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This SU2C Convergence effort will bring together biomedical researchers and leading data scientists to focus on DNA mismatch repair and other topics related to the human immune system and immuno-oncology. Datasets containing billions of pieces of information, derived from genetics, imaging, clinical prognoses, medication records, patient experiences, and other sources are currently being created at most major cancer centers. Typically, there are significant barriers to combining datasets from different studies or organizations, and to accessing sophisticated and sometimes novel tools needed for analysis. SU2C Convergence supports computational scientists working with cancer researchers, as well as clinicians, to pool their expertise to make the datasets useful for predicting the course of cancer, the likelihood of relapse, and to cure cancers. "As a new approach, Convergence -- bringing together life sciences, physical sciences and engineering in scientific research -- holds great promise," stated Phillip A. Sharp, PhD, chairman of the SU2C Scientific Advisory Committee and institute professor at the Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology. Dr. Sharp co-authored the January 2011 pivotal MIT white paper, "The Third Revolution: The Convergence of the Life Sciences, Physical Sciences, and Engineering" which signaled this new frontier and departure from tradition in biomedicine. "Stand Up To Cancer has taken the lead in accelerating this fundamentally different approach, through which the most innovative cancer research is evolving." Convergence 2.0 projects may explore questions such as, but not limited to: "Through collaboration of investigators across diverse disciplines, convergence grants offer a novel research model that spurs innovation in combating cancer," stated Arnold J. Levine, PhD, professor, Institute for Advance Study and vice chairperson of the SU2C Scientific Advisory Committee (SAC).  "By combining expertise from fields such as information technology, nanotechnology, new material research, imaging, optics, quantum physics, and other physical sciences -- often considered outside the realm of traditional biomedical research -- with traditional clinical and life science expertise, convergence grants may provide critical outcomes to advance the fight against cancer." Dr. Levine, as well as William G. Nelson, MD, PhD, director of oncology at Sidney Kimmel Comprehensive Cancer Center, V Foundation Scientific Advisory Committee member, and who also serves as vice chairperson of the SU2C SAC, will jointly oversee this Convergence 2.0 program. Optimally, SU2C Convergence 2.0 projects will include a basic science or translational component and propose a small clinical trial to test ideas or early proof of concept. SU2C strongly recommends that Applicants offer existing data sets of clinical measurements from immunotherapy trials to advance proposed hypotheses and test ideas, and to design and test new algorithms.  Teams with the strongest proposals will be invited to participate in a Fall 2017 Convergence 2.0 Ideas Lab to further develop research concepts and design. SU2C will explore possible collaborations with computer science researchers involving machine learning, and other advanced statistical methods for analysis of large complex data sets. In 2015, SU2C and the National Science Foundation engaged in a first-of-its-kind collaboration, to combine quantitative and clinical approaches to studying cancer and advancing therapies. Four SU2C Convergence Translational Research Teams were funded and their research is currently underway. Each team engages post-doctoral fellows who are paired with investigators. Funding and grants from the National Science Foundation, the V Foundation for Cancer Research (whose funding specifically supports the post-doctoral fellows), as well as the Breast Cancer Research Foundation, The Lustgarten Foundation for Pancreatic Cancer Research, and Bristol-Myers Squibb Company support the following projects: Details on the "Convergence 2.0" program are available via the SU2C web site at: http://progress.su2c.org/convergenceapplications/. The deadline for Letters of Intent for SU2C Convergence 2.0 is June 30, 2017. Selected applicants will be invited to a Fall 2017 "Ideas Lab" to discuss the proposed research concepts. Following these deliberations, small groups of investigators will form teams, or will be commissioned by the SU2C Convergence Joint Scientific Advisory Committee to form teams. The submission of full proposals will be invited from those selected for further consideration reflecting the topics for investigation discussed at the Ideas Lab. About the Stand Up To Cancer Initiative Stand Up To Cancer (SU2C) raises funds to accelerate the pace of research to get new therapies to patients quickly and save lives now. SU2C, a program of the Entertainment Industry Foundation (EIF), a 501(c)(3) charitable organization, was established in 2008 by film and media leaders who utilize the industry's resources to engage the public in supporting a new, collaborative model of cancer research, and to increase awareness about cancer prevention as well as progress being made in the fight against the disease. As SU2C's scientific partner, the American Association for Cancer Research (AACR) and a Scientific Advisory Committee led by Nobel Laureate Phillip A. Sharp, PhD, conduct rigorous, competitive review processes to identify the best research proposals to recommend for funding, oversee grants administration, and provide expert review of research progress. Current members of the SU2C Council of Founders and Advisors (CFA) include Katie Couric, Sherry Lansing, Lisa Paulsen, Rusty Robertson, Sue Schwartz, Pamela Oas Williams, Ellen Ziffren, and Kathleen Lobb. The late Laura Ziskin and the late Noreen Fraser are also co-founders. Sung Poblete, PhD, RN, has served as SU2C's president and CEO since 2011. For more information on Stand Up To Cancer, visit www.StandUpToCancer.org. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/stand-up-to-cancer-issues-call-for-ideas-for-10-million-convergence-20-teams-to-address-key-questions-about-the-immune-systems-role-in-cancer-development-and-treatment-300464326.html


