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Combination AZD5363 with Enzalutamide Significantly Delays Enzalutamide-resistant Prostate Cancer in Preclinical Models.

The phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt (PI3K/Akt) pathway is a key pathway activated in castrate-resistant prostate cancer (CRPC). This preclinical study evaluates targeting of Akt with AZD5363 alone and in combination with enzalutamide (ENZ) to prevent and delay resistance. Our results demonstrate AZD5363 has significant proapoptotic, antiproliferative activity as monotherapy in ENZ-resistant cell lines in vitro and significantly decreased tumour growth in ENZ-resistant xenograft. The combination of AZD5363 and ENZ showed synergistic decreases in cell proliferation and induced cell-cycle arrest and apoptosis in prostate cancer cell lines LNCaP and C4-2. Notably, the combination of AZD5363 and ENZ resulted in an impressive regression of castrate-resistant LNCaP xenograft tumours without any recurrence demonstrated, whereas progression occurred with both monotherapies. Serum prostate-specific antigen (PSA) levels were also continuously suppressed, and nadir PSA levels were lower in the combination arm compared to ENZ alone. Combination AZD5363 and ENZ at time of castration similarly resulted in significant regression of tumours, with greater relative suppression of PSA compared to when administered to castrate-resistant xenografts. In summary, combination AZD5363 and ENZ significantly delays the development of ENZ resistance in preclinical models through synergistic increases in apoptosis and cell cycle arrest. Our results also suggest greater efficacy may be seen with earlier combination treatment. This study provides preclinical data to support evaluation of combination targeting of the PI3K/Akt pathway and the androgen-receptor axis in the clinic using AZD5363 and ENZ, respectively.
Targeting of the Akt and androgen receptor pathways with AZD5363 and enzalutamide, respectively, significantly delayed the development of enzalutamide-resistant prostate cancer through increased apoptosis and cell cycle arrest. This preclinical synergy provides a strong rationale for clinical evaluation of this combination.
Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment.

This long-term follow-up analysis evaluated overall survival (OS) and relapse-free survival (RFS) in a phase 2 study of the bispecific T-cell engager antibody construct blinatumomab in 36 adults with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). In the primary analysis, 25 (69%) patients with relapsed/refractory ALL achieved complete remission with full (CR) or partial (CRh) hematologic recovery of peripheral blood counts within the first 2 cycles. Twenty-five patients (69%) had a minimal residual disease (MRD) response (&lt;10(-4) blasts), including 22 CR/CRh responders, 2 patients with hypocellular bone marrow, and 1 patient with normocellular bone marrow but low peripheral counts. Ten of the 36 patients (28%) were long-term survivors (OS ≥30 months). Median OS was 13.0 months (median follow-up, 32.6 months). MRD response was associated with significantly longer OS (Mantel-Byar P = .009). All 10 long-term survivors had an MRD response. Median RFS was 8.8 months (median follow-up, 28.9 months). A plateau for RFS was reached after ∼18 months. Six of the 10 long-term survivors remained relapse-free, including 4 who received allogeneic stem cell transplantation (allo-SCT) as consolidation for blinatumomab and 2 who received 3 additional cycles of blinatumomab instead of allo-SCT. Three long-term survivors had neurologic events or cytokine release syndrome, resulting in temporary blinatumomab discontinuation; all restarted blinatumomab successfully. Long-term survivors had more pronounced T-cell expansion than patients with OS &lt;30 months.
© 2015 by The American Society of Hematology (ASH) (Free ASH Whitepaper).

A mouse model of a human congenital disorder of glycosylation caused by loss of PMM2.

