Center for Cancer Research
Center for Cancer Research
News Article | February 27, 2017
PHILADELPHIA -- (Feb. 27, 2017) -- Scientists at The Wistar Institute in collaboration with Roswell Park Cancer Institute found a significant association between a rare genetic variant of the p53 gene present in African American women and their risk of developing breast cancer in premenopausal age. The study was published online by the journal NPJ Breast Cancer. TP53 is the most frequently mutated gene in human cancer. The p53 protein is a critical tumor suppressor in the cell and genetic mutations that occur in cancer cause a loss of its function in regulating proliferation arrest and cell death. In addition to these changes, there are several minor, naturally occurring genetic variants of the p53 gene, also known as polymorphisms, and some of them are associated with an increased risk of cancer. The rare p53 polymorphism analyzed in this study is found almost exclusively in populations of African descent. Wistar scientists have previously shown that this polymorphism impairs the ability of p53 to induce cell death in vitro and significantly increases cancer risk when recreated in a mouse model. The new study analyzed the statistical association of this variant with the risk of developing breast cancer in African American women. "Based on our previous studies on the functional effects of this genetic variant on the p53 protein, we sought to verify if it alters cancer risk in human carriers," said Maureen Murphy, Ph.D., professor and program leader of the Molecular and Cellular Oncogenesis Program at Wistar and senior author of the study. "This genetic variant is present exclusively in people of African descent, so our study addresses cancer disparities in African American women, a historically underrepresented group in research studies." "Our results show that the risk of developing breast cancer is increased by nearly 70 percent in premenopausal women who carry this polymorphism," Murphy said. "Because its frequency is very low in the African American population, larger studies will be needed to confirm our observations." Murphy and colleagues conducted statistical studies on a cohort of more than 14,000 women of African descent and didn't find any association of the polymorphism with increased breast cancer risk overall. However, as previously observed with other genetic variants of p53, a significant association was present in women in premenopausal age. Elucidating the effects of p53 polymorphisms on cancer risk is a challenging task, especially due to the limited availability of sample cohorts from specific populations. This study provides a strong suggestion that the genetic variant considered might be associated with a significant increase in breast cancer risk, although this association will need to be confirmed in a larger sample set. This work was supported by National Institutes of Health grants R01 CA102184, CA201430, P01 CA151135, R01 CA092447, R01 CA135288, P01 CA82707, R25-CA57726, NICHD-N01-HD-3-3175, NCO-N01-PC-67010, NIEHS-ES07084, R01 CA142996, P50 CA125183, R01 CA89085, and U01 CA161032; National Cancer Institute grant UM1CA164974 and the Intramural Research Program of the National Cancer Institute, Center for Cancer Research; grants from the Breast Cancer Research Foundation, the University Cancer Research Fund of North Carolina, the Department of Defense Breast Cancer Research Program, the Era of Hope Scholar Award Program W81XWH-08-1-0383, the Komen Foundation for the Cure, and the Stacy Goldstein Faculty Scholar Award. Core support for The Wistar Institute and the Rutgers Cancer Institute of New Jersey was provided by the Cancer Center Support Grants P30CA010815 and P30CA072720, respectively. Qin Liu is a co-author of this study from The Wistar Institute. Other co-authors include: Song Liu, Chi-Chen Hong, Qiang Hu and Christine B. Ambrosone from Roswell Park Cancer Institute; Dezheng Huo and Olufunmilayo I. Olopade from the University of Chicago; Sonia C. Dolfi and Kim M. Hirshfield from Rutgers Cancer Institute of New Jersey; Andrew F. Olshan and Sarah Nyante from University of North Carolina; Temidayo O. Ogundiran from University of Ibadan, Nigeria; Clement Adebamowo from University of Maryland; Susan M. Domchek and Katherine L. Nathanson from the University of Pennsylvania; Barbara Nemesure from Stony Brook University; Stefan Ambs and Regina G. Ziegler from National Cancer Institute; William J. Blot, Wei Zheng and Sandra L. Deming from Vanderbilt University; Ye Feng, Sue A. Ingles, Michael F. Press and Christopher A. Haiman from University of Southern California; Esther M. John from Stanford University; Leslie Bernstein from Beckman Research Institute; Jennifer J. Hu and Jorge L. Rodriguez-Gil from University of Miami; Kathryn L. Lunetta and Julie R. Palmer from Boston University. The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.
