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Chromatin structure in vehicle treated C4-2 cells

Seven Supplementary Figures and Legends

Abiraterone is a standard treatment for metastatic castrate-resistant prostate cancer (mCRPC) that slows disease progression by abrogating androgen synthesis and antagonizing the androgen receptor (AR). Here we report that inhibitors of the mitotic regulator polo-like kinase-1 (Plk1), including the clinically active third-generation Plk1 inhibitor onvansertib, synergizes with abiraterone in vitro and in vivo to kill a subset of cancer cells from a wide variety of tumor types in an androgen-independent manner. Gene-expression analysis identified an AR-independent synergy-specific gene set signature upregulated upon abiraterone treatment that is dominated by pathways related to mitosis and the mitotic spindle. Abiraterone treatment alone caused defects in mitotic spindle orientation, failure of complete chromosome condensation, and improper cell division independently of its effects on AR signaling. These effects, although mild following abiraterone monotherapy, resulted in profound sensitization to the antimitotic effects of Plk1 inhibition, leading to spindle assembly checkpoint-dependent mitotic cancer cell death and entosis. In a murine patient-derived xenograft model of abiraterone-resistant metastatic castration-resistant prostate cancer (mCRPC), combined onvansertib and abiraterone resulted in enhanced mitotic arrest and dramatic inhibition of tumor cell growth compared with either agent alone. Overall, this work establishes a mechanistic basis for the phase II clinical trial (NCT03414034) testing combined onvansertib and abiraterone in mCRPC patients and indicates this combination may have broad utility for cancer treatment.Significance:Abiraterone treatment induces mitotic defects that sensitize cancer cells to Plk1 inhibition, revealing an AR-independent mechanism for this synergistic combination that is applicable to a variety of cancer types.

Abiraterone is a standard treatment for metastatic castrate-resistant prostate cancer (mCRPC) that slows disease progression by abrogating androgen synthesis and antagonizing the androgen receptor (AR). Here we report that inhibitors of the mitotic regulator polo-like kinase-1 (Plk1), including the clinically active third-generation Plk1 inhibitor onvansertib, synergizes with abiraterone in vitro and in vivo to kill a subset of cancer cells from a wide variety of tumor types in an androgen-independent manner. Gene-expression analysis identified an AR-independent synergy-specific gene set signature upregulated upon abiraterone treatment that is dominated by pathways related to mitosis and the mitotic spindle. Abiraterone treatment alone caused defects in mitotic spindle orientation, failure of complete chromosome condensation, and improper cell division independently of its effects on AR signaling. These effects, although mild following abiraterone monotherapy, resulted in profound sensitization to the antimitotic effects of Plk1 inhibition, leading to spindle assembly checkpoint-dependent mitotic cancer cell death and entosis. In a murine patient-derived xenograft model of abiraterone-resistant metastatic castration-resistant prostate cancer (mCRPC), combined onvansertib and abiraterone resulted in enhanced mitotic arrest and dramatic inhibition of tumor cell growth compared with either agent alone. Overall, this work establishes a mechanistic basis for the phase II clinical trial (NCT03414034) testing combined onvansertib and abiraterone in mCRPC patients and indicates this combination may have broad utility for cancer treatment. Significance: Abiraterone treatment induces mitotic defects that sensitize cancer cells to Plk1 inhibition, revealing an AR-independent mechanism for this synergistic combination that is applicable to a variety of cancer types.

Background: PLK1 is a serine/threonine kinase master regulator of the cell cycle, overexpressed in AML blasts. Onvansertib (ONV) is an oral, highly selective next-generation PLK1 inhibitor that demonstrated anti-tumor activity in AML preclinical models. The safety and efficacy of ONV in combination with decitabine (DAC) in patients with R/R AML is under study in an ongoing phase 1b/2 clinical trial (NCT03303339). Here we report results of correlative studies to identify molecular predictors of response to the ONV-DAC combination. Methods: R/R AML patients were treated for 5 days with ONV (orally) and DAC (20 mg/m 2 IV qd x 5d) in 21- or 28-day cycles. Patients who completed at least 1 cycle of treatment were considered evaluable for efficacy. At baseline, bone marrow (BM) samples were collected for targeted next-generation sequencing (Myeloid VariantPlex, Archer) and blood samples for RNA-sequencing. Results: As of July 7, 2021, 23 patients were treated with ONV (12 - 90 mg/m 2) + DAC in Phase 1b and 32 patients with ONV 60 mg/m 2 + DAC in Phase 2. Nine (20%) of the 46 patients that were evaluable for efficacy achieved a complete remission with or without complete hematologic recovery (CR/CRi) as their best response (7 CR and 2 CRi). Another 6 patients had ≥50% BM blast decrease from baseline at one point on trial therapy. Those 6 patients plus the 9 patients who achieved CR/CRi are referred to as BM responders (n=15). RNA-seq was performed on blood collected from 32 patients, including 12 BM responders. Differential gene expression, gene-set, and machine learning analyses of BM responders versus non-responders identified a gene expression signature predictive of response to the ONV-DAC combination. No association between the ONV-DAC signature and DAC response was observed after applying the ONV-DAC signature to gene expression profiles from patients treated with DAC as a single agent in a multicenter Phase 2 study (NCT00866073), indicating that the gene signature is specific to the combination. The ONV-DAC signature was also applied to the BeatAML cohort (n=399) and identified 241 predicted responders. Mutation analysis of the BeatAML cohort revealed a positive association between predicted ONV-DAC response and mutations in splicing factors (SF) such as SRSF2, suggesting that SF mutations may serve as a response biomarker for the ONV-DAC combination. Indeed, genomic analysis of baseline BM samples from patients evaluable for efficacy in our Phase 1b/2 (n=46), showed a significant increase in clinical responses in patients with SRSF2 and SF3B1 mutations versus patients with other alterations (Figure 1 and Table 1). In addition, biomarkers reported to be positively correlated with DAC responses (TP53 and TET2 mutations, high fetal hemoglobin expression) were not associated with ONV-DAC clinical responses (Figure 1). Conclusion: We identified a gene expression signature associated with clinical response to the ONV-DAC combination, that did not predict response to DAC single agent. The ONV-DAC predictive signature was found to be correlated with SF mutations in the BeatAML cohort. In our cohort, we confirmed the association between clinical response to ONV-DAC and SF mutations. These analyses support further investigation of the ONV-DAC combination in R/R AML patients with SF mutations and the potential use of ONV-DAC for other hematological diseases with high prevalence of SF mutations such as myelodysplastic syndrome and chronic myelomonocytic leukemia. Figure 1 Figure 1. Disclosures Zeidan: Janssen: Consultancy; Astellas: Consultancy; Astex: Research Funding; Genentech: Consultancy; Daiichi Sankyo: Consultancy; Aprea: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Epizyme: Consultancy; BeyondSpring: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Pfizer: Other: Travel support, Research Funding; BioCryst: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Geron: Other: Clinical Trial Committees; Kura: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Incyte: Consultancy, Research Funding; AstraZeneca: Consultancy; Jasper: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Jazz: Consultancy; Amgen: Consultancy, Research Funding; Agios: Consultancy; ADC Therapeutics: Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Ridinger: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Croucher: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Samuëlsz: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Erlander: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Ruffner: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company; ALX Oncology: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company; Anthem INC: Current equity holder in publicly-traded company; Cardinal Health: Current equity holder in publicly-traded company; Change Healthcare: Current equity holder in publicly-traded company; CVS Health Corp: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Organon: Current equity holder in publicly-traded company. Wang: GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

