Humanized monoclonal anti-human growth factor receptor 2 (HER2) antibody trastuzumab was approved for HER2 positive breast cancer patient treatment 11 years after the demonstration of HER2 gene amplification associated with the HER2 protein overexpression in breast cancer in 1987. HER2 positive status of breast cancer patients is assessed by HER2 gene amplification with in situ hybridization (ISH) and/or HER2 protein overexpression with immunohistochemistry (IHC). Because the discordance between quantitative HER2 ISH and subjective, semi-quantitative HER2 IHC assay results is a well-recognized issue of HER2 testing, we developed an assay combining HER2 ISH and HER2 IHC assays (HER2 gene-protein assay; HER2 GPA) as one test on the same tissue section. HER2 GPA allows pathologists to score the HER2 gene and HER2 protein status simultaneously at the individual cell level. The possibility that HER2 GPA may become the next generation of HER2 testing is discussed, particularly for cases in which it is difficult to assess the HER2 status of breast cancer patients due to the HER2 heterogeneity.
© 2016 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

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This study compared the cost-effectiveness of direct-acting antiviral therapies currently recommended for treating genotypes (GT) 1 and 4 chronic hepatitis C (CHC) patients in the United States (US).
A cost-effectiveness analysis of treatments for CHC from a US payer’s perspective over a lifelong time horizon was performed. A Markov model based on the natural history of CHC was used for a population that included treatment-naïve and -experienced patients. Treatment alternatives considered for GT1 included ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (3D±R), sofosbuvir + ledipasvir (SOF/LDV), sofosbuvir + simeprevir (SOF+SMV), simeprevir + pegylated interferon/ribavirin (SMV+PR), and no treatment (NT). For GT4 treatments were ombitasvir/paritaprevir/ritonavir + ribavirin (2D+R), SOF/LDV, and NT were compared. Transition probabilities, utilities, and costs were obtained from published literature. Outcomes included rates of compensated cirrhosis (CC), decompensated cirrhosis (DCC), hepatocellular carcinoma (HCC) and liver-related death (LrD), total costs, life-years, quality-adjusted life-years (QALYs). Costs and QALYs were used to calculate incremental cost-effectiveness ratios.
In GT1 patients, 3D±R and SOF-containing regimens have similar long term outcomes; 3D±R had the lowest lifetime risks of all liver disease outcomes: CC 30.2%, DCC 5.0%, HCC 6.8%, LT 1.9% and LrD 9.2%. In GT1 patients, 3D±R had the lowest cost and the highest QALYs. As a result, 3D±R dominated these treatment options. In GT4 patients, 2D+R had lower rates of liver morbidity and mortality, lower cost, and more QALYs than SOF/LDV and NT.
While the results are based on input values, which were obtained from a variety of heterogeneous sources – including clinical trials, the findings were robust across a plausible range of input values as demonstrated in probabilistic sensitivity analyses.
Among currently recommended treatments for GT1 and GT4 in the US, 3D±R (for GT1) and 2D+R (for GT4) have a favorable cost-effectiveness profile.

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Type 2 diabetes (T2D) has been suggested to be a risk factor for multiple myeloma (MM), but the relationship between the two traits is still not well understood. The aims of this study were to evaluate whether 58 genome-wide-association-studies (GWAS)-identified common variants for T2D influence the risk of developing MM and to determine whether predictive models built with these variants might help to predict the disease risk. We conducted a case-control study including 1420 MM patients and 1858 controls ascertained through the International Multiple Myeloma (IMMEnSE) consortium. Subjects carrying the KCNQ1rs2237892T allele or the CDKN2A-2Brs2383208G/G, IGF1rs35767T/T and MADDrs7944584T/T genotypes had a significantly increased risk of MM (odds ratio (OR)=1.32-2.13) whereas those carrying the KCNJ11rs5215C, KCNJ11rs5219T and THADArs7578597C alleles or the FTOrs8050136A/A and LTArs1041981C/C genotypes showed a significantly decreased risk of developing the disease (OR=0.76-0.85). Interestingly, a prediction model including those T2D-related variants associated with the risk of MM showed a significantly improved discriminatory ability to predict the disease when compared to a model without genetic information (area under the curve (AUC)=0.645 vs AUC=0.629; P=4.05×10(-) (06)). A gender-stratified analysis also revealed a significant gender effect modification for ADAM30rs2641348 and NOTCH2rs10923931 variants (Pinteraction=0.001 and 0.0004, respectively). Men carrying the ADAM30rs2641348C and NOTCH2rs10923931T alleles had a significantly decreased risk of MM whereas an opposite but not significant effect was observed in women (ORM=0.71 and ORM=0.66 vs ORW=1.22 and ORW=1.15, respectively). These results suggest that TD2-related variants may influence the risk of developing MM and their genotyping might help to improve MM risk prediction models.
© 2015 Society for Endocrinology.

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On April 13, 2016 CTI BioPharma Corp. (CTI) (NASDAQ and MTA:CTIC) reported that data highlighting pacritinib, pixantrone and tosedostat will be presented at the upcoming American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting to be held April 16-20 in New Orleans, LA (Press release, CTI BioPharma, APR 12, 2016, View Source;p=RssLanding&cat=news&id=2156655 [SID:1234510734]). The abstracts are available on the AACR (Free AACR Whitepaper) website at www.aacr.org.

