Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer

Jones, Robert J.; Vuky, Jacqueline; Elliott, Tony; Mead, G. M.; Arranz, José Ángel; Chester, John D.; Dudek, Arkadiusz Z.; Müller-Mattheis, V.; Grimm, Marc‐Oliver; Gschwend, Jürgen E.; Wülfing, Christian; Albers, Peter; Li, Jianguo; Osmukhina, Anna; Skolnik, Jeffrey; Hudes, Gary R.

doi:10.1007/s10637-013-9926-y

Cited by 34 publications

(21 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, it has been reported that KIF15 could assist cancer cells to develop chemotherapy resistance, thus affecting the efficiency of cancer treatment [45]. KIF15 tends to be compensatorily up-regulated when Eg5 is inhibited by anticancer drugs because of its structural and functional similarities to Eg5 in mitosis [46,47]. Therefore, whether KIF15 plays a role in chemotherapy of GC also needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

KIF15 facilitates gastric cancer via enhancing proliferation, inhibiting apoptosis, and predict poor prognosis

Ding

et al. 2020

Cancer Cell Int

View full text Add to dashboard Cite

Background: Kinesin superfamily proteins (KIFs) can transport membranous organelles and protein complexes in an ATP-dependent manner. Kinesin family member 15 (KIF15) is overexpressed in various cancers. However, the function of KIF15 in gastric cancer (GC) is still unclear. Methods: GC patients' data from The Cancer Genome Atlas (TCGA) were analyzed by bioinformatics methods. The expression of KIF15 was examined in GC and paracarcinoma tissues from 41 patients to verify the analysis results. The relationship between KIF15 expression and clinical characteristics were also observed by bioinformatics methods. Kaplan-Meier survival analysis of 122 GC patients in our hospital was performed to explore the relationship between KIF15 expression levels and GC patients' prognosis. KIF15 was downregulated in GC cell lines AGS and SGC-7901 by transfecting a lentivirus-mediated shRNA plasmid targeting KIF15. In vitro, GC cell proliferation and apoptosis were detected by MTT assay, colony formation assay, and Annexin V-APC staining. In vivo, xenograft experiments were used to verify the in vitro results. Furthermore, Human Apoptosis Antibody Array kit was used to screen possible targets of KIF15 in GC cell lines. Results: The bioinformatics results showed that KIF15 expression levels were higher in GC tissues than in normal tissues. IHC showed same results. High expression of KIF15 was statistical correlated with high age and early histologic stage. Kaplan-Meier curves indicated that high KIF15 expression predict poor prognosis in patients with GC. MTT assay and colony formation assay showed that KIF15 promote GC cell proliferation. Annexin V-APC staining found that KIF15 can inhibit GC cell apoptosis. Xenograft experiments reveal that downregulating KIF15 can inhibit GC tumor growth and promote GC apoptosis. Through detection of 43 anti-apoptotic proteins by the Human Apoptosis Antibody Array kit, it was confirmed that knocking down KIF15 can reduce seven anti-apoptotic proteins expression. Conclusions: Taken together, our study revealed a critical role for KIF15 to inhibit GC cell apoptosis and promote GC cell proliferation. KIF15 may decrease anti-apoptotic proteins expression by regulating apoptosis pathways. High expression of KIF15 predicts a poor prognosis in patients with GC. KIF15 might be a novel prognostic biomarker and a therapeutic target for GC.

show abstract

Section: Discussionmentioning

confidence: 99%

KIF15 facilitates gastric cancer via enhancing proliferation, inhibiting apoptosis, and predict poor prognosis

Ding

et al. 2020

Cancer Cell Int

View full text Add to dashboard Cite

show abstract

“…In most clinical trials with Eg5 inhibitors in which G-CSF support was not used, treatment durations were short which may have precluded demonstration of responses resulting from Eg5 inhibition. For example, in a recent Phase II trial of the Eg5 inhibitor AZD4877 in urothelial cancers(Jones et al, 2013), the median treatment duration was only 43 days (∼1.5 months) and no responses were noted. Since lowering neutropenia allowed higher doses, greater treatment duration and the demonstration of efficacy with ARRY-520, further lowering of neutropenia with the specific mode of Eg5 inhibition we identified (combined with G-CSF support) has the potential to improve further outcomes of patients treated with this approach.…”

Section: Discussionmentioning

confidence: 99%

Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors

et al. 2015

View full text Add to dashboard Cite

Summary Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting a binding site distinct from known Eg5 inhibitors, and BRD9876 inhibited only microtubule-bound Eg5. Eg5 phosphorylation, which increases microtubule binding, uniquely enhanced BRD9876 activity. MM cells have greater phosphorylated Eg5 than hematopoietic cells, consistent with increased vulnerability specifically to BRD9876's mode of action. Thus, differences in Eg5-microtubule binding between malignant and normal blood cells may be exploited to treat multiple myeloma. Additional steps are required for further therapeutic development but our results indicate that unbiased chemical biology approaches can identify therapeutic strategies unanticipated by prior knowledge of protein targets.

show abstract

“…Ispinesib, a KIF11targeted inhibitor, was the first KIF-inhibitor that was evaluated both safety and efficacy in breast cancer in phase I clinical study [30]. Other KIF-targeted drugs further tested in various cancers by clinical trials including KIF11 inhibitors (litronesib [31,32], filanesib [33][34][35], SB-743921 [36], AZD4877 [37]), KIF5C inhibitors (Lidocaine and Tetracaine [38]) and KIFC1 inhibitors (AZ82 and SR31527 [39,40]). However, limited efficacy was seen in all inhibitors reported.…”

mentioning

confidence: 99%

Overexpression of kinesin superfamily members as prognostic biomarkers of breast cancer

Zeng

Zhang

et al. 2020

Cancer Cell Int

View full text Add to dashboard Cite

Background: Kinesin superfamily (KIFs) has a long-reported significant influence on the initiation, development, and progress of breast cancer. However, the prognostic value of whole family members was poorly done. Our study intends to demonstrate the value of kinesin superfamily members as prognostic biomarkers as well as a therapeutic target of breast cancer.Methods: Comprehensive bioinformatics analyses were done using data from TCGA, GEO, METABRIC, and GTEx. LASSO regression was done to select tumor-related members. Nomogram was constructed to predict the overall survival (OS) of breast cancer patients. Expression profiles were testified by quantitative RT-PCR and immunohistochemistry. Transcription factor, GO and KEGG enrichments were done to explore regulatory mechanism and functions.

show abstract

Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer

Abstract: AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.

Cited by 34 publications

References 29 publications

KIF15 facilitates gastric cancer via enhancing proliferation, inhibiting apoptosis, and predict poor prognosis

KIF15 facilitates gastric cancer via enhancing proliferation, inhibiting apoptosis, and predict poor prognosis

Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors

Overexpression of kinesin superfamily members as prognostic biomarkers of breast cancer

Contact Info

Product

Resources

About