News Article | February 15, 2017
PHILADELPHIA - More than six decades after Castleman disease (CD) was first described, a group of experts from Penn Medicine and other institutions around the world has established the first set of diagnostic criteria for a life-threatening subtype of the condition, idiopathic multicentric CD (iMCD), which is often misdiagnosed as other illnesses. The report was published online ahead of print in the journal Blood. Accurate diagnosis of iMCD has been challenging, with no standard diagnostic criteria to guide physicians and significant overlap with cancer and autoimmune, or infectious disorders. About 1,200 patients are diagnosed with iMCD each year in the United States. It can occur in patients of any age, and about 35 percent of iMCD patients die within five years of diagnosis; 60 percent die within 10 years. "The new criteria will accelerate time to diagnosis and, more importantly, administration of life-saving treatments for iMCD patients," said first author David Fajgenbaum, MD, MBA, MSc, an assistant professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania and associate director of patient impact at the Penn Orphan Disease Center. Many iMCD patients endure months without appropriate treatment, including Fajgenbaum, who is also an iMCD patient. It took over 11 weeks for Fajgenbaum to be correctly diagnosed, during which time he experienced two life-threatening episodes of the disease. "Previously, patients had to hope their doctors were familiar with the Castleman disease medical literature in order for them to even consider an iMCD diagnosis," Fajgenbaum said. "Then, for the doctors considering the diagnosis, actually diagnosing it was very difficult. Now, with these criteria, doctors will know exactly what to look for and what to check off to feel confident about a diagnosis." To establish the criteria, the international working group - led by Fajgenbaum and consisting of 34 pediatric and adult hematopathology, hematology/oncology, rheumatology, immunology, and infectious diseases experts in iMCD and related disorders representing eight countries on five continents, including two physicians that are also iMCD patients - reviewed 244 iMCD cases and 88 lymph node tissue biopsies over 15 months. Other working group members from Penn include senior authors Kojo Elenitoba-Johnson, MD, a professor of Pathology and Laboratory Medicine and director of the Center for Personalized Diagnostics, and Megan Lim, MD, PhD, a professor of Pathology and Laboratory Medicine. The criteria require that for a diagnosis of iMCD to be made, two major criteria and at least two of 11 minor criteria be met, including at least one laboratory abnormality, such as anemia or elevated C-reactive protein in the blood. Additionally, several diseases with similar clinical presentation to iMCD must be excluded, such as another sub-type of CD called HHV-8-associated multicentric CD. Several therapies have been used off-label to treat iMCD patients with varying success, including corticosteroids, cytotoxic chemotherapy, and immunosuppressants. In 2014, siltuximab, an anti-IL6 monoclonal antibody used to treat cancer, became the first U.S. Food and Drug Administration-approved iMCD therapy based on results from an international, randomized controlled trial in which 34 percent of patients had a complete or partial response to the drug compared to zero percent on placebo. "However, the lack of a defined diagnostic criteria has likely impeded the timely administration of treatment for many patients," Fajgenbaum said. "Such delays could lead to organ dysfunction and even death." The working group retrospectively applied the diagnostic criteria to patients from the siltuximab clinical trial. They found that individuals presumed to have iMCD, but who did not meet the diagnostic criteria, had a significantly lower (0 percent) response rate to siltuximab compared to patients who met the diagnostic criteria (43 percent). The working group will continue to improve upon the new diagnostic criteria, in part by relying on the ACCELERATE patient registry. ACCELERATE is a CD natural history registry based at Penn. The data collected from the registry will help researchers validate and potentially tweak the criteria. "I feel so pleased and optimistic that we're finally turning the tide against this disease," Fajgenbaum said. "I've heard of too many patients diagnosed with the disease only after they died and underwent an autopsy, and hopefully this will help doctors to diagnose it before it is too late." Co-authors also include Elaine Jaffe, MD and Thomas S. Uldrick, MD, MS, from the National Cancer Institute's Center for Cancer Research. The study was supported in part by the Castleman Disease Collaborative Network, the Penn Orphan Disease Center, and the Intramural Research Program of the National Institutes of Health. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.
