Abramson Family Cancer Research Institute

Philadelphia, PA, United States

Abramson Family Cancer Research Institute

Philadelphia, PA, United States
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Researchers at Weill Cornell Medicine have discovered an innovative method to make an unlimited supply of healthy blood cells from the readily available cells that line blood vessels. This achievement marks the first time that any research group has generated such blood-forming stem cells. "This is a game-changing breakthrough that brings us closer not only to treat blood disorders, but also deciphering the complex biology of stem-cell self-renewal machinery," said senior author Dr. Shahin Rafii, director of the Ansary Stem Cell Institute, chief of the Division of Regenerative Medicine and the Arthur B. Belfer Professor at Weill Cornell Medicine. "This is exciting because it provides us with a path towards generating clinically useful quantities of normal stem cells for transplantation that may help us cure patients with genetic and acquired blood diseases," added co-senior author Dr. Joseph Scandura, an associate professor of medicine and scientific director of the Silver Myeloproliferative Neoplasms Center at Weill Cornell Medicine. Hematopoietic stem cells (HSCs) are long-lasting cells that mature into all types of blood cells: white blood cells, red blood cells and platelets. Billions of circulating blood cells do not survive long in the body and must be continuously replenished. When this does not happen, severe blood diseases, such as anemia, bleeding or life-threatening infections, can occur. A special property of HSCs is that they can also "self-renew" to form more HSCs. This property allows just a few thousand HSCs to produce all of the blood cells a person has throughout one's life. Researchers have long hoped to find a way to make the body produce healthy HSCs in order to cure these diseases. But this has never been accomplished, in part because scientists have been unable to engineer a nurturing environment within which stem cells can convert into new, long-lasting cells--until now. In a paper published May 17 in Nature, Dr. Rafii and his colleagues demonstrate a way to efficiently convert cells that line all blood vessels, called vascular endothelial cells, into abundant, fully functioning HSCs that can be transplanted to yield a lifetime supply of new, healthy blood cells. The research team also discovered that specialized types of endothelial cells serve as that nurturing environment, known as vascular niche cells, and they choreograph the new converted HSCs' self-renewal. This finding may solve one of the most longstanding questions in regenerative and reproductive medicine: How do stem cells constantly replenish their supply? The research team showed in a 2014 study that converting adult human vascular endothelial cells into hematopoietic cells was feasible. However, the team was unable to prove that they had generated true HSCs because human HSCs' function and regenerative potential can only be approximated by transplanting the cells into mice, which don't truly mimic human biology. To address this issue, the team applied their conversion approach to mouse blood marrow transplant models that are endowed with normal immune function and where definitive evidence for HSC potential could rigorously tested. The researchers took vascular endothelial cells isolated from readily accessible adult mice organs and instructed them to overproduce certain proteins associated with blood stem-cell function. These reprogrammed cells were grown and multiplied in co-culture with the engineered vascular niche. The reprogrammed HSCs were then transplanted as single cells with their progenies into mice that had been irradiated to destroy all of their blood forming and immune systems, and then monitored to see whether or not they would self-renew and produce healthy blood cells. Remarkably, the conversion procedure yielded a plethora of transplantable HSCs that regenerated the entire blood system in mice for the duration of their lifespans, a phenomenon known as engraftment. "We developed a fully-functioning and long-lasting blood system," said lead author Dr. Raphael Lis, an instructor in medicine and reproductive medicine at Weill Cornell Medicine. In addition, the HSC-engrafted mice developed all of the working components of the immune systems. "This is clinically important because the reprogrammed cells could be transplanted to allow patients to fight infections after marrow transplants," Dr. Lis said. The mice in the study went on to live normal-length lives and die natural deaths, with no sign of leukemia or any other blood disorders. In collaboration with Dr. Olivier Elemento, associate director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, and Dr. Jenny Xiang, the director of Genomics Services, Dr. Rafii and his team also showed that the reprogrammed HSCs and their differentiated progenies -- including white and red bloods cells, as well as the immune cells -- were endowed with the same genetic attributes to that of normal adult stem cells. These findings suggest that the reprogramming process results in the generation of true HSCs that have genetic signature that are very similar to normal adult HSCs The Weill Cornell Medicine team is the first to achieve cellular reprogramming to create engraftable and authentic HSCs, which have been considered the holy grail of stem cell research. "We think the difference is the vascular niche," said contributing author Dr. Jason Butler, an assistant professor of regenerative medicine at Weill Cornell Medicine. "Growing stem cells in the vascular niche puts them back into context, where they come from and multiply. We think this is why we were able to get stem cells capable of self-renewing." If this method can be scaled up and applied to humans, it could have wide-ranging clinical implications. "It might allow us to provide healthy stem cells to patients who need bone marrow donors but have no genetic match," Dr. Scandura said. "It could lead to new ways to cure leukemia, and may help us correct genetic defects that cause blood diseases like sickle-cell anemia." "More importantly, our vascular niche-stem-cell expansion model may be employed to clone the key unknown growth factors produced by this niche that are essential for self-perpetuation of stem cells," Dr. Rafii said. "Identification of those factors could be important for unraveling the secrets of stem cells' longevity and translating the potential of stem cell therapy to the clinical setting." Additional study co-authors include Charles Karrasch, Dr. Michael Poulos, Balvir Kunar, David Redmond, Jose-Gabriel Barcia-Duran, Chaitanya Badwe, and Koji Shido of Weill Cornell Medicine; Dr. Will Schachterle, formerly of Weill Cornell Medicine, Dr. Arash Rafii of Weill Cornell Medicine-Qatar; Dr. Michael Ginsberg of Angiocrine Bioscience; and Dr. Nancy Speck of the Abramson Family Cancer Research Institute in the Perelman School of Medicine at the University of Pennsylvania. Various study authors have relationships with Angiocrine Bioscience that are independent of Weill Cornell Medicine. This study was funded in part by the National Institutes of Health, grants NIH-R01 DK095039, HL119872, HL128158, HL115128, HL099997, CA204308, HL133021, HL119872, HL128158 and HL091724; U54 CA163167; and NIH-T32 HD060600.

