The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Drug discovery in rare indications: opportunities and challenges

Abstract Over the past decade, the number of new therapies developed for the treatment of rare diseases continues to increase. The most rapid growth has been in the development of new drugs for oncology indications. One focus in drug discovery for oncology indications is the development of targeted therapies for select patient subgroups characterized by genetic alterations. The identification of these patient subgroups has increased in the past decade and has resulted in a corresponding increase in the development of new drugs for genetically defined patient subgroups. As an example of the development of new therapeutics for rare indications, I describe here the drug discovery efforts leading to the development of DOT1L inhibitors for the treatment of MLL-rearranged leukemia.</jats:p

Targeting histone deacetylases: development of vorinostat for the treatment of cancer

Reversible histone acetylation on lysine residues, regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs), plays an important role in the regulation of gene expression. Aberrant gene expression resulting from increased HDAC activity and histone hypoacetylation has been observed in human tumors and genetic knockdown studies support a role of HDACs in cancer. Treatment with small-molecule inhibitors of HDAC activity results in anti-tumor effects in a variety of transformed cell lines. Several HDAC inhibitors are in clinical development and show anti-tumor activity in cancer patients. Vorinostat (suberoylanilide hydroxamic acid) was the first HDAC inhibitor approved for the treatment of cancer and will be the focus of this article. </jats:p

Abstract SY02-01: Targeting the histone methyltransferase DOT1L in <i>MLL</i>-rearranged leukemia

Abstract Protein methyltransferases (PMTs) are enzymes that catalyze the addition of methyl groups to the lysine and arginine residues of proteins, including histones. Recent evidence shows that PMTs are misregulated in a variety of cancers and thus may serve as therapeutic targets. A subset of acute leukemias have reciprocal translocations at 11q23 involving the PMT gene mixed lineage leukemia (MLL). MLL translocations occur in approximately 5% of adult acute lymphocytic leukemias (ALL) and 5 to 10% of adult acute myeloid leukemias (AML) including therapy-related leukemias. Multiple studies have demonstrated that patients with leukemias bearing the MLL translocation have a poor prognosis and are in need of new therapies. Translocations of the MLL gene result in the loss of the catalytic domain of the protein. The most common translocation partners, AF4, AF9 and ENL, recruit another PMT, DOT1L that methylates histone H3K79. Recruitment of DOT1L to the MLL fusion protein results in increased H3K79 methylation at MLL fusion protein target genes and elevated expression of the MLL target genes resulting in leukemogenesis. Mistargeted DOT1L enzymatic activity has therefore been proposed to be required for the development and maintenance of leukemias bearing the MLL translocation. To evaluate the potential of DOT1L as a therapeutic target in MLL- rearranged leukemia, we designed and characterized the DOT1L inhibitor EPZ004777, a small molecule with sub-nanomolar affinity for this enzyme and &amp;gt;1000 fold selectivity against other PMTs. EPZ004777 selectively inhibits intracellular histone H3K79 methylation in a concentration and time dependent manner. Significant changes in genes expression were observed in MLL-rearranged cell lines following the decrease in histone H3K79 methylation. Gene set enrichment analysis (GSEA) of genes downregulated following EPZ004777 treatment demonstrated strong enrichment for genes overexpressed in MLL-rearranged human acute leukemias as compared with MLL-germline acute leukemias. Phenotypically, EPZ004777 inhibits proliferation and induces apoptosis in human MLL-rearranged leukemia cell lines, with little effect on non-MLL-translocated cells. In vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These studies provide compelling validation for the development of DOT1L inhibitors as targeted therapeutics for MLL-rearranged leukemia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY02-01. doi:1538-7445.AM2012-SY02-01</jats:p

<i>CCR</i> 20th Anniversary Commentary: Vorinostat—Gateway to Epigenetic Therapy

Abstract The study by Kelly and colleagues, published in the September 1, 2003, issue of Clinical Cancer Research, established the safety and biologic activity of the first-in-class histone deacetylase inhibitor, vorinostat, which was administered intravenously. Subsequent studies led to the development of oral vorinostat and the regulatory approval of vorinostat for cutaneous T-cell lymphomas, which opened the door for the next generation of inhibitors. Clin Cancer Res; 21(10); 2198–200. ©2015 AACR. See related article by Kelly et al., Clin Cancer Res 2003;9(10) September 1, 2003;3578–88</jats:p