barasertib-HQPA (AZD2811)

In the present study, the cellular and molecular effects of pharmacological inhibitors of aurora kinases, such as aurora A inhibitor I, AZD1152-HQPA, and reversine, were evaluated in Ba/F3 expressing the CSF3R mutation...Reversine more efficiently modulated genes associated with cell cycle and apoptosis compared to other drugs. In summary, our findings shed new insights into the use of AURKB inhibitors in the context of CNL.

BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models.

At RP2D, AZD2811 was tolerable with G-CSF support. Neutropenia was a pharmacodynamic biomarker.

We selected 4 combinations based on clinical need and validated them further in vitro and in vivo (selumetinib plus venetoclax or AZD5991, AZD2811 plus venetoclax, and capivasertib plus AZD5991).To understand how molecular context affects drug response, we also used GDSC tools ANOVA to perform over 5.4 million statistical tests to identify statistically significant associations between drug response metrics and multi-omics features including mutations, CNAs, gene expression and methylation. This resulted in identification of 1,631 ‘emergent’ biomarkers.In summary, our screen and pipeline have been designed to optimize preclinical interpretation with a focus on actionability, particularly by our unique approach, and to provide a valuable resource for exploration by the wider research community. As a result of this screen, we identified and validated novel combination-tumor types in multiple cancer types.

Finally, a doxycycline-inducible pTRIPZ vector was used for ectopic expression while silencing was achieved by shRNA lentiviruses Results and Discussions Among the 60 tumor cell lines and clones, BID upregulation was consistently associated with sensitivity to AZD2811; independently of 22q11 amplification (p<0.0001). Analysis of the COSMIC database revealed a prevalence of 1% and 5% for Chr22q11 amplification and BID overexpression in human tumors, respectively. In patients from our institution, we found a frequency of 0.7% (1/143 samples analyzed) for 22q11 amplification and 6% (10/163) for high BID mRNA levels Conclusion BID upregulation is present in 5-6% of human tumors and associates with sensitivity to AURKBi in cancer cells of different origins, thus implying its potential use as a predictive biomarker for AURKB inhibitors in clinical trials

The current standard of care is comprised of a regimen of 4 drugs (cyclophosphamide, doxorubicin, vincristine, and prednisone) combined with immunotherapy using a chimeric mAb against the protein CD20 (rituximab), R-CHOP. While both monotherapies were unable to prevent progressive tumor growth, a combination dosing regimen of AZD2811 and venetoclax drove progressive tumor regression resulting in statistically significant complete regression (98% regression) by the third week of dosing. These results suggest combining AZD2811 with venetoclax has potential to be active in DLBCL patients.

Using the AURKB specific inhibitor barasertib-HQPA we evaluated drug sensitivity in a set of BCa cell lines...In conclusion, we have found Ts65Dn mice have reduced tumor formation when exposed to the BCa carcinogen BBN and furthermore, have identified AURKB as a potential therapeutic target. Use of Ts65Dn mice may be a relevant model for identifying potentially undefined tumorigenic agents in multiple cancers including bladder.

Then, we determined the dose-response curves of the cell lines for AZD2811, a specific AURKB inhibitor... BID upregulation switches cell fate from survival to apoptosis in response to AURKB inhibition in a wide range of tumor cell lines from different origins. Our results pave the way to clinical exploration of AURKB inhibitors in BID overexpressing tumors.

P2, N=4, Terminated, Se-Hoon Lee | N=46 --> 4 | Recruiting --> Terminated | Trial primary completion date: Sep 2021 --> Jan 2022; Recommended completion of the study due to SUSAR occurring in other clinical trials conducted with the same drug.

BCL2+ lymphoma cells, WSU-NHL (single hit; BCL2 only), DoHH2 (DHL; BCL2 and MYC), and VAL (THL; BCL2, MYC, and BCL6) were evaluated for cell viability (ATP quantification) and apoptosis (Annexin V/7AAD staining), after treatment with various concentrations of VEN with or without MLN8237 (AURK-A inhibitor), LY3295668 (AURK-A inhibitor), or AZD2811 (AURK-B inhibitor). p53 knockdown in DoHH2 cells resulted in similar resistance to VEN and combination treatment. Taken together these data suggest AURK inhibition overcomes downregulation of p53/p21/BAX axis by BCL2+ lymphomas in response to BCL2 inhibition, hence lay the groundwork for further evaluation of this combination in clinical settings.

No abstract available

Amplification of 22q11, leading to BID overexpression, predicts sensitivity to AURKB inhibition in cell line models of resistance to osimertinib and other EGFR TKIs. These data are consistent with overdrive in 22q11 amplified cells of a recently reported mitotic checkpoint mediated by AURKB phosphorylation of CASP2, and suppression of BID cleavage.

Furthermore, we show that AZD1152, a specific inhibitor of AURKB, can suppress the expression of CCND1 in the gastric cancer cells and inhibit cell proliferation in vitro and in vivo. Importantly, we found that high AURKB and CCND1 expression levels are correlated with shorter overall survival of gastric cancer patients. This study demonstrates that AURKB promotes gastric tumorigenesis potentially through epigenetically activating CCND1 expression, suggesting AURKB as a promising therapeutic target in gastric cancer.