Cash T.P.,Abramson Family Cancer Research Institute | Cash T.P.,University of Pennsylvania | Gruber J.J.,Abramson Family Cancer Research Institute | Hartman T.R.,Chase Medical | And 4 more authors.
Oncogene | Year: 2011

Birt-Hogg-Dubé (BHD) syndrome is an inherited cancer susceptibility disease characterized by skin and kidney tumors, as well as cystic lung disease, which results from loss-of-function mutations in the BHD gene. BHD is also inactivated in a significant fraction of patients with sporadic renal cancers and idiopathic cystic lung disease, and little is known about its mode of action. To investigate the molecular and cellular basis of BHD tumor suppressor activity, we generated mutant Bhd mice and embryonic stem cell lines. BHD-deficient cells exhibited defects in cell-intrinsic apoptosis that correlated with reduced expression of the BH3-only protein Bim, which was similarly observed in all human and murine BHD-related tumors examined. We further demonstrate that Bim deficiency in Bhd/cells is not a consequence of elevated mTOR or ERK activity, but results instead from reduced Bim transcription associated with a general loss of TGFΒ-mediated transcription and chromatin modifications. In aggregate, this work identifies a specific tumor suppressive mechanism for BHD in regulating TGFΒ-dependent transcription and apoptosis, which has implications for the development of targeted therapies. © 2011 Macmillan Publishers Limited All rights reserved.

Ascierto P.A.,Instituto Nazionale Tumori Fondazione G Pascale | Kalos M.,Abramson Family Cancer Research Institute | Kalos M.,University of Pennsylvania | Schaer D.A.,Sloan Kettering Cancer Center | And 5 more authors.
Clinical Cancer Research | Year: 2013

Modulation of the immune system by targeting coinhibitory and costimulatory receptors has become a promising newapproach of immunotherapy for cancer. The recent approval of the CTLA-4-blocking antibody ipilimumab for the treatment of melanoma was a watershed event, opening up a new era in the field of immunotherapy. Ipilimumab was the first treatment to ever show enhanced overall survival (OS) for patients with stage IVmelanoma. However, measuring response rates using standard Response Evaluation Criteria in Solid Tumors (RECIST) or modified World Health Organization criteria or progression-free survival does not accurately capture the potential for clinical benefit for ipilimumab-treated patients. As immunotherapy approaches are translated into more tumor types, it is important to study biomarkers, which may be more predictive of OS to identify the patients most likely to have clinical benefit. Ipilimumab is the first-in-class of a series of immunomodulating antibodies that are in clinical development. Anti-PD1 (nivolumab and MK-3475), anti-PD-L1 (BMS-936 559, RG7446, and MEDI4736), anti-CD137 (urelumab), anti-OX40, anti- GITR, and anti-CD40 monoclonal antibodies are just some of the agents that are being actively investigated in clinical trials, each having the potential for combination with the ipilimumab to enhance its effectiveness. Development of rational combinations of immunomodulatory antibodies with small-molecule pathway inhibitor therapies such as vemurafenib makes the discovery of predictive biomarkers even more important. Identifying reliable biomarkers is a necessary step in personalizing the treatment of each patient's cancer through a baseline assessment of tumor gene expression and/or immune profile to optimize therapy for the best chance of therapeutic success. © 2012 American Association for Cancer Research.

