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RRx-001 in Refractory Small-Cell Lung Carcinoma: A Case Report of a Partial Response after a Third Reintroduction of Platinum Doublets.

RRx-001 is a pan-active, systemically nontoxic epigenetic inhibitor under investigation in advanced non-small cell lung cancer, small-cell lung cancer and high-grade neuroendocrine tumors in a Phase II clinical trial entitled TRIPLE THREAT (NCT02489903), which reexposes patients to previously effective but refractory platinum doublets after treatment with RRx-001. The purpose of this case study is first to report a partial response to carboplatin and etoposide in a patient with small-cell lung cancer pretreated with RRx-001, indicating episensitization or resensitization by epigenetic mechanisms, and second to discuss the literature related to small-cell lung cancer and episensitization.

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OCT-4: a novel estrogen receptor-α collaborator that promotes tamoxifen resistance in breast cancer cells.

Tamoxifen has shown great success in the treatment of breast cancer; however, long-term treatment can lead to acquired tamoxifen (TOT) resistance and relapse. TOT classically antagonizes estradiol (E2) -dependent breast cancer cell growth, but exerts partial agonist/antagonist behavior on gene expression. Although both E2 and TOT treatment of breast cancer cells results in recruitment of the estrogen receptor (ER) to common and distinct genomic sites, the mechanisms and proteins underlying TOT preferential recruitment of the ER remains poorly defined. To this end, we performed in silico motif-enrichment analyses within the ER-binding peaks in response to E2 or TOT, to identify factors that would specifically recruit ER to genomic binding sites in the presence of TOT as compared to E2. Intriguingly, we found Nkx3-1 and Oct-transcription factor homodimer motifs to be enriched in TOT preferential binding sites and confirmed the critical role of Oct-3/4 (aka Oct-4) in directing ER recruitment to TOT preferential genomic binding sites, by chromatin immunoprecipitation (ChIP) analyses. Further investigation revealed Oct-4 expression to be basally repressed by Nkx3-1 in MCF-7 cells and TOT treatment appeared to elevate Nkx3-1 degradation through a p38MAPK-dependent phosphorylation of the E3 ligase, Skp2 at serine-64 residue, as observed by quantitative mass-spectrometry analyses. Consistently, Oct-4 upon induction by phospho-Ser64-Skp2-mediated proteasomal degradation of Nkx3-1, participated in ER transcriptional complexes along with p38MAPK and Skp2 in a tamoxifen-dependent manner leading to TOT-dependent gene activation and cell proliferation of the TOT-resistant MCF-7-tam(r) breast cancer cells. Notably, Oct-4 levels were highly elevated in MCF-7-tam(r) cells, and appeared critical for their TOT sensitivity in cell proliferation assays. Furthermore, overexpression of Oct-4 enhanced tumor growth in the presence of tamoxifen in mice in vivo. Collectively, our work presents a novel mechanism for tamoxifen-specific gene activation by ER, secondary to its TOT preferential recruitment to genomic sites by specific activation of Oct-4, a phenomenon that appears to underlie tamoxifen resistance in breast cancer cells and in xenograft tumor models, and could be useful in designing therapeutic interventions to improve treatment outcome.Oncogene advance online publication, 11 April 2016; doi:10.1038/onc.2016.105.

Direct binding of hepatocyte growth factor and vascular endothelial growth factor to CD44v6.

CD44v6, a member of the CD44 family of transmembrane glycoproteins is a co-receptor for two receptor tyrosine kinases (RTKs), Met and VEGFR-2 (vascular endothelial growth factor receptor 2). CD44v6 is not only required for the activation of these RTKs but also for signalling. In order to understand the role of CD44v6 in Met and VEGFR-2 activation and signalling we tested whether CD44v6 binds to their ligands, HGF (hepatocyte growth factor) and VEGF (vascular endothelial growth factor), respectively. FACS analysis and cellular ELISA showed binding of HGF and VEGF only to cells expressing CD44v6. Direct binding of CD44v6 to HGF and VEGF was demonstrated in pull-down assays and the binding affinities were determined using MicroScale Thermophoresis, fluorescence correlation spectroscopy and fluorescence anisotropy. The binding affinity of CD44v6 to HGF is in the micromolar range in contrast with the high-affinity binding measured in the case of VEGF and CD44v6, which is in the nanomolar range. These data reveal a heparan sulfate-independent direct binding of CD44v6 to the ligands of Met and VEGFR-2 and suggest different roles of CD44v6 for these RTKs.
© 2015 Authors.

Clovis Oncology Provides Update on FDA Oncologic Drugs Advisory Committee Meeting to Review Rociletinib for Treatment of Advanced T790M-Positive Mutant Epidermal Growth Factor Receptor Non-Small Cell Lung Cancer

On April 12, 2016 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) met to discuss 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 12, 2016, View Source [SID:1234510716]).

