On April 4, 2016 The National Cancer Institute (NCI), part of the National Institutes of Health, reported a Blue Ribbon Panel of scientific experts, cancer leaders, and patient advocates that will inform the scientific direction and goals at NCI of Vice President Joe Biden’s National Cancer Moonshot Initiative (Press release, US NCI, APR 4, 2016, View Source [SID:1234510392]). The panel will serve as a working group of the presidentially appointed National Cancer Advisory Board (NCAB) and will provide scientific guidance from thought-leaders in the cancer community.

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"This Blue Ribbon Panel will ensure that, as NIH allocates new resources through the Moonshot, decisions will be grounded in the best science," said the Vice President. "I look forward to working with this panel and many others involved with the Moonshot to make unprecedented improvements in prevention, diagnosis, and treatment of cancer."

Over the next several months, the panel will consider how to advance the themes that have been proposed for the initiative. The themes include the development of cancer vaccines, highly sensitive approaches to early detection, advances in immunotherapy and combination therapies, single-cell genomic profiling of cancer cells and cells in the tumor microenvironment, enhanced data sharing, and new approaches to the treatment of pediatric cancers.

In addition, the cancer community, including the American public, will be provided a forum to post comments and insights to help inform the panel’s deliberations. Findings of the panel will be reported to the NCAB, which in turn will make its recommendations to NCI and contribute to the overall approach of the initiative.

"Thanks to advances in science, we are now in a historically unique position to make profound improvements in the way we treat, detect, and prevent cancer," said NIH Director Francis S. Collins, M.D., Ph.D. "The Vice President’s deep personal commitment to this noble cause will make a tremendous difference in our ability to lift the terrible burden of cancer. His call to action, including the establishment of this panel, comes at just the right time for all the right reasons."

"The Vice President’s enthusiasm about this effort is welcomed by the community of researchers, health professionals, and patients who share his passion and belief that great things are possible by accelerating cancer research with leadership and resources," said NCI Acting Director Douglas Lowy, M.D. "We are committed to breaking down silos and stimulating the groundbreaking work already underway. To be successful, we must hear a broad range of perspectives to take full advantage of the exceptional current opportunities in cancer research."

The Blue Ribbon Panel members represent a spectrum of scientific areas, including biology, immunology, genomics, diagnostics, bioinformatics, and cancer prevention and treatment. Scientific members also include investigators with expertise in clinical trials and cancer health disparities. Importantly, the members of cancer advocacy groups and pharmaceutical and biotechnology companies will be represented on the panel and its working groups.

The members of the Blue Ribbon Panel are:

Tyler Jacks, Ph.D. (Co-Chair)
Chair, National Cancer Advisory Board, and Director, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge

Elizabeth Jaffee, M.D. (Co-Chair)
Professor and Deputy Director for Translational Research, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore

Dinah Singer, Ph.D. (Co-Chair)
Acting Deputy Director and Director, Division of Cancer Biology, National Cancer Institute, Bethesda, Maryland

Peter Adamson, M.D.
Professor and Director, Experimental Therapeutics in Oncology, The Children’s Hospital of Philadelphia

James Allison, Ph.D.
Professor and Chair of Immunology, University of Texas MD Anderson Cancer Center, Houston

David Arons, J.D.
Chief Executive Officer, National Brain Tumor Society, Newton, Massachusetts

Mary Beckerle, Ph.D.
CEO and Director, Huntsman Cancer Institute, Salt Lake City

Mitch Berger, M.D.
Professor and Chair, Department of Neurological Surgery, University of California, San Francisco

Jeff Bluestone, Ph.D.
Executive Vice Chancellor and Provost, University of California, San Francisco

Mikael Dolsten, M.D., Ph.D.
President, Pfizer Worldwide Research and Development, and Executive Vice President, Pfizer, Inc., New York

James Downing, M.D.
President and CEO, St. Jude Children’s Research Hospital, Memphis, Tennessee

Levi Garraway, M.D., Ph.D.
Associate Professor of Medicine, Harvard Medical School, and Assistant Professor of Medicine, Dana-Farber Cancer Institute, Boston

Gad Getz, Ph.D.
Director, Cancer Genome Computational Analysis Group, Broad Institute of MIT and Harvard, Cambridge, Massachusetts