Powell J.D.,Sidney Kimmel Comprehensive Cancer Center | Pollizzi K.N.,Sidney Kimmel Comprehensive Cancer Center | Heikamp E.B.,Sidney Kimmel Comprehensive Cancer Center | Horton M.R.,Johns Hopkins University
Annual Review of Immunology | Year: 2012

mTOR is an evolutionarily conserved serine/threonine kinase that plays a central role in integrating environmental cues in the form of growth factors, amino acids, and energy. In the study of the immune system, mTOR is emerging as a critical regulator of immune function because of its role in sensing and integrating cues from the immune microenvironment. With the greater appreciation of cellular metabolism as an important regulator of immune cell function, mTOR is proving to be a vital link between immune function and metabolism. In this review, we discuss the ability of mTOR to direct the adaptive immune response. Specifically, we focus on the role of mTOR in promoting differentiation, activation, and function in T cells, B cells, and antigen-presenting cells. © 2012 by Annual Reviews. All rights reserved.


Higgins M.J.,Massachusetts General Hospital | Stearns V.,Sidney Kimmel Comprehensive Cancer Center
Annual Review of Medicine | Year: 2011

The selective estrogen receptor modulator tamoxifen has been used for more than three decades for the treatment, and more recently prevention, of breast cancer in women of all ages. The conversion of tamoxifen to active metabolites involves several cytochrome P450 (CYP) enzymes. CYP2D6 is the key enzyme responsible for the conversion of N-desmethyl tamoxifen to endoxifen. Single nucleotide polymorphisms in the CYP2D6 gene are not uncommon, and some alleles code for enzymes with reduced, null, or increased activity. Multiple studies suggest that women who carry one or two variant CYP2D6 alleles that encode enzymes with null or reduced activity may have an inferior breast cancer outcome when treated with tamoxifen in the adjuvant setting compared to women carrying two alleles encoding an enzyme with normal activity. Unfortunately, the data are not uniformly concordant, and definitive evidence that would change routine clinical practice is not yet available. CYP2D6 activity can also be reduced by concomitant use of drugs that inhibit the enzyme, including antidepressants used for psychiatric conditions or to relieve hot flashes, and these should be avoided in tamoxifen users whenever possible. Emerging data suggest that host factors may also predict interpatient variability in response to aromatase inhibitors. © 2011 by Annual Reviews. All rights reserved.