News Article | February 24, 2017
Massachusetts General Hospital (MGH) researchers have identified a mechanism that controls the expression of genes regulating the growth of the most aggressive form of medulloblastoma, the most common pediatric brain tumor. In their report published online in Cancer Discovery, the team also identifies potential targets for future treatments. "We set out to find the most important regulators of gene expression programs in medulloblastoma," says senior author Miguel Rivera, MD, of theMGH Department of Pathology / and the Center for Cancer Research. "To do that we used a powerful genomic technology called chromatin profiling to map all the genomic elements contributing to transcription regulation in Group 3 medulloblastoma - the most aggressive subtype. This goes beyond measuring gene expression because it tells you how genes are turned on and off." Medulloblastoma is a fast-growing tumor that arises in the developing brain and most commonly affects children under the age of 10. Four molecular variants, each with different patterns of DNA alteration and gene expression, have been identified. Subtypes WNT and SSH are the best understood; the other two - Group 3 and Group 4 - are poorly understood and account for 60 percent of tumors. Cells regulate whether specific genes are transcribed into RNA through the action of transcription factors, proteins that bind to DNA and either stimulate or suppress the expression of their target genes. Rivera's team used advanced genomic technologies to identify key DNA elements called enhancers that were active in primary Group 3 medulloblastoma samples and cell lines. The transcription factor OTX2, which plays a role in normal brain development and is known to be highly expressed in Group 3 medulloblastomas, was present at the majority of active enhancer sites in tumors, suggesting it may have a role in promoting the expression of tumor-associated genes. Subsequent experiments revealed that OTX2 can function as a "pioneer factor," opening up chromatin - which consists of DNA wound around proteins called histones - to activate enhancers and that its function is amplified by a second transcription factor called NEUROD1. The investigators then identified a set of genes the expression of which was significantly reduced when OTX2 was suppressed. Among these genes, they found that expression of the kinase NEK2 responded to OTX2 levels and that its depletion or pharmacologic inhibition strongly reduced the growth and survival of medulloblastoma cells. "Overall, our findings show that OTX2 is a critical factor in regulating gene expression programs in Group 3 medulloblastoma and possibly in the WNT and Group 4 subtypes, where it is also expressed," says Rivera, who is an assistant professor of Pathology at Harvard Medical School. "This work points to OTX2 itself and its target genes - including NEK2 - as potential therapeutic targets. Disruption of the relationship between OTX2 and NEUROD1 may also be a potential treatment strategy. We now need to get a more a detailed picture of the mechanisms OTX2 uses to activate enhancers and improve our understanding of the function of NEK2 and other target genes regulated by OTX2." Gaylor Boulay, PhD, of the MGH Center for Cancer Research is lead author of the Cancer Discovery paper. Additional co-authors are Mary Awad, Sowmya Iyer, Wannaporn Boonseng, Nikki Rossetti, Beverly Naigles, Shruthi Rengarajan, Angela Volorio, James Kim, and Martin Aryee, PhD, MGH Center for Cancer Research; Nicolo Riggi, MD, PhD, University of Lausanne, Switzerland; Tenley Archer, PhD, and Scott Pomeroy, MD, PhD, Boston Children's Hospital; and Jill Mesirov, PhD, and Pablo Tamayo, PhD, University of California, San Diego. The research team also worked in close contact with clinical colleagues at MGH - including Nancy Tarbell, MD, David Ebb, MD, Torunn Yock, MD, MCh, and Howard Weinstein, MD. The study was supported by grants from A Kids' Brain Tumor Cure Foundation/The PLGA Foundation. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."
