The cohesin complex consists of multiple core subunits that play critical roles in mitosis and transcriptional regulation. The cohesin-associated protein Wapal plays a central role in off-loading cohesin to facilitate sister chromatid separation, but its role in regulating mammalian gene expression is not understood. We used embryonic stem cells as a model, given that the well-defined transcriptional regulatory circuits were established through master transcription factors and epigenetic pathways that regulate their ability to maintain a pluripotent state.
RNAi-mediated depletion of Wapal causes a loss of pluripotency, phenocopying loss of core cohesin subunits. Using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq), we determine that Wapal occupies genomic sites distal to genes in combination with CTCF and core cohesin subunits such as Rad21. Interestingly, genomic sites occupied by Wapal appear enriched for cohesin, implying that Wapal does not off-load cohesin at regions it occupies. Wapal depletion induces derepression of Polycomb group (PcG) target genes without altering total levels of Polycomb-mediated histone modifications, implying that PcG enzymatic activity is preserved. By integrating ChIP-seq and gene expression changes data, we identify that Wapal binding is enriched at the promoters of PcG-silenced genes and is required for proper Polycomb repressive complex 2 (PRC2) recruitment. Lastly, we demonstrate that Wapal is required for the interaction of a distal cis-regulatory element (CRE) with the c-Fos promoter.
Collectively, this work indicates that Wapal plays a critical role in silencing of PcG target genes through the interaction of distal CREs with promoters.

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On April 20, 2016 CTI BioPharma Corp. (CTI) (NASDAQ and MTA:CTIC) reported findings from an investigator-sponsored preclinical study indicating that pacritinib, an inhibitor of JAK2, FLT3, IRAK1 and CSF1R, may be effective in reducing survival of myelofibrosis and acute myeloid leukemia (AML) repopulating cells (Press release, CTI BioPharma, APR 19, 2016, View Source;p=RssLanding&cat=news&id=2158522 [SID:1234511114]). Further, this study also demonstrated that the combination of pacritinib at low nanomolar concentrations with dasatinib may eliminate self-renewing leukemia stem cells in blast crisis of chronic myeloid leukemia (CML) with minimal toxicity toward normal progenitors. In myeloid leukemias, these leukemic stem cells can evade initial treatment and hide within the bone marrow microenvironment, develop resistance to current therapies, self-renew and eventually cause relapse.

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These findings were presented by Larissa Balaian, Ph.D. from the Moores Cancer Center, University of California San Diego in a poster presentation (abstract #3338) titled: "Pacritinib reduces human myeloid leukemia stem cell maintenance in a defined niche," during the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting held April 16-20 in New Orleans, LA.

"The potential ability for pacritinib to eradicate therapy resistant leukemia stem cells in relapse AML as a single-agent, as well as eliminate self-renewing stem cells in CML, when used in combination with standard of care therapy, demonstrates that targeting niche-dependent signaling with pacritinib could represent a new approach to treating patients with refractory acute myeloid leukemia and blast crisis of CML," said Dr. Balaian.

Additional data being presented at the meeting include:

A poster (abstract #2602) titled: "The nonclinical toxicology profile of pacritinib, a JAK2/FLT3 inhibitor with no dose-limiting clinical myelosuppression." In this poster, CTI BioPharma researchers presented data from studies of pacrinitib in nonclinical models that were evaluated in comparison to publicly available information for the currently approved JAK inhibitors. The nonclinical toxicology profile findings showed that pacritinib is unique for its mild myelosuppressive effects in the nonclinical studies. Of interest, only pacritinib was not associated with increased opportunistic infections in the long-term toxicology studies.

A poster (abstract #1609) titled: "Investigation of absorption, metabolism, excretion, and mass balance of [14C]-pacritinib in healthy subjects: a phase 1 study." In this poster, CTI BioPharma researchers investigated clearance pathways, excretion, pharmacokinetics and recovery of pacritinib’s major metabolites in healthy volunteers. Intact pacritinib was minimally excreted in urine and feces while most radioactivity was recovered as metabolites in feces, suggesting extensive biliary clearance and hepatic metabolism of pacritinib. No dose adjustments are anticipated to be required for patients with renal impairment.