Laurie Glimcher, M.D.
Professor of Medicine and Dean, Weill Cornell Medical College, and Incoming President and CEO, Dana-Farber Cancer Institute, Boston

Lifang Hou, M.D., Ph.D.
Associate Professor of Preventive Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago

Neal Kassell, M.D.
Professor of Neurosurgery, University of Virginia, Charlottesville

Maria Elena Martinez, Ph.D.
Professor of Family Medicine and Public Health, Reducing Cancer Disparities Program, UC San Diego Moores Cancer Center

Deborah Mayer, Ph.D., R.N.
Professor of Adult and Geriatric Health, University of North Carolina School of Nursing, and Director of Cancer Survivorship, UNC Lineberger Comprehensive Cancer Center, Chapel Hill

Edith Mitchell, M.D., F.A.C.P
Professor of Medical Oncology and Associate Director for Diversity Services, Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia

Augusto Ochoa, M.D.
Professor of Pediatrics and Director, Stanley S. Scott Cancer Center, Louisiana State University, New Orleans

Jennifer Pietenpol, Ph.D.
Professor of Biochemistry and Director, Vanderbilt-Ingram Cancer Center, Nashville

Angel Pizarro, M.S.E.
Technical Business Development Manager, Amazon Web Services Scientific Computing and Research Computing, Philadelphia

Barbara Rimer, Dr.P.H.
Alumni Distinguished Professor and Dean, University of North Carolina Gillings School of Global Public Health, Chapel Hill

Charles Sawyers, M.D.
Chair, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, and Investigator, Howard Hughes Medical Institute, New York

Ellen Sigal, Ph.D.
Founder and Chair, Friends of Cancer Research, Washington, DC

Patrick Soon-Shiong, M.B.B.Ch.
Founder, Chair, and CEO, NantWorks LLC, Los Angeles

Chi Van Dang, M.D., Ph.D.
Professor of Medicine and Director, Abramson Cancer Center, University of Pennsylvania, Philadelphia

Wai-Kwan Alfred Yung, M.D.
Professor of Neuro-Oncology and Chair of Clinical Cancer Care, University of Texas MD Anderson Cancer Center, Houston

The NCAB will advise the NCI director based on its consideration of the Blue Ribbon Panel’s recommendations, expected to be delivered later this summer. A final report by the White House Cancer Moonshot Task Force, chaired by Vice President Biden, will be produced and delivered to President Barack Obama by Dec. 31, 2016.

To meet its milestones, the panel will begin its work immediately, convening its first meeting in the coming weeks. The panel will also consider public comments over the next several months prior to making its recommendations.

Members of the research community and the public can engage in the initiative initially by subscribing to updates on the initiative’s main website (www.cancer.gov/moonshot-cancer-initiative) or by emailing the panel at [email protected]. In addition, an online forum for submitting scientific ideas and comments to the panel will be available on the site in the coming weeks.