Unlike a geometric object whose definition does not change, the definitions of "America" and "American" vary by time and space. Historically, responses to the question of what it means to be American have been fluid and contested and?although some would wish it otherwise?no single definition of the term exists. Our nation's history is replete, indeed, with examples of conflict over exactly how to (re)define the meaning of "America" and the parameters of citi zenship (2). America projected this debate abroad in the first half of the twentieth cen

Optimization of individual stages within a production-marketing chain (PMCh) may cause a suboptimal result of the PMCh as a whole. Market imperfections and conflicting interest may be the causal factors. Although vertical integration is often mentioned as the conventional solution, certain disadvantages and the large scale differences in agricultural PMChs make vertical cooperation a more appropriate alternative. Moreover, specific characteristics of agricultural food chains and changing market circumstances, including increased interest in the quality of products and production processes, justify renewed attention to vertical cooperation and product differentiation in agriculture. Current developments in the Dutch pork PMCh and implications on future research are described. © 1996 John Wiley & Sons, Inc.

The effects of nasal continuous positive airway pressure (CPAP) on expiratory flow, arterial blood gas tensions, cardiovascular status, and dyspnea were studied in 21 patients with acute asthma. Therapy consisted of the following CPAP sequence: 30 minutes at 5 cm H2O, 20 minutes at 0 cm H2O, 30 minutes at 7.5 cm H2O, and 20 minutes at 0 cm H2O. Six control patients were fitted with a CPAP mask but given no positive-pressure therapy. Significant reductions in respiratory rate occurred from a baseline of 22.0 +/- 1.0 to 19.8 +/- 3.8 breaths/min at CPAP 5 cm H2O and to 19.4 +/- 4.3 breaths/min at CPAP 7.5 cm H2O (P < .05). No significant change occurred in forced expiratory volume in 1 second (FEV1), heart rate, mean arterial blood pressure, or arterial blood gas tension with either level of CPAP. Dyspnea, as assessed by a breathlessness score, improved during CPAP therapy (P < .05). These levels of CPAP were tolerated without deleterious side effects. In comparison, the control group showed no change in heart rate, respiratory rate, or breathlessness score during the study period. These data show that application of CPAP in acute asthma reduces respiratory rate and dyspnea with no untoward effects on gas exchange, expiratory airflow, or hemodynamics.

Brazil is the world beef export leader since 2004, when he Bovine Spongiform Encephalopathy (BSE) crisis in the United States and the severe draught in Australia dropped those countries beef exports and gave Brazilian beef chain a unique opportunity to enter in new markets. Brazil is facing now a major challenge in terms of aggregating value, since its export volume is already stabilizing. The European Union (EU) represents the most demanding market in terms of quality and one in which Brazil can get a better remuneration for its products, as long as the country beef chain can develop new relationship strategies to provide such a specific product. This study aims to present some trends in the European market as well as to discuss them as opportunities for the Brazilian beef chain, especially in terms of coordination forms, following New Institutional Economy principles. It shows that new forms of relationship within the network are emerging (like alliances and associations) and that new strategies should be focused on the consumer desires.

We investigate the factors that influence vertical coordination in the fresh produce industry. Elaborating on the concept of governance structure, price and non-price coordination systems will be distinguished. Under previous research, there is a specific consideration as to how market conditions and institutional considerations influence the coordination of supply chains. In my presentation for the Food Distribution Research Society in Monterey, California, I analyzed how retail companies in the United States, France, and the Netherlands coordinate their supply chains of fruits and vegetables. Differences in product category and institutional environments do not contribute directly to the explanation of differences found in supply chain coordination systems. Industry-specific factors and firm-resource-based factors may supply a better understanding of these differences.