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Pipkin M.E.,Harvard University | Pipkin M.E.,Immune Disease Institute | Sacks J.A.,University of Washington | Sacks J.A.,Howard Hughes Medical Institute | And 7 more authors.
Immunity | Year: 2010

Interleukin(IL)-2 and inflammation regulate effector and memory cytolytic T-lymphocyte (CTL) generation during infection. We demonstrate a complex interplay between IL-2 and inflammatory signals during CTL differentiation. IL-2 stimulation induced the transcription factor eomesodermin (Eomes), upregulated perforin (Prf1) transcription, and repressed re-expression of memory CTL markers Bcl6 and IL-7Rα. Binding of Eomes and STAT5 to Prf1 cis-regulatory regions correlated with transcriptional initiation (increased recruitment of RNA polymerase II to the Prf1 promoter). Inflammation (CpG, IL-12) enhanced expression of IL-2Rα and the transcription factor T-bet, but countered late Eomes and perforin induction while preventing IL-7Rα repression by IL-2. After infection of mice with lymphocytic choriomeningitis virus, IL-2Rα-deficient effector CD8+ T cells expressed more Bcl6 but less perforin and granzyme B, formed fewer KLRG-1+ and T-bet-expressing CTL, and killed poorly. Thus, inflammation influences both effector and memory CTL differentiation, whereas persistent IL-2 stimulation promotes effector at the expense of memory CTL development. © 2010 Elsevier Inc. All rights reserved.


News Article | October 10, 2016
Site: www.medicalnewstoday.com

A study published by researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine describes that certain proteins playing a role in cancer progression and metastasis are stored as amyloid bodies in dormant cancer cells. Once the amyloid bodies disaggregate, the cancer cells become active again. The findings were published in the journal Developmental Cell. Amyloid bodies are known to play a role in the development of neurological diseases such as Alzheimer's and Parkinson's disease but their contributions to the progression of cancer have been largely unknown. This discovery points to a new avenue for the treatment of various types of cancers by applying knowledge we have gained from neuroscience to tumor biology. "The amyloid state of protein organization is typically associated with debilitating human neuropathies and rarely observed in physiology," said Stephen Lee, Ph.D., director of the Tumor Biology Program at Sylvester, professor of biochemistry and molecular biology at the Miller School, and corresponding author of the study. "Yet, we found that a large number of proteins are stored as amyloid bodies in cancer cells that are dormant. The heat shock chaperone pathway can disaggregate the amyloid bodies and turn the dormant cancer cells into active, progressing cancer cells." The team of researchers found that ribosomal intergenic noncoding RNA regulates the process of amyloid formation in cancer cells, making it a target for drug discovery and development. "If we can stop the amyloid bodies from disaggregating in cancer cells, the hope is that they will remain dormant indefinitely," said Lee. "In addition, we may also be able to turn active cancer cells into dormant ones by encouraging them to store the proteins as amyloid bodies." Amyloidogenesis enables cells to remain viable during prolonged periods of extracellular stress, highlighting the non-toxic and protective nature of the process, not just in cancer cells. "Following this approach, we wouldn't necessarily rid the body of cancer cells, but we would keep them inactive - shut off, if you will - and not allow them to become active again," said Lee. "I am optimistic this could become a novel way of treating cancer. There are already drugs on the market, and others are being studied, that target the ribosomal intergenic noncoding RNA as well as the heat shock chaperone pathway." This research was supported by grants from the National Institute of General Medical Sciences (R01GM115342) and the National Cancer Institute (R01CA200676) of the National Institutes of Health, Sylvester Comprehensive Cancer Center, and the Canadian Institutes of Health Research.