The most common congenital disorder of glycosylation, PMM2-CDG, is caused by mutations in phosphomannomutase 2 (PMM2) that limit availability of mannose precursors required for protein N-glycosylation. The disorder has no therapy and there are no models to test new treatments. We generated compound heterozygous mice with the R137H and F115L mutations inPmm2that correspond to the most prevalent alleles found in patients with PMM2-CDG. ManyPmm2(R137H/F115L)mice died prenatally, while survivors had significantly stunted growth. These animals and cells derived from them showed protein glycosylation deficiencies similar to those found in patients with PMM2-CDG. Growth-related glycoproteins insulin-like growth factor (IGF) 1, IGF binding protein-3, and acid-labile subunit, along with antithrombin III, were all deficient inPmm2(R137H/F115L)mice, but their levels in heterozygous mice were comparable to wild-type (WT) littermates. These imbalances, resulting from defective glycosylation, are likely the cause of the stunted growth seen both in our model and in PMM2-CDG patients. BothPmm2(R137H/F115L)mouse and PMM2-CDG patient-derived fibroblasts displayed reductions in PMM activity, GDP-mannose, lipid-linked oligosaccharide precursor, and total cellular protein glycosylation, along with hypoglycosylation of a new endogenous biomarker, glycoprotein 130 (gp130). Over-expression of WT-PMM2 in patient-derived fibroblasts rescued all these defects, showing that restoration of mutant PMM2 activity is a viable therapeutic strategy. This functional mouse model of PMM2-CDG,in vitroassays, and identification of the novel gp130 biomarker all shed light on the human disease, and moreover, provide the essential tools to test potential therapeutics for this untreatable disease.
© The Author 2016. Published by Oxford University Press.

p53 Maintains Genomic Stability by Preventing Interference between Transcription and Replication.

p53 tumor suppressor maintains genomic stability, typically acting through cell-cycle arrest, senescence, and apoptosis. We discovered a function of p53 in preventing conflicts between transcription and replication, independent of its canonical roles. p53 deficiency sensitizes cells to Topoisomerase (Topo) II inhibitors, resulting in DNA damage arising spontaneously during replication. Topoisomerase IIα (TOP2A)-DNA complexes preferentially accumulate in isogenic p53 mutant or knockout cells, reflecting an increased recruitment of TOP2A to regulate DNA topology. We propose that p53 acts to prevent DNA topological stress originating from transcription during the S phase and, therefore, promotes normal replication fork progression. Consequently, replication fork progression is impaired in the absence of p53, which is reversed by transcription inhibition. Pharmacologic inhibition of transcription also attenuates DNA damage and decreases Topo-II-DNA complexes, restoring cell viability in p53-deficient cells. Together, our results demonstrate a function of p53 that may underlie its role in tumor suppression.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

FDA Posts Briefing Documents for Advisory Committee Meeting to Review Clovis Oncology’s Rociletinib for Treatment of Advanced T790M-Positive Mutant Epidermal Growth Factor Receptor Non-Small Cell Lung Cancer

On April 8, 2016 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that the U.S. Food and Drug Administration (FDA) posted briefing materials in advance of the Oncologic Drugs Advisory Committee (ODAC) meeting to discuss accelerated approval of the New Drug Application (NDA) for rociletinib, an investigational therapy for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) who have been previously treated with an EGFR-targeted therapy and have the T790M mutation (Press release, Clovis Oncology, APR 8, 2016, View Source [SID:1234510568]).

The ODAC meeting is scheduled to take place on April 12, 2016 from 8:30 a.m. ET to 1 p.m. ET. Briefing materials and webcast information can be found on the FDA website at View Source

The FDA has set a target action date of June 28, 2016 for rociletinib under the Prescription Drug User Fee Act (PDUFA).

About T790M-Positive Mutant EGFR NSCLC

Lung cancer is the second most common cancer in the United States, with more than 200,000 new cases each year, and is the leading cause of cancer-related death. NSCLC accounts for almost 85 percent of lung cancers, and the five-year survival rate in locally advanced and metastatic patients is 27 and four percent, respectively.

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Approximately 10-15 percent of patients with NSCLC in the United States have the EGFR mutation. While the majority of these patients will respond to treatment with first- or second-generation EGFR-targeted tyrosine kinase inhibitors (TKIs), most patients will eventually develop acquired resistance to these therapies, predominantly due to the primary resistance mutation, T790M.

About Rociletinib

Rociletinib is the company’s novel, oral, targeted covalent (irreversible) mutant-selective inhibitor of EGFR in development for the treatment of NSCLC in patients with initial activating EGFR mutations, as well as the dominant resistance mutation T790M. Data from both the pivotal, single-arm TIGER-X and TIGER-2 clinical trials served as the basis for the U.S. and EU regulatory submissions for the treatment of advanced mutant EGFR T790M-positive lung cancer. Rociletinib was granted Breakthrough Therapy designation by the FDA in May 2014.