Beatty G.L.,University of Pennsylvania | Torigian D.A.,University of Pennsylvania | Gabriela Chiorean E.,University of Washington | Saboury B.,University of Pennsylvania | And 8 more authors.
Clinical Cancer Research | Year: 2013

Purpose: This phase I study investigated the maximum-tolerated dose (MTD), safety, pharmacodynamics, immunologic correlatives, and antitumor activity of CP-870,893, an agonist CD40 antibody, when administered in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDA). Experimental Design: Twenty-two patients with chemotherapy-naive advanced PDA were treated with 1,000 mg/m2 gemcitabine once weekly for three weeks with infusion of CP-870,893 at 0.1 or 0.2 mg/kg on day three of each 28-day cycle. Results: CP-870,893 was well-tolerated; one dose-limiting toxicity (grade 4, cerebrovascular accident) occurred at the 0.2 mg/kg dose level, which was estimated as the MTD. The most common adverse event was cytokine release syndrome (grade 1 to 2). CP-870,893 infusion triggered immune activation marked by an increase in inflammatory cytokines, an increase in B-cell expression of costimulatory molecules, and a transient depletion of B cells. Four patients achieved a partial response (PR). 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) showed more than 25% decrease in FDG uptake within primary pancreatic lesions in six of eight patients; however, responses observed in metastatic lesions were heterogeneous, with some lesions responding with complete loss of FDG uptake, whereas other lesions in the same patient failed to respond. Improved overall survival correlated with a decrease in FDG uptake in hepatic lesions (R = -0.929; P - 0.007). Conclusions: CP-870,893 in combination with gemcitabine was well-tolerated and associated with antitumor activity in patients with PDA. Changes in FDG uptake detected on PET/CT imaging provide insight into therapeutic benefit. Phase II studies are warranted. Clin Cancer Res; 19(22); 6286-95. © 2013 AACR. © 2013 American Association for Cancer Research.

Thiel A.T.,University of Pennsylvania | Blessington P.,University of Pennsylvania | Zou T.,Abramson Family Cancer Research Institute | Feather D.,University of Pennsylvania | And 7 more authors.
Cancer Cell | Year: 2010

Oncogenic fusion proteins are capable of initiating tumorigenesis, but the role of their wild-type counterparts in this process is poorly understood. The mixed lineage leukemia (MLL) gene undergoes chromosomal translocations, resulting in the formation of oncogenic MLL fusion proteins (MLL-FPs). Here, we show that menin recruits both wild-type MLL and oncogenic MLL-AF9 fusion protein to the loci of HOX genes to activate their transcription. Wild-type MLL not only catalyzes histone methylation at key target genes but also controls distinct MLL-AF9-induced histone methylation. Notably, the wild-type Mll allele is required for MLL-AF9-induced leukemogenesis and maintenance of MLL-AF9-transformed cells. These findings suggest an essential cooperation between an oncogene and its wild-type counterpart in MLL-AF9-induced leukemogenesis. © 2010 Elsevier Inc. All rights reserved.

Yzaguirre A.D.,Abramson Family Cancer Research Institute | Speck N.A.,Abramson Family Cancer Research Institute
Developmental Biology | Year: 2016

The de novo generation of hematopoietic cells occurs during midgestation when a population of endothelial cells called hemogenic endothelium transitions into hematopoietic progenitors and stem cells. In mammalian embryos, the newly formed hematopoietic cells form clusters in the lumens of the major arteries in the embryo proper and in the vascular plexus of the yolk sac. Small clusters of hematopoietic cells that are independent of the vasculature (referred to here as extravascular islands) were shown to form in the mesentery during vascular remodeling of the vitelline artery. Using three-dimensional imaging of whole mouse embryos we demonstrate that extravascular budding of hematopoietic clusters is a more widespread phenomenon that occurs from the vitelline and the umbilical arteries both proximal to the embryo proper and distal in the extraembryonic yolk sac and placenta. Furthermore, we show that there are several mechanisms by which hematopoietic clusters leave the arteries, including vascular remodeling and extrusion. Lastly, we provide static images suggesting that extravascular islands contribute to the formation of new blood vessels. Thus, extravascular islands may represent a novel mechanism of vasculogenesis whereby established vessels contribute endothelial and hematopoietic cells to developing vascular beds. © 2016 Elsevier Inc.