News Article | February 15, 2017
Site: www.prweb.com

Polyglass U.S.A., Inc. announced today that it is a funding partner of the 2017 Dolphins Cancer Challenge (DCC), the Miami Dolphins’ signature health initiative. The $50,000 sponsorship represents part of Polyglass’ commitment to this charity, along with its team of employees who will raise funds and participate in the DCC event scheduled for February 11, 2017. “Everyone has been touched by cancer in some way and the Polyglass organization wants to help find a cure,” said Director of Strategic Marketing, Scott Lelling. “The money raised at the DCC has made a difference in the lives of many people affected by cancer and Polyglass is proud to be a funding partner of this worthy initiative for the second year.” Since founded by the Miami Dolphins organization in 2010, the DCC has raised $16.5 million to further cancer research at the University of Miami, Sylvester Comprehensive Cancer Center. One hundred percent of the participant-raised funds has been used by Sylvester to make life-changing discoveries leading to more individualized treatments, better outcomes and more hope for cancer patients. The allocation of the donations include translational research, clinical trials, pediatric oncology treatment, breast cancer research, genitourinary cancer research and radiation oncology research. At the DCC event in February, Polyglass employees will join other bikers, runners and walkers in a race to beat cancer. All participants will end their race at the Hard Rock Stadium in Miami Gardens, Fla. The event closes with a concert at the finish line. DCC has announced that multiplatinum musicians Counting Crows will headline the 2017 DCC Finish Line Celebration. The DCC has also incorporated the hashtag #CancerFighters as part of its campaign. About the Dolphins Cancer Challenge (DCC): The DCC is dedicated to improving people’s lives through the financial support of innovative cancer research at the Sylvester Comprehensive Cancer Center. Launched in 2010 as the signature initiative of the Miami Dolphins Foundation, the DCC is a way all of us can be cancer fighters! 100% of participant-raised funds go to innovative cancer research at the Sylvester Comprehensive Cancer Center. About Sylvester Comprehensive Cancer Center: Sylvester serves as the hub for cancer diagnosis and treatment for UHealth -University of Miami Health System. In 2003, Sylvester expanded its cancer services to patients in Broward and Palm Beach with the opening of Sylvester at Deerfield Beach. A third facility, Sylvester at Kendall, was opened in 2009 to serve patients in southern Miami-Dade county. About Polyglass: Polyglass U.S.A. Inc. is a leading manufacturer of modified bitumen roof membranes. Known for its self-adhered roofing systems based on the company’s patented ADESO® technology and its new patent-pending CURE Technology®, Polyglass also produces a full line of premium roof coatings and roof maintenance systems. Providing quality, innovation and service at its best, Polyglass adds value worldwide. For more information about the premium products and services offered by Polyglass, call 800.222.9782 or visit http://www.polyglass.us.