News Article | March 1, 2017
NEW YORK, March 01, 2017 (GLOBE NEWSWIRE) -- Icahn Enterprises L.P. (NASDAQ:IEP) today announced that Icahn Capital LP, its wholly owned subsidiary, has hired Dr. Richard C. Mulligan as a Portfolio Manager. Dr. Mulligan will be focused on biotechnology investments for Icahn Partners LP and Icahn Partners Master Fund LP, the private investment funds comprising Icahn Enterprises’ Investment segment. "We are very pleased to have Richard join Icahn Capital given the depth and level of experience he brings as we look to enhance our focus on the biotechnology sector," said Carl C. Icahn, Chairman of Icahn Enterprises. Richard C. Mulligan is currently the Mallinckrodt Professor of Genetics, Emeritus, at Harvard Medical School, and Visiting Scientist at the Koch Institute for Integrative Cancer Research at MIT. Previously, Professor Mulligan was the Mallinckrodt Professor of Genetics at Harvard Medical School, and Director of the Harvard Gene Therapy Initiative, an integrated effort amongst basic science and clinical investigators at Harvard University and its Affiliated Hospitals directed towards the pre-clinical and clinical evaluation of novel gene-based therapies for inherited and acquired diseases. Professor Mulligan received his B.S. degree from Massachusetts Institute of Technology (MIT), and his Ph.D. from the Department of Biochemistry at Stanford University School of Medicine, where he studied under Nobel Laureate Paul Berg. After receiving postdoctoral training at the Center for Cancer Research at MIT with Nobel Laureates David Baltimore and Phillip Sharp, Professor Mulligan joined the MIT faculty and subsequently was appointed Professor of Molecular Biology and Member of the Whitehead Institute for Biomedical Research before moving to Harvard and Children’s Hospital in 1996. His honors include the MacArthur Foundation ‘Genius’ Prize, the Rhodes Memorial Award of the American Association for Cancer Research, the ASMB-Amgen Award, and the Nagai Foundation International Prize. Professor Mulligan is an internationally recognized pioneer in the development of new technologies for transferring genes into mammalian cells. A major interest in Professor Mulligan’s laboratory has been the development of genetically engineered animal viruses as gene transfer ‘vectors’. Scientists use the specialized tools created in his laboratory to unravel basic questions about human development and to devise new clinical ‘gene therapies’ for the treatment of both inherited diseases and acquired diseases. Professor Mulligan has been previously associated with a number of public biotechnology and pharmaceutical companies, either as a consultant or as a member of the company’s Board of Directors (BOD). These companies include: Dupont (consultant), Genetics Institute (consultant), Amgen (consultant), Somatix Therapy Corporation (founder, scientific advisory board (SAB), chief scientific officer (CSO), and member, BOD), Cell Genesys (SAB), Imclone (SAB, member, BOD, and member of Executive Committee of the Board), Cellectis (member, BOD, then private), Enzon (member, BOD), and, currently, Biogen (member, BOD). He has also served on the US National Institutes of Health Recombinant DNA Advisory Committee (RAC), which provides guidance to the NIH regarding experiments involving recombinant DNA, and on the FDA Biological Response Modifiers Advisory Committee (BRMAC), which advises the FDA on matters related to cell and gene therapies, including stem cell-based technologies. From 2013-2016, Professor Mulligan was Founding Partner and Senior Managing Director of Sarissa Capital Management LP. Icahn Enterprises L.P. (NASDAQ:IEP), a master limited partnership, is a diversified holding company engaged in ten primary business segments: Investment, Automotive, Energy, Railcar, Gaming, Metals, Mining, Food Packaging, Real Estate and Home Fashion.
News Article | December 15, 2016
In five studies being presented today during the 58th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, researchers are applying advanced biomedical engineering methods to improve the delivery of life-saving treatments to patients with a variety of medical conditions. These new methods are designed to carry therapies directly to the sites in the body where they are needed most, which could provide a substantial advantage over traditional, systemic methods. The studies highlight the benefits of emerging technological tools such as nanotechnology and engineered drug delivery vehicles. “All of these studies represent substantial advances resulting from biomedical engineering. They build upon established science with bioengineering strategies that could make therapies significantly more effective if they are pursued and refined,” said Armand Keating, M.D., press briefing moderator, professor of medicine and biomedical engineering, and director of the Cell Therapy Program, University Health Network in Toronto, Canada. “I believe each of these has the potential to change practice.” Researchers have developed the first artificial red blood cells designed to emulate vital functions of natural red blood cells. If confirmed safe for use in humans, the nanotechnology-based product could represent an innovative alternative to blood transfusions that would be especially valuable on the battlefield and in other situations where donated blood is difficult to obtain or store. The artificial cells, called ErythroMer, are designed to be freeze-dried, stored at ambient temperatures, and simply reconstituted with water when needed. “One key goal is