Triazoles

Exportin 1 (XPO1), also called chromosome region maintenance 1 (CRM1), is the sole exportin mediating transport of many multiple tumor suppressor proteins out of the nucleus.. To verify the hypothesis that XPO1 inhibition affects prostate cancer (PCa) metastatic potential, orally available, potent and selective, SINE compounds, Selinexor (KPT- 330) and KPT-251, were tested in preclinical models known to generate bone lesions and systemic tumor spread.. In vitro, Selinexor reduced both secretion of proteases and ability to migrate and invade of PCa cells. SINEs impaired secretion of pro-angiogenic and pro-osteolytic cytokines and reduced osteoclastogenesis in RAW264.7 cells. In the intra-prostatic growth model, Selinexor reduced DU145 tumor growth by 41% and 61% at the doses of 4 mg/Kg qd/5 days and 10 mg/Kg q2dx3 weeks, respectively, as well as the incidence of macroscopic visceral metastases. In a systemic metastasis model, following intracardiac injection of PCb2 cells, 80% (8/10) of controls, 10% (1/10) Selinexor- and 20% (2/10) KPT-251-treated animals developed radiographic evidence of lytic bone lesions. Similarly, after intra-tibial injection, the lytic areas were higher in controls than in Selinexor and KPT-251 groups. Analogously, the serum levels of osteoclast markers (mTRAP and type I collagen fragment, CTX), were significantly higher in controls than in Selinexor- and KPT-251-treated animals. Importantly, overall survival and disease-free survival were significantly higher in Selinexor- and KPT-251-treated animals when compared to controls.. Selective blockade of XPO1-dependent nuclear export represents a completely novel approach for the treatment of advanced and metastatic PCa.

Topics: Active Transport, Cell Nucleus; Animals; Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Cell Movement; Exportin 1 Protein; Humans; Hydrazines; Karyopherins; Male; Mice, SCID; Neoplasm Metastasis; Osteoblasts; Prostatic Neoplasms; Receptors, Cytoplasmic and Nuclear; Triazoles; Xenograft Model Antitumor Assays