News Article | December 20, 2016
Site: www.eurekalert.org

Scientists at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, the Veterans Affairs Medical Center in Miami, and Shantou University Medical College in China, have shown that the hormone receptor GHRH-R could be a potential biomarker for gastric cancer, enabling earlier diagnoses and better staging. In addition, the team found that the GHRH-R antagonist MIA-602 inhibited gastric cancer in both cell lines and human xenografts. The research was recently published in the journal PNAS. "The GHRH receptor is both a biomarker that can confirm prognosis and a therapeutic target," said Andrew V. Schally, Ph.D., M.D.h.c., D.Sc.h.c., cancer researcher at Sylvester, professor of pathology at the Miller School, distinguished medical research investigator at the Veterans Affairs Medical Center in Miami, and a Nobel Prize in Physiology or Medicine recipient. "Gastric cancer is the second deadliest in the world - we need new approaches." Though occurring less frequently than other cancers in the United States, gastric cancer kills around 700,000 people worldwide each year, second only to lung cancer. The problem is two-fold: Diagnoses are often delayed, allowing the cancer to spread, and there are few effective treatments. Chemotherapy is often ineffective and surgery works best when the disease is caught early. The two-pronged study combined epidemiology and lab work. The researchers studied nearly 1,000 tumors from patients in China and other parts of the world. They linked the prevalence of GHRH receptors with larger, more-aggressive tumors and lower overall survival. "We found that measuring GHRH receptor overexpression could be very useful, both for prognosis and identifying the stage of the cancer," said Schally. The GHRH receptor also offers a potential therapeutic target. The receptor helps drive the aberrant growth associated with gastric and other cancers. Schally and his collaborators have been working for many years to develop an inhibitor that will reduce or eliminate these signals, culminating in the peptide drug candidate MIA-602. In the study, MIA-602 inhibited gastric cancer growth in cell lines and human tumor xenografts, decreasing both tumor size and weight. Further research showed that MIA-602 works by mitigating a network of proteins controlled by PAK1, ultimately inhibiting the well-known inflammatory proteins STAT and NF-κB. In addition, MIA-602 showed no evidence of side effects. While developing an effective agent against gastric cancer would be an enormous advance, MIA-602 may also benefit other patients. "This compound is an efficient inhibitor for a variety of cancers," noted Schally, "including lung, prostate, breast and brain." Schally hopes the therapy will soon move forward into clinical trials. Sylvester Comprehensive Cancer Center, part of UHealth - the University of Miami Health System and the University of Miami Miller School of Medicine, is among the nation's leading cancer centers and South Florida's only Cancer Center of Excellence. A 2015 study by Memorial Sloan Kettering Cancer Center, published in The Journal of the American Medical Association, showed that cancer patients treated at Sylvester have a 10 percent higher chance of survival than those treated at nearly any other cancer center in the nation. With the combined strength of more than 120 cancer researchers and 130 cancer specialists, Sylvester discovers, develops and delivers more targeted therapies, providing the next generation of cancer clinical care - precision cancer medicine - to each patient. Our comprehensive diagnostics, coupled with teams of scientific and clinical experts who specialize in just one type of cancer, enable us to better understand each patient's individual cancer and develop treatments that target the cells and genes driving the cancer's growth and survival, leading to better outcomes. At Sylvester, patients have access to more treatment options and more cancer clinical trials than most hospitals in the southeastern United States. To better serve current and future patients, Sylvester has a network of conveniently located outpatient treatment facilities in Miami, Kendall, Hollywood, Plantation, Deerfield Beach and Coral Springs, with plans to open in Coral Gables in 2016. For more information, visit sylvester.org.


BOSTON, Feb. 15, 2017 /PRNewswire/ -- BERG LLC, a biopharmaceutical company uncovering health solutions through a data-driven, biological research approach, today announced that it has initiated a Phase I/II monotherapy clinical trial for its drug candidate BPM 31510-IV for the potential treatment of glioblastoma multiforme. The compound was guided in development by BERG's unique AI-based Interrogative Biology® platform that combines patient biology and artificial intelligence-based analytics to better understand the differences between healthy and disease environments. "Glioblastoma is one of the deadliest and most insidious forms of cancer and we are working to make a much-needed difference in the lives of patients with glioblastoma to improve survival, and quality of life," said Niven R. Narain, BERG Co-Founder, President and Chief Executive Officer of BERG. "The initiation of this Phase I/II trial marks the continued advancement of BPM 31510-IV, and further demonstrates BERG's Interrogative Biology® platform." Currently, there are minimal treatment options for patients with GBM and with the five-year relative survival rate at only 5.1 percent new treatment strategies are urgently needed (National Brain Tumor Society). Standard of care treatment options are limited, often resulting in recurrence of the disease after multiple lines of therapy. As such, patients with GBM are in critical need of an effective and tolerable treatment option to increase rates of survival and quality of life. The Phase I/II open-label, non-randomized clinical trial is designed to evaluate the safety and tolerability of BPM 31510-IV in subjects with glioblastoma multiforme that has recurred on a bevacizumab-containing regimen. Secondary outcome measures are to characterize the pharmacokinetics and pharmacodynamics of BPM31510-IV in subjects with glioblastoma multiforme that has recurred on a bevacizumab-containing regimen. The trial is initially being conducted at the Stanford University School of Medicine by principal investigators Dr. Seema Nagpal and Dr. Lawrence Recht. BPM 31510-IV was previously demonstrated to be safe in patients in a Phase I clinical trial in solid tumors. Additionally, preclinical studies conducted by BERG, the Stanford University School of Medicine and the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine suggest the therapeutic efficacy of BPM 31510-IV as single agent in GBM. These studies also demonstrate the possible beneficial effect of BPM 31510-IV in combination with temozolamide (TMZ), the existing standard of care for GBM. In pre-clinical models, pretreatment with BPM 31510-IV followed by TMZ showed reduced cancer cell proliferation when compared to monotherapy. For more detail regarding this trial, please visit: https://clinicaltrials.gov/ct2/show/NCT03020602 BPM 31510-IV has the potential to slow or stop cancer cell growth by reversing the compromised metabolism of cancer cells, which is hypothesized to be a fundamental driver of many different types of cancer.  BERG has also initiated a Phase II clinical trial for BPM 31510-IV in advanced pancreatic cancer in combination with a common cancer drug, among other ongoing and planned trials for BPM31510-IV in various oncological indications. According to the National Brain Tumor Society, glioblastoma multiforme is the most common and deadliest of malignant primary brain tumors in adults. GBM accounts for 45% of all brain cancers, with nearly 11,000 men, women, and children diagnosed each year. About BERG  BERG is a clinical-stage company disrupting and redefining the approach to drug discovery, research and development through its Interrogative Biology® platform.  Its platform identifies therapies and biomarkers by applying algorithm and probability based artificial intelligence to analyze large numbers of patients' genotypic, phenotypic and other characteristics.  BERG believes this allows the company to better understand patients' disease profiles and consequently to reveal molecular signatures that guide and accelerate product candidate selection and development. By identifying biomarkers and patient characteristics that are unique to disease states, BERG is able to identify novel therapeutic product candidates and develop companion diagnostics to enhance specificity in its drug development process. BERG has leveraged its Interrogative Biology® platform to develop a robust pipeline of therapeutic product candidates and diagnostics in cancer, diabetes and neurology.