Anagnostou V.K.,Sidney Kimmel Comprehensive Cancer Center | Brahmer J.R.,Sidney Kimmel Comprehensive Cancer Center
Clinical Cancer Research | Year: 2015

Emerging evidence on the role of the antitumor activity of the immune system has generated great interest in immunotherapy even for tumors that were historically considered as nonimmunogenic. Immunotherapy is emerging as a major modality in non-small cell lung cancer (NSCLC) treatment focusing on vaccine approaches to elicit specific immune responses and development of inhibitors of the molecular mediators of cancer-induced immunosuppression (immune checkpoints) to boost antitumor immune responses. Amplification of the host response against evolving tumors through vaccination is being investigated in ongoing clinical trials with tumor cell vaccines; however, the clinical efficacy of these agents has been limited. Blocking inhibitory pathways such as the CTL antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) checkpoint pathways with mAbs has generated antitumor immune responses that are transforming cancer therapeutics. PD-1 and programmed cell death ligand 1 (PD-L1) antibodies have shown durable responses in NSCLC, with a favorable safety profile and manageable side effects. The activity of immune checkpoint inhibitors is currently been assessed in treatment-naive patients with PD-L1-positive advanced NSCLC. Combinatorial approaches with other immune checkpoint inhibitors, chemotherapy, or targeted agents are being explored in ongoing clinical trials, and may improve outcome in NSCLC. © 2015 American Association for Cancer Research.


Connolly R.M.,Sidney Kimmel Comprehensive Cancer Center | Nguyen N.K.,Sidney Kimmel Comprehensive Cancer Center | Sukumar S.,Sidney Kimmel Comprehensive Cancer Center
Clinical Cancer Research | Year: 2013

Retinoids and their naturally metabolized and synthetic products (e.g., all-trans retinoic acid, 13-cis retinoic acid, bexarotene) induce differentiation in various cell types. Retinoids exert their actions mainly through binding to the nuclear retinoic acid receptors (a , b, g ), which are transcriptional and homeostatic regulators with functions that are often compromised early in neoplastic transformation. The retinoids have been investigated extensively for their use in cancer prevention and treatment. Success has been achieved with their use in the treatment of subtypes of leukemia harboring chromosomal translocations. Promising results have been observed in the breast cancer prevention setting, where fenretinide prevention trials have provided a strong rationale for further investigation in young women at high risk for breast cancer. Ongoing phase III randomized trials investigating retinoids in combination with chemotherapy in non-small cell lung cancer aim to definitively characterize the role of retinoids in this tumor type. The limited treatment success observed to date in the prevention and treatment of solid tumors may relate to the frequent epigenetic silencing of RARb. Robust evaluation of RARb and downstream genes may permit optimized use of retinoids in the solid tumor arena. ©2013 AACR.


Choi Y.B.,Sidney Kimmel Comprehensive Cancer Center | Harhaj E.W.,Sidney Kimmel Comprehensive Cancer Center
PLoS Pathogens | Year: 2014

The human T-cell leukemia virus type 1 (HTLV-1) Tax protein hijacks the host ubiquitin machinery to activate IκB kinases (IKKs) and NF-κB and promote cell survival; however, the key ubiquitinated factors downstream of Tax involved in cell transformation are unknown. Using mass spectrometry, we undertook an unbiased proteome-wide quantitative survey of cellular proteins modified by ubiquitin in the presence of Tax or a Tax mutant impaired in IKK activation. Tax induced the ubiquitination of 22 cellular proteins, including the anti-apoptotic BCL-2 family member MCL-1, in an IKK-dependent manner. Tax was found to promote the nondegradative lysine 63 (K63)-linked polyubiquitination of MCL-1 that was dependent on the E3 ubiquitin ligase TRAF6 and the IKK complex. Tax interacted with and activated TRAF6, and triggered its mitochondrial localization, where it conjugated four carboxyl-terminal lysine residues of MCL-1 with K63-linked polyubiquitin chains, which stabilized and protected MCL-1 from genotoxic stress-induced degradation. TRAF6 and MCL-1 played essential roles in the survival of HTLV-1 transformed cells and the immortalization of primary T cells by HTLV-1. Therefore, K63-linked polyubiquitination represents a novel regulatory mechanism controlling MCL-1 stability that has been usurped by a viral oncogene to precipitate cell survival and transformation. © 2014 Choi, Harhaj.


