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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.


Gaillard S.,Sidney Kimmel Comprehensive Cancer Center | Stearns V.,Sidney Kimmel Comprehensive Cancer Center
Breast Cancer Research | Year: 2011

Aromatase inhibitors are widely used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer. While the agents are associated with slightly improved survival outcomes when compared to tamoxifen alone, bone and musculoskeletal side effects are substantial and often lead to discontinuation of therapy. Ideally, the symptoms should be prevented or adequately treated. This review will focus on bone and musculoskeletal side effects of aromatase inhibitors, including osteoporosis, fractures, and arthralgias. Recent advances have been made in identifying potential mechanisms underlying these effects. Adequate management of symptoms may enhance patient adherence to therapy, thereby improving breast cancer-related outcomes. © 2011 BioMed Central Ltd.


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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