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Poster Presentations

Pacritinib

Combinatorial strategies for glioblastoma using brain tumor-initiating cells: targeting the JAK/STAT and EGFR pathways
First Author: Hema Luchman, Ph.D., Hotchkiss Brain Institute, University of Calgary, Calgary, AB
Date/Time: Sunday, April 17 at 1:00 p.m.-5:00 p.m. ET
Location: Section 15
Poster Session: Combinatorial Strategies
Abstract #279 / Poster Board #20

The nonclinical toxicology profile of pacritinib, a JAK2/FLT3 inhibitor with no dose-limiting clinical myelosuppression
First Author: Rebecca Watson, CTI BioPharma Corp., Seattle, WA
Date/Time: Monday, April 18 at 1:00 p.m.-5:00 p.m. ET
Location: Section 37
Poster Session: Targets, Markers, and Agents in Cancer Prevention
Abstract #2602 / Poster Board #2

Pacritinib reduces human myeloid leukemia stem cell maintenance in a defined niche
First Author: Larissa Balaian, Ph.D., Moores Cancer Center, University of California, San Diego, CA
Date/Time: Tuesday, April 19 at 8:00 a.m.-12:00 p.m. ET
Location: Section 32
Poster Session: Stemness Properties of Leukemias and Carcinomas
Abstract #3338 / Poster Board #6

Investigation of absorption, metabolism, excretion, and mass balance of [14C]-pacritinib in healthy subjects: a phase 1 study
First Author: Suliman Al-Fayoumi, CTI BioPharma Corp., Seattle, WA
Date/Time: Wednesday, April 20 at 8:00 a.m.-12:00 p.m. ET
Location: Section 13
Poster Session: Phase 1 Clinical Trials 2
Abstract #CT159 / Poster Board #20

Synergistic effect of pacritinib with erlotinib on JAK2-mediated resistance in epidermal growth factor receptor mutation-positive non-small cell lung cancer
First Author: Nobuaki Ochi, M.D., Ph.D., Kawasaki Medical School, Okayama, Japan
Date/Time: Wednesday, April 20 at 8:00 a.m.-12:00 p.m. ET
Location: Section 15
Poster Session: Combination Therapies and Approaches to Sensitizing Cancer Cells to Drugs
Abstract #4675 / Poster Board #16

Pixantrone

Combinations containing the aza-anthracenedione pixantrone show preclinical activity in diffuse large B-cell lymphoma (DLBCL)
First Author: Chiara Tarantelli, Ph.D., IOR Institute of Oncology Research, Bellinzona, Switzerland
Date/Time: Wednesday, April 20 at 8:00 a.m.-12:00 p.m. ET
Location: Section 19
Poster Session: Novel Chemotherapies
Abstract #4793 / Poster Board #18

Tosedostat

Enhancing the efficacy of tosedostat through carboxylesterase induction
First Author: Priscilla Wei Ling Hong, Ph.D., The University of Queensland Diamantina Institute, Brisbane, Australia
Date/Time: Wednesday, April 20 at 8:00 a.m.-12:00 p.m. ET
Location: Section 20
Poster Session: Targeted Therapy
Abstract #4806 / Poster Board #1

About Pacritinib

Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate and high risk myelofibrosis including, but not limited to, patients with disease-related thrombocytopenia (low platelet counts); patients experiencing treatment-emergent thrombocytopenia on other JAK2 inhibitor therapy; or patients who are intolerant of, or whose symptoms are not well controlled (sub-optimally managed) on other JAK2 therapy. Clinical studies for pacritinib are currently subject to a full clinical hold issued by the U.S. Food and Drug Administration in February 2016.

CTI BioPharma and Baxalta Incorporated are parties to a worldwide license agreement to develop and commercialize pacritinib. CTI BioPharma and Baxalta will jointly commercialize pacritinib in the U.S. while Baxalta has exclusive commercialization rights for all indications outside the U.S.

About PIXUVRI (pixantrone)

PIXUVRI is a novel aza-anthracenedione with unique structural and physiochemical properties. PIXUVRI was structurally designed so that it cannot bind iron and perpetuate oxygen radical production or form a long-lived hydroxyl metabolite — both of which are the putative mechanisms for anthracycline induced acute and chronic cardiotoxicity.

In May 2012, the European Commission granted conditional marketing authorization for PIXUVRI as a monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive NHL. The benefit of PIXUVRI treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy. The Summary of Product Characteristics (SmPC) has the full prescribing information, including the safety and efficacy profile of PIXUVRI in the approved indication. The SmPC is available at www.pixuvri.eu. PIXUVRI does not have marketing approval in the United States.

About Tosedostat

Tosedostat is an investigational oral aminopeptidase inhibitor that has demonstrated anti-tumor responses in blood-related cancers and solid tumors in Phase 1-2 clinical trials. Tosedostat is currently being evaluated in multiple Phase 2 clinical trials for the treatment of patients with AML or high-risk MDS. Tosedostat is not approved or commercially available.

CD146 (MUC-18, MCAM) expression on cancer cells correlates with cancer progression and a bad prognosis in several tumors, including melanoma and pancreatic tumors. Deciphering the mechanism mediating the CD146 role in cancer is essential for generating new therapeutic strategies. We found that CD146 expression in cancer cells is associated with a secretion of soluble CD146 (sCD146) that constitutes an active player in tumor development. Indeed, sCD146 induces the overexpression of its binding protein, angiomotin, on both endothelial and cancer cells and promotes both paracrine effects on angiogenesis and autocrine effects on cancer cells proliferation and survival. These last effects are mediated in part through the induction and phosphorylation of c-myc in cancer cells. In mice models xenografted with human CD146-positive melanoma or pancreatic cancer cells, administration of a novel monoclonal antibody specifically targeting sCD146, but not its membrane form, successfully suppresses tumor vascularization and growth. Our findings demonstrate that sCD146 secreted by CD146-positive tumors mediates important pro-angiogenic and pro-tumoral effects. Targeting sCD146 with a novel neutralizing antibody could thus constitute an innovative therapeutic strategy for the treatment of CD146-positive tumors.Oncogene advance online publication, 11 April 2016; doi:10.1038/onc.2016.83.

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