The foregoing summaries of such reported findings and posters are not complete and are qualified in their entirety by reference to the referenced posters. These and other poster presentations are available in the publication section of the CTI BioPharma website at ctibiopharma.com.

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. The Company is in the process of responding to the full clinical hold by working through the FDA’s recommendations prior to requesting a meeting with them. In March 2016, the FDA expressed interest in allowing patients who were receiving benefit from pacritinib treatment at the time the clinical hold was imposed to submit requests to the FDA to resume pacritinib treatment under a Single Patient IND (SPI) program on a case-by-case basis. The Company is working with investigators in submitting SPI requests to the FDA. Separately, the FDA has informed clinical investigators that emergency requests may be submitted to the FDA for individual patient Expanded Access to pacritinib. Expanded Access, sometimes called "compassionate use," is the use outside of a clinical trial of an investigational medical product. Pacritinib does not have regulatory approval and is not commercially available.

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.

A new, sensitive ELISA method has been developed which measures catabolites in cells and media upon processing of antibody-drug conjugates (ADCs) by target cancer cells. This ELISA method, exemplified for maytansinoid ADCs, uses competitive inhibition by a maytansinoid analyte of the binding of biotinylated antimaytansine antibody to an immobilized BSA-maytansinoid conjugate. Synthetic standards of several maytansinoid catabolites derived from ADCs with different linkers were tested and showed similar inhibition curves, with an EC50 of about 0.1 nM (0.03 pmol in an assay volume of 0.25 mL). This high sensitivity allowed quantification of catabolites from a methanolic cell extract and from the medium, generated from an ADC in 1 day using only about 1 million cells. The processing of anti-EpCAM and anti-CanAg ADCs with noncleavable linker (SMCC-DM1), disulfide linker (SPDB-DM4), and charged sulfonate-bearing disulfide linker (sulfo-SPDB-DM4), each containing an average of about four maytansinoid molecules per antibody, were compared in colon cancer cell lines (COLO 205 and HT-29). An 8-10-fold higher total level of catabolite was observed for anti-CanAg ADCs than for anti-EpCAM ADCs upon processing by COLO 205 cells, consistent with a higher cell-surface expression of CanAg. In a multidrug resistant HCT-15 colon cancer cell line, the anti-EpCAM-SPDB-DM4 linker conjugate was not cytotoxic and showed a significantly lower level of catabolite within cells compared to that in medium, presumably due to Pgp-mediated efflux of the nonpolar DM4 catabolite. In contrast, sulfo-SPDB-DM4 and SMCC-DM1 linker conjugates were cytotoxic, which correlated with higher amounts of catabolites found within the HCT-15 cells relative to amounts in medium. In a nonmultidrug resistant HT-29 cell line, the anti-EpCAM-SPDB-DM4 linker conjugate was cytotoxic, with most of the catabolite found in cells and little in the medium. In conclusion, this highly sensitive ELISA method for measurement of ADC catabolite is convenient for screening multiple ADC parameters such as linkers and antibodies in a number of cell lines, does not require concentration of sample or extraction of media, and is complementary to other reported methods such as radiolabeling of ADCs or mass spectrometry.