to advance field resuscitation of civilian trauma victims in remote settings and soldiers who are wounded in austere environments without access to timely evacuation,” said lead study author Allan Doctor, MD, of Washington University in Saint Louis. “ErythroMer would be a blood substitute that a medic can carry in his or her pack and literally take it out, add water, and inject it. There are currently no simple, practical means to bring transfusion to most trauma victims outside of hospitals. Delays in resuscitation significantly impact outcomes; it is our goal to push timely, effective care to field settings.” Proof-of-concept studies in mice, conducted in partnership with Greg Hare M.D., Ph.D., at the University of Toronto, demonstrate that the artificial cells capture oxygen in the lungs and release it to tissues — the main functions of red blood cells — in a pattern that is indistinguishable from that seen in a control group of mice injected with their own blood. In rats, ErythroMer effectively resuscitated animals in shock following acute loss of 40 percent of their blood volume. The donut-shaped artificial cells are formulated with nanotechnology, in partnership with Dipanjan Pan, Ph.D., at the University of Illinois at Urbana-Champaign, and are about one-fiftieth the size of human red blood cells. A special lining encodes a control system that links ErythroMer oxygen binding to changes in blood pH, thus enhancing oxygen acquisition in the lungs and then dispensing oxygen in tissues with the greatest need. Tests show ErythroMer matches this vital oxygen binding feature of human red blood cells within 10 percent, a level the researchers say should be sufficient to stabilize a bleeding patient until a blood transfusion can be obtained. So far, tests suggest ErythroMer has overcome key barriers that halted development of previous blood substitutes, including efficacy and blood vessel narrowing. The team’s next steps are testing in larger animals, ongoing safety assessment, optimizing pharmacokinetics, and ultimately conducting in-human clinical trials. The researchers are also pursuing methods for scaling up production. If further testing goes well, they estimate ErythroMer could be ready for use by field medics and emergency responders within 10-12 years. ErythroMer development has been supported by the Children’s Discovery Institute at Washington University and St. Louis Children’s Hospital, the Skandalaris Center at Washington University and the BioSTL Fundamentals Program. Gene Therapy Could Potentially Improve Quality of Life for Hemophilia Patients Preliminary data from an ongoing Phase I/II trial suggest that patients with hemophilia B, who are born unable to produce the blood-clotting protein factor IX (FIX), began producing FIX at sufficient levels after receiving a single infusion of an investigational gene therapy product called SPK-9001. The results show the highest and most consistent levels of FIX production of any gene therapy tested to date, according to the researchers. FIX is crucial to the formation of blood clots and prevention of life-threatening uncontrolled bleeding. This ongoing trial involves nine previously treated adult patients with a baseline FIX of less than 2 percent, which is considered extremely deficient. As of the November 30, 2016, data cut off, seven of the nine patients who have progressed to at least 12 weeks post-vector administration showed FIX levels in the range of 12-46 percent with a mean steady-state level greater than 28 percent, a range the researchers say is close enough to normal (at least 50% in healthy adults). Maintaining a minimum level of 12 percent is considered necessary to prevent minor, chronic bleeding in the joints, a common cause of disability in patients with hemophilia. SPK-9001 uses an inactive virus to deliver into a patient’s cells a small section of DNA that, when stabilized in the patient’s own liver cells, allows the body to produce FIX. Current standard of care for hemophilia B requires patients to self-administer intravenous infusions of laboratory-produced FIX at regular intervals, typically one to two times a week. A key downside of this standard regimen is that it causes FIX levels to fluctuate widely, and patients may need to limit their activities to avoid breakthrough bleeding when their FIX levels are low. The FIX levels achieved with SPK-9001 to date in this study have been sufficient to allow patients to engage in normal daily activities without the need for FIX infusions. Eight of the infused patients have required no factor IX concentrates to prevent or control bleeding events since the day after vector administration. One participant with severe joint disease self-administrated a precautionary infusion two days after administration of SPK-9001 for a suspected ankle bleed and again at week 35 post the data cut-off date and despite a factor IX activity level of 36, for a suspected knee bleed. In addition, six patients reported increased physical activity and improved quality of life. “One of the potential innovations with a gene therapy for hemophilia B, compared to factor IX infusions, is that once an individual establishes a stable factor activity level, then they may remain at that level for an extended time,” said Katherine A. High, MD, of Spark Therapeutics, Inc. in Philadelphia. “At the factor IX levels seen in this study, most normal activities of daily living should be open to people with hemophilia. It could be a potential paradigm shift in the treatment of hemophilia.” Two participants recently suffered an