Collectively, t(6;9) primary samples also showed a selective drug sensitivity to XPO1 (selinexor and eltanexor) and JAK inhibitors (ruxolitinib, tofacitinib and momelotinib) compared to other cytogenetic risk groups. On the other hand, a comparison of in vitro drug sensitivity data with genomic data of our entire cohort of patients demonstrated that TP53 wt AMLs (n=37) were more sensitive to all four MDM2 inhibitors (AMG-232, idasanutlin, SAR405838 and NVP-CGM097) compared to TP53 mutated cases (n=13). Comparisons of transcriptomics with the in vitro sensitivity to drugs included in early/late phase AML clinical trials, identified signatures of response associated with MDM2 and Aurora B kinase (AZD1152-HQPA) inhibitors...Functionally, group A presented with elevated HOXA10 protein expression and enhanced in vitro response to genotoxic drugs and cell cycle inhibitors when compared to group B leukemia. Conclusions : Our study demonstrates the feasibility of simultaneously generating omics data from several different platforms and highlights that a combination of genetic and proteomic profiles may help to inform the choice of therapies based on the underlying biology of a patient’s AML.

P2, N=46, Recruiting, Keunchil Park | Not yet recruiting --> Recruiting

Pharmacological inhibition of AURKB with AZD1152 increases H2Aub levels causing down-regulation of RING1B/EWSR1-FLI1 common targets. Our findings demonstrate that RING1B is a critical modulator of EWSR1-FLI1-induced chromatin remodeling, and its inhibition is a potential therapeutic strategy for the treatment of these tumors.

P2, N=46, Not yet recruiting, Keunchil Park

To the best of the authors' knowledge, the current study is the first biomarker-driven umbrella study conducted in patients with recurrent SCLC. Although the current study demonstrated the limited clinical efficacy of monotherapy, novel biomarker approaches using other cell cycle inhibitor(s) or combinations warrant further investigation.

Multiple associations indicate potential epigenetic mechanisms affecting SCLC response to chemotherapy and suggest targets for combination therapies. While many correlations were not specific to SCLC lineages, several lineage markers were associated with specific agents.

The clinical data showed that the expression level of AURKB in GC patients' sera and tissues were positively correlated with those of C-Myc, GLUT1 and LDHA, but negatively with that of RPS7. Therefore, these findings provide new evidence that barasertib regulates GC cell glucose metabolism by inducing the RPS7/C-Myc signal pathway, and have important implications for the development of therapeutic approaches using AURKB as a target protein to prevent tumor recurrence.

Although recent clinical trials suggest promising response rates for the BCL-2 inhibitor venetoclax (Ven) in combination with DNA methyltransferase inhibitors (DNMTi) or low-dose cytarabine, survival outcomes remain poor among patients with TP53mut (Strickland et al, EHA 2018)...Using a competitive growth assay incorporating a fluorescent reporter for TP53 KO cells, we showed the relative resistance of TP53 defective cells to Ven and decitabine (DEC) alone, as well as Ven + DEC, compared to wild type cells...Remarkably, combined AZD2811NP and Ven treatment was more effective than Ven + azacitidine treatment in vivo... We report for the first time that AZD2811NP can overcome venetoclax resistance in TP53-mutant AML in vitro and in vivo. These findings therefore, support the clinical investigation of combined aurora kinase and BCL-2 targeting in the clinic for patients with TP53-mutant AML, who currently lack effective treatment options.

Notably, 2/5 PDX models screened (DFAM-68555 and DFAM-10360) were insensitive to both venetoclax and the combination of venetoclax + 5-azacytidine (HMA) ex vivo...However, in DFAM-68555, AZD5153, AZD5991, and AZD2811 showed improved activity over venetoclax alone (67%, 54%, and 67% vs. 26% decrease in viability for venetoclax alone, respectively)...Using this platform and subsequent in vivo efficacy, we identified venetoclax combinations across multiple mechanisms (pro-apoptotic, cell cycle regulation, transcriptional regulation, DNA damage response) with activity in venetoclax-insensitive models. These results suggest potential therapeutic options to explore clinically for AML patients.

Increased methylation and low expression of TREX1 were associated with SCLC cell line sensitivity to multiple Aurora kinase inhibitors AZD-1152, SCH-1473759, SNS-314, and TAK-901, as well as to the CDK inhibitor R-547, Vertex ATR inhibitor Cpd 45, and the mitotic spindle disruptor vinorelbine...Among other examples, EPAS1 (HIF2A) was associated with several Aurora kinase inhibitors, the PLK1 inhibitor GSK-461364, and the Bcl-2 inhibitor ABT-737...IGFBP5, which is expressed in the tuft cell-like SCLC subtype, was associated with the mTOR inhibitor INK-128...Methylation and expression of YAP1, a SCLC lineage driver regulating the Hippo pathway, were correlated with the MTOR inhibitor rapamycin...The 5’ UTR region of the epigenetic modifier EZH2 was associated with Aurora kinase inhibitors and the FGFR inhibitor BGJ-398. These and multiple other associations identified in this study provide a novel understanding of epigenetic mechanisms which may modulate SCLC response to chemotherapy, and suggest potential molecular targets for combination therapies. This research was supported in part with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E.