The Committee recommended that the FDA wait to see results from TIGER-3, Clovis’ ongoing Phase 3, randomized, controlled trial of rociletinib, before making a decision on approval of the treatment. Patient enrollment for the trial is expected to complete in late 2018.

"We are disappointed with today’s outcome, as we believe in the strength of the data we presented for rociletinib," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We will work with the FDA to evaluate the best path forward as it continues to review our application."

The FDA set a target action date of June 28, 2016 under the Prescription Drug User Fee Act (PDUFA). The TIGER-3 trial, Clovis’ confirmatory randomized, controlled Phase 3 study for rociletinib, is ongoing, with patient enrollment expected to complete in late 2018.

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 percent and four percent, respectively.

Approximately 15 percent of patients with NSCLC 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), almost all 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.

Cell and Gene Therapy Catapult, UCLB and Imperial Innovations announce positive interim review in ongoing AML WT1 T cell clinical trial

On April 12, 2016 The Cell and Gene Therapy Catapult, the UK organisation dedicated to the growth of the UK cell and gene therapy industry by bridging the gap between scientific research and commercialisation, alongside UCL Business PLC (UCLB) and Imperial Innovations, reported a positive interim review in the phase I/II trial conducted by Catapult Therapy TCR using a T cell therapy to target acute myeloid leukaemia (AML) (Press release, UCLB, APR 12, 2016, View Source [SID:1234510708]).

The review has been conducted by the Data Safety Monitoring Board (DSMB), an independent panel of specialists in the field. The reviewed data shows that in the first cohort comprising 3 patients treated, there was a good safety profile with no serious adverse events (SAEs) related to the WT1-TCR T cell therapy. Importantly, the therapy also met the protocol specified requirements for cell persistence, showing that the WT1 targeted T cells can survive and expand in patients.

Passing this first interim review has enabled the clinical trial to enter its second phase. Dosing has now successfully started in the second cohort of patients in the trial which allows patients to receive a higher dose of the gene modified WT1 TCR T cells.

The therapy uses TCR gene-modified T cells to target WT1-overexpressing cells. It involves modification by gene therapy of the patient’s own T cells, so that they may recognise and destroy WT1-expressing cells when infused back into the body. It shows potential in disorders such as acute myeloid leukaemia and myelodysplastic syndrome and has been ranked by the US National Cancer Institute (NCI) as the number 1 target for cancer immunotherapy.

The trial is operated by Catapult Therapy TCR Limited, a company formed by the Cell and Gene Therapy Catapult with UCLB and Imperial Innovations to develop the T cell therapy, and is supported by the NIHR Biomedical Research Centre (BRC) at University College London Hospitals. Pre-clinical development of the TCR gene therapy programme was supported by Bloodwise, previously Leukaemia and Lymphoma Research. In August 2015 the Cell and Gene Therapy Catapult appointed Cellular Therapeutics Limited (CTL), as a manufacturer for the clinical trial.

"Developing TCR gene-modified T cells to target WT1-overexpressing cells continues to show promise as an immunotherapy for a range of cancers including the trials that we have underway in acute myeloid leukaemia and myelodysplastic syndrome," said Keith Thompson, CEO, the Cell and Gene Therapy Catapult. "The progress of the WT1 TCR clinical trials supported by the positive DSMB review, is encouraging and we look forward to expanding these trials across the UK and Europe. Further results are expected during 2017."

"We are delighted with the progress of this clinical trial in acute myeloid leukaemia," said Professor Emma Morris, UCL Institute of Immunity and Transplantation, Chief Investigator and co-inventor as well as Director of the Infection, Immunity and Inflammation Programme at the National Institute for Health Research University College London Hospitals Biomedical Research Centre. "This is an important area of unmet medical need and we are progressing with the next stages of recruitment now ongoing in the second cohort of the AML trial."

"We are pleased to note the progress of this innovative therapy," said Tony Hickson, Managing Director of Technology Transfer at Imperial Innovations. "Catapult Therapy TCR is a great example of collaboration between UK universities and technology transfer organisations and we look forward to the results of forthcoming trials."

About the Cell and Gene Therapy Catapult
The Cell and Gene Therapy Catapult was established in 2012 as an independent centre of excellence to advance the growth of the UK cell and gene therapy industry, by bridging the gap between scientific research and full-scale commercialisation. With more than 100 employees focusing on cell and gene therapy technologies, we work with our partners in academia and industry to ensure these life-changing therapies can be developed for use in health services throughout the world. We offer leading-edge capability, technology and innovation to enable companies to take products into clinical trials and provide clinical, process development, manufacturing, regulatory, health economics and market access expertise. We aim to make the UK the most compelling and logical choice for UK and international partners to develop and commercialise these advanced therapies. Regenerative medicine is one of the UK government’s "eight great technologies" that support UK science strengths and business capabilities. The Cell and Gene Therapy Catapult works with Innovate UK. For more information go to ct.catapult.org.uk or visit www.gov.uk/innovate-uk.