autoimmune response and were put on corticosteroids. Despite the immune response and decline in FIX activity level, these two participants have not had any bleeds or required replacement FIX. The researchers will continue to track patient outcomes for at least five years. Funding for the study was provided by Spark Therapeutics and Pfizer, Inc. Microcapsules Could Be Game-Changer for Hemophilia Patients Prone to Immune Response A new drug delivery technology uses the body’s natural processes to supply the blood-clotting protein factor VIII (FVIII) directly to the site of a developing clot to stop bleeding in patients with hemophilia A. The approach, in which small amounts of FVIII are encased within microscopic capsules that are injected into the bloodstream, could significantly improve outcomes for the approximately 30 percent of patients with severe hemophilia A in which direct infusion of FVIII triggers an immune response. People with hemophilia A do not produce FVIII, a protein necessary for forming blood clots, putting them at risk of dangerous uncontrolled bleeding. The standard treatment for these patients is intravenous infusion of FVIII; however, if the patient’s immune system attacks the infused FVIII, the drug’s effectiveness is greatly reduced. These patients often require several infusions a day to control a single bleeding event. In vitro experiments show the new microcapsules act as a shield that allows the FVIII payload to fly under the immune system’s radar and potentially stem bleeding with only one or two injections. In addition, the microcapsules are designed to go directly to the site where FVIII is needed by hitchhiking on platelets, cell fragments present in blood that play a key role in clot formation. “This is a completely new way to target delivery of a biologic drug, capitalizing on the natural functions of cells that are already in your body,” said Caroline E. Hansen, a graduate student in the laboratory of bioengineer and pediatric hematologist Wilbur A. Lam, MD, PhD, of the Georgia Institute of Technology and Emory University in Atlanta. “We’re utilizing platelets’ natural behavior to accomplish targeting and delivery. Because platelets are so heavily relied upon in the clot formation process, they could actually carry these microcapsules to the forming clot or the site of injury.” After binding to platelets and traveling to a forming clot, the microcapsules are designed to burst open, releasing FVIII. This bursting occurs when platelets join a clot and contract. The FVIII then stimulates the formation of fibrin at the site, creating a mesh network that holds the blood clot together. The researchers recently tested their microcapsules in laboratory experiments that model sites of blood vessel injuries, comparing the amount of fibrin formed when FVIII was delivered via microcapsules versus traditional systemic infusions. They found that the microcapsules resulted in 2.7 times as much fibrin formation compared to a systemic FVIII infusion when immune antibodies were present, a test that mimicked what happens when FVIII infusions trigger an immune response in a person with hemophilia A. After further examination of how the microcapsules influence the formation of fibrin, the team plans to test the microcapsules in mouse models. Funding for the study was provided by the NIH and the NSF. New Chemotherapy Delivery Method Improves Survival After Bone Marrow Transplant in Older Acute Myeloid Leukemia Patients A new analysis shows older patients with acute myeloid leukemia (AML) survived longer after receiving an allogeneic stem cell transplant if they were first treated with the experimental chemotherapy delivery method known as CPX-351 instead of the standard “7+3” administration of chemotherapy drugs cytarabine and daunorubicin. Researchers say the findings are encouraging for improving survival among high-risk AML patients who currently have limited treatment options and poor survival rates. The new study is a subgroup analysis of a large Phase III randomized controlled trial completed earlier this year that found CPX-351 nearly doubled overall survival compared to the 7+3 regimen. The researchers examined survival and other health outcomes among trial participants who received chemotherapy and then hematopoietic stem cell transplantation, a treatment that provides healthy replacement stem cells to the bone marrow to better equip patients to fight the disease on their own. Of 309 total trial participants, 91 received an allogeneic stem cell transplant, including 52 in patients who received CPX-351 compared with 39 in patients receiving 7+3. CPX-351-treated patients were also more likely to undergo transplantation while in a remission state (75 percent of CPX-351 vs. 62 percent of 7+3). In the first 100 days after transplantation there were 53 percent fewer deaths among patients receiving CPX-351 compared with those receiving 7+3 therapy. The active ingredients of CPX-351 are the same as those in the 7+3 regimen, but in contrast to 7+3 in which cytarabine and daunorubicin are delivered separately, CPX-351 encapsulates the drugs into a single delivery vehicle in a fixed synergistic molar ratio. “The two drugs together are delivered to the cell in the proper synergistic ratio that optimizes the cell-killing ability of these two drugs,” said lead study author Jeffrey E. Lancet, MD, of the Moffitt Cancer Center in Tampa, Fla. “We think that by doing this, we can improve delivery to the cancer cells at the proper ratio.” The trial focused on the group of AML patients considered at