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During adolescence the breasts undergo rapid growth and development under the influence of sex hormones. Although the hormonal etiology of breast cancer is hypothesized, it remains unknown whether adolescent sex hormones are associated with adult breast density, which is a strong risk factor for breast cancer.
Percentage of dense breast volume (%DBV) was measured in 2006 by magnetic resonance imaging in 177 women aged 25-29 years who had participated in the Dietary Intervention Study in Children from 1988 to 1997. They had sex hormones and sex hormone-binding globulin (SHBG) measured in serum collected on one to five occasions between 8 and 17 years of age. Multivariable linear mixed-effect regression models were used to evaluate the associations of adolescent sex hormones and SHBG with %DBV.
Dehydroepiandrosterone sulfate (DHEAS) and SHBG measured in premenarche serum samples were significantly positively associated with %DBV (all P trend ≤0.03) but not when measured in postmenarche samples (all P trend ≥0.42). The multivariable geometric mean of %DBV across quartiles of premenarcheal DHEAS and SHBG increased from 16.7 to 22.1 % and from 14.1 to 24.3 %, respectively. Estrogens, progesterone, androstenedione, and testosterone in pre- or postmenarche serum samples were not associated with %DBV (all P trend ≥0.16).
Our results suggest that higher premenarcheal DHEAS and SHBG levels are associated with higher %DBV in young women. Whether this association translates into an increased risk of breast cancer later in life is currently unknown.
ClinicalTrials.gov Identifier, NCT00458588 April 9, 2007; NCT00000459 October 27, 1999.

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On April 19, 2016 Endocyte, Inc. (NASDAQ:ECYT), a leader in developing targeted small molecule drug conjugates (SMDCs) and companion imaging agents for personalized therapy, reported in a late-breaking poster session the presentation of new research from investigators and faculty at the Purdue University Center for Drug Discovery on the application of Endocyte’s SMDC technology in a chimeric antigen receptor (CAR) therapy setting (Poster #LB-254 – A Universal Remedy for CAR T cell limitations) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans (Press release, Endocyte, APR 19, 2016, View Source [SID:1234511043]).

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"This technology and these data reflect a potentially significant advance in overcoming several challenges specific to CAR therapies as well as the powerful versatility of Endocyte’s SMDC platform," said Ron Ellis, president and CEO at Endocyte. "This is still in the early stages of research, and we look forward to our continued collaboration with Phil Low and his lab at the Purdue Drug Discovery Center to further explore the potential of this CAR therapeutic approach as we look to build our SMDC platform in immuno-oncology."

The presentation discusses a novel approach that makes possible the engineering of a single universal CAR T cell, which binds with extraordinarily high affinity to a benign molecule designated as FITC. These cells are then used to treat various cancer types when co-administered with bispecific SMDC adaptor molecules. These unique bispecific adaptors are constructed with a FITC molecule and a tumor-homing molecule to precisely bridge the universal CAR T cell with the cancer cells, which causes localized T cell activation. Data in this poster show that anti-tumor activity in mice is induced only when both the universal CAR T cells plus the correct antigen-specific adaptor molecules are present. Findings also show that anti-tumor activity and toxicity can be sensitively controlled by adjusting the dosing of the administered adaptor molecule. Furthermore, treatment of antigenically heterogeneous tumors can be achieved by administration of a mixture of the desired antigen-specific adaptors. Thus, several challenges of current CAR T cell therapies, such as i) the inability to control the rate of cytokine release and tumor lysis, ii) the absence of an "off switch" that can terminate cytotoxic activity when tumor eradication is complete, and iii) a requirement to generate a different CAR T cell for each unique tumor antigen, may be solved or mitigated using this novel universal CAR T cell approach.

"Through our strong, ongoing collaboration with Endocyte, we are optimistic that this exciting approach might advance the enormous potential of CAR T cell therapies to benefit patients in truly meaningful ways," said Phil Low, Ph.D., professor of chemistry and director of the Center for Drug Discovery at Purdue University. Dr. Low is the chief scientific officer, a board member and founder of Endocyte.

Endocyte and Purdue University have an exclusive agreement to research, develop and commercialize SMDC therapeutics and companion imaging agents for the treatment of disease through a long-standing partnership with Dr. Low and Purdue University. Endocyte holds the global rights to the CAR and SMDC adaptors for all indications. Additionally, Endocyte and Purdue University jointly own this technology, which is covered by both allowed and pending patent applications.