Gordon S.M.,Abramson Family Cancer Research Institute | Chaix J.,Abramson Family Cancer Research Institute | Chaix J.,Columbia University | Rupp L.J.,Abramson Family Cancer Research Institute | And 6 more authors.
Immunity | Year: 2012

Natural killer (NK) cells play critical roles defending against tumors and pathogens. We show that mice lacking both transcription factors Eomesodermin (Eomes) and T-bet failed to develop NK cells. Developmental stability of immature NK cells constitutively expressing the death ligand TRAIL depended on T-bet. Conversely, maturation characterized by loss of constitutive TRAIL expression and induction of Ly49 receptor diversity and integrin CD49b (DX5 +) required Eomes. Mature NK cells from which Eomes was deleted reverted to phenotypic immaturity if T-bet was present or downregulated NK lineage antigens if T-bet was absent, despite retaining expression of Ly49 receptors. Fetal and adult hepatic hematopoiesis restricted Eomes expression and limited NK development to the T-bet-dependent, immature stage, whereas medullary hematopoiesis permitted Eomes-dependent NK maturation in adult mice. These findings reveal two sequential, genetically separable checkpoints of NK cell maturation, the progression of which is metered largely by the anatomic localization of hematopoiesis. © 2012 Elsevier Inc.

Dilley R.L.,Abramson Family Cancer Research Institute | Greenberg R.A.,Abramson Family Cancer Research Institute
Trends in Cancer | Year: 2015

Activation of a telomere maintenance mechanism (TMM) is permissive for replicative immortality and a hallmark of human cancer. While most cancers rely on reactivation of telomerase, a significant fraction utilizes the recombination-dependent alternative lengthening of telomeres (ALT) pathway. ALT is enriched in tumors of mesenchymal origin, including those arising from bone, soft tissue, and the nervous system, and usually portends a poor prognosis. Recent insights into the mechanisms of ALT are uncovering novel avenues to exploit vulnerabilities and may facilitate clinical development of ALT-detection assays and personalized treatment decisions based on TMM status. Treatments targeting ALT may hold promise for a broadly-applicable therapeutic modality specific to mesenchymal lineage tumors, something that has thus far remained elusive. © 2015 Elsevier Ltd.

Lee K.E.,Abramson Family Cancer Research Institute | Lee K.E.,Howard Hughes Medical Institute | Simon M.C.,Abramson Family Cancer Research Institute | Simon M.C.,Howard Hughes Medical Institute
Current Opinion in Cell Biology | Year: 2012

Hypoxia, a condition of insufficient oxygen availability, occurs during normal development as well as tumorigenesis. Cellular responses to hypoxia are primarily mediated by hypoxia-inducible factors (HIFs). Recent studies have revealed that dormant hematopoietic stem cells (HSCs) reside within hypoxic regions of the bone marrow and that HIF is a critical player in HSC homeostasis. The functional significance of HIF in maintaining stemness also applies to cancer stem cells in hematological malignancies. These findings indicate that better understanding of the mechanisms underlying HIF functions in stem cells should permit the development of new therapies for tissue regeneration and cancer. © 2012 Elsevier Ltd.

Brignier A.C.,Abramson Family Cancer Research Institute | Gewirtz A.M.,Abramson Family Cancer Research Institute
Journal of Allergy and Clinical Immunology | Year: 2010

There are many types of stem cells. All share the characteristics of being able to self-renew and to give rise to differentiated progeny. Over the last decades, great excitement has been generated by the prospect of being able to exploit these properties for the repair, improvement, and/or replacement of damaged organs. However, many hurdles, both scientific and ethical, remain in the path of using human embryonic stem cells for tissue-engineering purposes. In this report we review current strategies for isolating, enriching, and, most recently, inducing the development of human pluripotent stem cells. In so doing, we discuss the scientific and ethical issues associated with this endeavor. Finally, progress in the use of stem cells as therapies for type 1 diabetes mellitus, congestive heart failure, and various neurologic and immunohematologic disorders, and as vehicles for the delivery of gene therapy, is briefly discussed. © 2010 American Academy of Allergy, Asthma & Immunology.

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