Immunosuppressive strategies currently used in hematopoietic stem cell transplantation reliably decrease graft-versus-host disease (GVHD) rates, but also impair pathogen-specific immunity. Experimental transplant studies indicate that GVHD-initiating alloreactive T cells reside primarily in naive and central memory T-cell compartments. In contrast, virus-specific T cells comprise a more differentiated memory population. After finding that the rat sarcoma/mitogen-activated protein kinase kinase/extracellular receptor kinase (RAS/MEK/ERK) pathway is preferentially activated in naive and central memory human T cells, we hypothesized that MEK inhibitors would preferentially inhibit alloreactive T cells, while sparing more differentiated virus-specific T cells. Confirming our hypothesis, we found that MEK inhibitors including selumetinib preferentially inhibited cytokine production and alloreactivity mediated by naive and central memory human CD4(+) and CD8(+) T cells while sparing more differentiated T cells specific for the human herpesviruses cytomegalovirus and Epstein-Barr virus. We then demonstrated that short-term posttransplant administration of selumetinib in a major histocompatibility complex major- and minor-mismatched murine model significantly delayed the onset of GVHD-associated mortality without compromising myeloid engraftment, demonstrating the in vivo potential of MEK inhibitors in the setting of hematopoietic stem cell transplantation. These findings demonstrate that targeting memory-dependent differences in T-cell signaling is a potent and selective approach to inhibition of alloreactivity.


Ahn E.R.,Sylvester Comprehensive Cancer Center | Vogel C.L.,Sylvester Comprehensive Cancer Center
Breast Cancer Research and Treatment | Year: 2012

Approximately 15-20% of all breast cancers are human epidermal growth factor receptor 2 (HER2) positive, with clinical studies having validated the HER2 receptor tyrosine kinase pathway as an important therapeutic target. Presently, two HER2-targeted therapies are approved by the Food and Drug Administration for treatment of HER2-positive breast cancer: the HER2-targeted humanized monoclonal antibody trastuzumab and the small-molecule tyrosine kinase inhibitor lapatinib. Despite use of these HER2-targeted agents, many patients still experience disease progression. For this reason, numerous new agents and therapeutic strategies are under investigation. Based on preclinical data suggesting synergistic effects from dual therapy targeting HER2, clinical trials that test the effects of combining anti-HER2 agents have been conducted and are ongoing. Here, we review recently presented data from several clinical trials, which indicate that the strategy of combining HER2 blockade therapies can offer greater clinical efficacy, with adverse effects of varying degrees. Specifically, we review new data reported at the 2010 San Antonio Breast Cancer Symposium (SABCS 2010), including the phase II NeoSphere and phase III NeoALTTO clinical trials, and data from three clinical trials reported at the 2011 American Society of Clinical Oncology (ASCO 2011) meeting. Together these trials elucidate the potential role of combining trastuzumab with lapatinib or pertuzumab. We also discuss additional ongoing studies that will help further define the role of dual HER2 blockade therapies and its impact on clinical practice. © 2011 Springer Science+Business Media, LLC (outside the USA).