Armstrong D.K.,Sidney Kimmel Comprehensive Cancer Center
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2013

Most patients with ovarian cancer require systemic therapy upfront and again on recurrence. Treatment advances over the past decade have been few, but bevacizumab prolongs disease remission, if not survival. Other targeted agents have not been effective, but emerging data for experimental agents suggest this outlook may change. In her presentation at the NCCN 18th Annual Conference, Dr. Deborah K. Armstrong reviewed findings supporting intraperitoneal chemotherapy, the use of bevacizumab, the use of neoadjuvant chemotherapy, and the potential of poly (ADP-ribose) polymerase (PARP) inhibitors and other newer agents. © JNCCN-Journal of the National Comprehensive Cancer Network.


Fuchs E.J.,Sidney Kimmel Comprehensive Cancer Center
Immunological Reviews | Year: 2014

Tolerance induction and alloreactivity can be applied to the clinic for the transplantation of solid organs and in the treatment of human cancers respectively. Hematopoietic chimerism, the stable coexistence of host and donor blood cells, guarantees that a solid organ from the same donor will be tolerated without a requirement for maintenance immunosuppression, and it also serves as a platform for the adoptive immunotherapy of hematologic malignancies using donor lymphocyte infusions. This review focuses on clinically relevant methods for inducing hematopoietic chimerism and transplantation tolerance, with a special emphasis on reduced intensity transplantation conditioning and high dose, post-transplantation cyclophosphamide to prevent graft rejection and graft-versus-host disease (GVHD). Reduced intensity transplantation regimens permit a transient cooperation between donor and host immune systems to eradicate malignancy without producing GVHD. Their favorable toxicity profile also enables the application of allogeneic stem cell transplantation to treat non-malignant disorders of hematopoiesis and to induce tolerance for solid organ transplantation. © 2014 John Wiley & Sons A/S.


Connolly R.,Sidney Kimmel Comprehensive Cancer Center | Stearns V.,Sidney Kimmel Comprehensive Cancer Center
Journal of Mammary Gland Biology and Neoplasia | Year: 2012

Epigenetics refers to alterations in gene expression due to modifications in histone acetylation and DNA methylation at the promoter regions of genes. Unlike genetic mutations, epigenetic alterations are not due to modifications in the gene primary nucleotide sequence. The importance of epigenetics in the initiation and progression of breast cancer has led many investigators to incorporate this novel and exciting field in breast cancer drug development. Several drugs that target epigenetic alterations, including inhibitors of histone deacetylase (HDAC) and DNA methyltransferase (DNMT), are currently approved for treatment of hematological malignancies and are available for clinical investigation in solid tumors. In this manuscript, we review the critical role of epigenetics in breast cancer including the potential for epigenetic alterations to serve as biomarkers determining breast cancer prognosis and response to therapy. We highlight initial promising results to date with use of epigenetic modifiers in patients with breast cancer and the ongoing challenges involved in the successful establishment of these agents for the treatment of breast cancer. © 2012 Springer Science+Business Media, LLC.


Fuchs E.J.,Sidney Kimmel Comprehensive Cancer Center
Bone Marrow Transplantation | Year: 2015

In the past, partially HLA-mismatched related donor, or HLA-haploidentical, blood or marrow transplantation (haploBMT), for hematologic malignancies has been complicated by unacceptably high incidences of graft rejection or GvHD resulting from intense bi-directional alloreactivity. Administration of high doses of cyclophosphamide early after haploBMT selectively kills proliferating, alloreactive T cells while sparing non-alloreactive T cells responsible for immune reconstitution and resistance to infection. In the clinic, haploBMT with high-dose, post-transplantation cyclophosphamide is associated with acceptably low incidences of fatal graft rejection, GvHD and non-relapse mortality, and provides an acceptable treatment option for hematologic malignancies patients lacking suitably HLA-matched donors. HaploBMT with PTCy is now being investigated as a treatment of hemoglobinopathy and as a method for inducing tolerance to solid organs transplanted from the same donor. Ongoing and future clinical trials will establish the hierarchy of donor preference for hematologic malignancy patients lacking an HLA-matched sibling. © 2015 Macmillan Publishers Limited All rights reserved.

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