Dysregulated cellular apoptosis and resistance to cell death are hallmarks of neoplastic initiation and disease progression. Therefore, the development of agents that overcome apoptosis dysregulation in tumor cells is an attractive therapeutic approach. Activation of the extrinsic apoptotic pathway is strongly dependent on death receptor (DR) hyperclustering on the cell surface. However, strategies to activate DR5 or DR4 through agonistic antibodies have had only limited clinical success. To pursue an alternative approach for tumor targeted induction of apoptosis, we engineered a bispecific antibody (BsAb) which simultaneously targets fibroblast-activation protein (FAP) on cancer-associated fibroblasts in tumor stroma and DR5 on tumor cells. We hypothesized that bivalent binding to both FAP and DR5 leads to avidity-driven hyper-clustering of DR5 and subsequently strong induction of apoptosis in tumor cells but not in normal cells. Here, we show that RG7386, an optimized FAP-DR5 BsAb, triggers potent tumor cell apoptosis in vitro and in vivo in preclinical tumor models with FAP-positive stroma. RG7386 antitumor efficacy was strictly FAP-dependent, was independent of FcR crosslinking, and was superior to conventional DR5 antibodies. In combination with irinotecan or doxorubicin, FAP-DR5 treatment resulted in substantial tumor regression in patient-derived xenograft models. FAP-DR5 also demonstrated single-agent activity against FAP-expressing malignant cells, due to cross-binding of FAP and DR5 across tumor cells. Taken together, these data demonstrate that RG7386, a novel and potent antitumor agent in both mono- and combination therapies, overcomes limitations of previous DR5 antibodies and represents a promising approach to conquer tumor-associated resistance to apoptosis.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Umbilical cord blood-derived haematopoietic stem cells (HSCs) are essential for many life-saving regenerative therapies. However, despite their advantages for transplantation, their clinical use is restricted because HSCs in cord blood are found only in small numbers. Small molecules that enhance haematopoietic stem and progenitor cell (HSPC) expansion in culture have been identified, but in many cases their mechanisms of action or the nature of the pathways they impinge on are poorly understood. A greater understanding of the molecular circuitry that underpins the self-renewal of human HSCs will facilitate the development of targeted strategies that expand HSCs for regenerative therapies. Whereas transcription factor networks have been shown to influence the self-renewal and lineage decisions of human HSCs, the post-transcriptional mechanisms that guide HSC fate have not been closely investigated. Here we show that overexpression of the RNA-binding protein Musashi-2 (MSI2) induces multiple pro-self-renewal phenotypes, including a 17-fold increase in short-term repopulating cells and a net 23-fold ex vivo expansion of long-term repopulating HSCs. By performing a global analysis of MSI2-RNA interactions, we show that MSI2 directly attenuates aryl hydrocarbon receptor (AHR) signalling through post-transcriptional downregulation of canonical AHR pathway components in cord blood HSPCs. Our study gives mechanistic insight into RNA networks controlled by RNA-binding proteins that underlie self-renewal and provides evidence that manipulating such networks ex vivo can enhance the regenerative potential of human HSCs.

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Chronic immune thrombocytopenia (ITP) in children can negatively impact their health-related quality of life (HRQoL) and impose a burden on their parents. This study sought to examine the effect of romiplostim on HRQoL and parental burden in children with primary ITP.
This was a phase 3, randomized, double-blind, placebo-controlled study. Children aged <18 years with ITP ≥6 months were randomly assigned to receive romiplostim or placebo for 24 weeks. The Kids’ ITP Tool (KIT) was used to measure HRQoL and was administered to patients and/or their parents at baseline and weeks 8, 16, and 25. Mean KIT scores at each assessment and mean changes in KIT scores from baseline were calculated overall by treatment group and platelet response status. Psychometric properties of the KIT were evaluated and the minimally important difference (MID) was estimated for different KIT versions.
Sixty-two patients (42 romiplostim and 20 placebo) were enrolled. Changes in KIT scores by treatment group showed numerically greater and more often statistically significant improvements from baseline to each assessment for children receiving romiplostim versus placebo. Mixed-effects analysis demonstrated statistically significantly greater reduction in parental burden from baseline in the romiplostim group versus placebo. Ranges for the MID were estimated as 9-13 points for the Child Self-Report version and 11-13 points for the Parent Impact version.
The treatment with romiplostim may be associated with improved HRQoL in children with primary ITP and reduced burden to their parents.
© 2016 Wiley Periodicals, Inc.

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With the recent FDA approvals of pembrolizumab and nivolumab, and a host of additional immunomodulatory agents entering clinical development each year, the field of cancer immunotherapy is changing rapidly. Strategies that can assist researchers in choosing the most promising drugs and drug combinations to move forward through clinical development are badly needed in order to reduce the likelihood of late-stage clinical trial failures. On October 5, 2014, the Cancer Immunotherapy Consortium of the Cancer Research Institute, a collaborative think tank composed of stakeholders from academia, industry, regulatory agencies, and patient interest groups, met to discuss strategies for de-risking immunotherapy development, with a focus on integrating preclinical and clinical studies, and conducting smarter early-phase trials, particularly for combination therapies. Several recommendations were made, including making better use of clinical data to inform preclinical research, obtaining adequate tissues for biomarker studies, and choosing appropriate clinical trial endpoints to identify promising drug candidates and combinations in nonrandomized early-phase trials.Cancer Immunol Res; 4(4); 279-88. ©2016 AACR (Free AACR Whitepaper).
©2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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