Principal goals of therapy for women with hormone receptor (HR)-positive metastatic breast cancer (MBC) are to maintain a good quality of life and to prolong survival; another important goal is to delay initiation of chemotherapy. Most women with tumors that are estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, or both are treated initially with endocrine therapy because of its effectiveness and relatively low toxicity. Several classes of single-agent endocrine therapies are available for postmenopausal women, including the nonsteroidal aromatase inhibitors (AIs), steroidal AIs, selective ER modulators, selective ER downregulators, progestins, androgens, and high-dose estrogen. In addition, combination therapy, either with 2 different endocrine agents or with endocrine therapy plus newer targeted therapies, provides some relatively new strategies for the treatment of these patients. Nevertheless, disease resistance ultimately develops with each endocrine regimen, and many questions remain regarding the optimal timing and sequencing of these treatments. This article reviews the efficacy and safety of endocrine therapy regimens in women with HR-positive MBC, and it addresses the effect of prior endocrine therapies and the mechanisms of action of the different endocrine regimens within the context of overall treatment goals. © 2014 Elsevier Inc. All rights reserved.


Newman R.G.,Sylvester Comprehensive Cancer Center | Newman R.G.,University of Miami | Dee M.J.,University of Miami | Malek T.R.,University of Miami | And 2 more authors.
Blood | Year: 2014

Tumor relapse is the primary cause of mortality in patients with hematologic cancers following autologous hematopoietic stem cell transplantation (HSCT). Vaccination early after HSCT can exploit both the state of lymphopenia and minimal residual disease for generating antitumor immunity. Here, multiple vaccinations using lymphoma cells engineered to secrete heat shock protein fusion gp96-Ig within 2 weeks of T cell-replete syngeneic HSCT led to cross-presentation and increased survival of lymphoma-bearing mice. To enhance vaccine efficacy, interleukin (IL)-2 was directed to predominantly memory phenotype CD8+ T lymphocytes and natural killer (NK) cells via administration bound to anti-IL-2 monoclonal antibody clone S4B6 (IL-2 S4B6). Combination therapy with gp96-Ig vaccination and coordinated infusions of IL-2S4B6 resulted in marked prolongation of survival, which directly correlated with ∼500% increase in effector CD8+ T-cell numbers. Notably, this dual regimen elicited large increases in both donor CD8+ T and NK cells, but not CD4+ T lymphocytes; the former 2 populations are essential for both vaccine efficacy and protection against opportunistic infections after HSCT. Indeed, IL-2S4B6-treated HSCT recipients infected with Listeria monocytogenes exhibited decreased bacterial levels. These preclinical studies validate a new strategy particularly well suited to the post-HSCT environment, which may augment adaptive and innate immune function in patients with malignant disease receiving autologous HSCT. © 2014 by The American Society of Hematology.


Carcas L.P.,Sylvester Comprehensive Cancer Center
Current Colorectal Cancer Reports | Year: 2014

Colorectal cancer is a leading cause of cancer-related mortality in the USA. Although recent years have brought significant advances in treatment in the metastatic setting, the last major advance in the adjuvant setting was the addition of oxaliplatin to fluorouracil and leucovorin in the treatment of stage III disease. The benefit of adjuvant therapy in patients with stage II disease is not as clear. Prognostic and predictive markers help stratify patient risk and thereby indentify patients who may benefit from adjuvant therapy. The goal of this review is to help define the prognostic markers and molecular predictors that should be considered when attempting to personalize adjuvant therapy. © 2013 Springer Science+Business Media.

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