high risk; all participants were older than 60 and had AML related to prior chemotherapy, AML arising from MDS, or AML MDS-related cytogenetic abnormalities. The study was funded by Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc. New CAR-T Treatment Holds Promise for Children and Young Adults with Hard-to-Treat Leukemia Children and young adults with relapsed or refractory ALL who receive chimeric antigen receptor (CAR) T-cell therapy targeting CD22, a protein found on the surface of leukemic cells, appear to mount a clinical response and, in some cases, achieve remission. Researchers from the Pediatric Oncology Branch of the National Cancer Institute of the National Institutes of Health genetically altered patients’ own T cells to track down and kill cancer cells expressing CD22. The study — the first to evaluate CAR targeting CD22 in humans — also gives a first glimpse into how patients who already received CAR-T therapy directed at a different antigen, CD19, might fare when given a second immunotherapy. Data are presented for 16 patients who received the new anti-CD22 therapy. One of the six patients treated at a lower dose initially set by the U.S. Food and Drug Administration (FDA) and other agencies attained remission. The majority – eight of 10 – participants treated at a higher dose level (a dose comparable to that used by current CD19 CAR programs) attained a complete remission without evidence of residual disease after one month of their infusion. There have since been relapses among six out of nine patients who achieved remission, the majority of which are due to drops in CD22 expression on the cells, which has similarly been observed with CD19 CAR therapy. So far, one patient remains in remission beyond one year. “We’ve been able to show that you can give a second CAR therapy that is directed against a different antigen and have it be safe and effective,” said study author Terry J. Fry, MD, of the Center for Cancer Research, National Cancer Institute in Bethesda, MD. Dr. Fry said this adds to the notion that a single antigen-directed CAR immunotherapy probably won’t be sufficient for long-term durable remissions in many patients and points to the potential for targeting multiple cancer-related proteins (also called bispecific targeting). Participants in this Phase 1 trial had relapsed or treatment-resistant ALL and were either CAR naïve or previously treated with anti-CD19 CAR T cells and/or blinatumomab therapy and some who became resistant to CD19 CAR due to loss of CD19. The patients, ranging in age from 7– 22 years old, all had CD22+ ALL and had previously undergone at least one allogeneic stem cell transplant. A majority of participants (11 out of 16) had relapsed after receiving anti-CD19 CAR T cell before entering the trial. Researchers collected T cells from eligible patients and modified them to recognize and bind to CD22. Patients then received an infusion of their own modified cells and were evaluated for response and adverse effects after an average of 28 days. The primary adverse event was cytokine release syndrome, a common, potentially dangerous reaction to this type of infusion, which Dr. Fry reports was mild in all cases; fever and low blood pressure were the main symptoms. There was one death due to sepsis that occurred after resolution of cytokine release syndrome. While the trial is continuing to accrue patients, these early results raise new questions about how anti-CD22 CAR therapy might best be used; for example, if it is better to wait for relapse after initial CAR therapy or preempt it by co-treating it. Dr. Fry and his team plan to investigate the combined use of anti-CD19 and CD22 CAR targeting approaches with the hypothesis that this will increase the likelihood of sustained remission. This study was funded by the National Institutes of Health.
News Article | February 17, 2017
SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Exelixis, Inc. (NASDAQ:EXEL) today announced results from a phase 1 trial of cabozantinib in combination with either nivolumab or nivolumab plus ipilimumab in patients with refractory genitourinary tumors. The primary endpoint of the trial is to determine the dose limiting toxicity (DLT) and recommended phase 2 doses of the doublet and triplet combinations. The findings were presented during a poster session (Abstract #293) on February 17 at the 2017 Genitourinary Cancers Symposium, which is being held in Orlando, Florida, February 16 – 18, 2017. Between July 22, 2015 and December 31, 2016, 48 patients were accrued with previously treated metastatic urothelial carcinoma (mUC, n=19), urachal adenocarcinoma (n=4), squamous cell carcinoma of the bladder or urethra (n=2), germ cell tumor (n=4), castration-resistant prostate cancer (n=9), renal cell carcinoma (n=4), trophoblastic tumor (n=1), sertoli cell tumor (n=1) or penile squamous cell carcinoma (n=4) and treated in two parts. In Part I, 30 patients were treated with the doublet combination of cabozantinib and nivolumab at four dose levels. In Part II, 18 patients were treated with the triplet combination of cabozantinib, nivolumab and ipilimumab at three dose levels. Among the 43 patients who were evaluable for response, the objective response rate (ORR) for all tumor types was 30 percent (38 percent for the doublet dosing schedule and 18 percent for the triplet dosing schedule), with a 7 percent complete response (CR) rate and a 23 percent partial response (PR) rate. Stable disease (SD) was reported in 56 percent of patients. The ORR for patients with mUC was 38 percent, and 2 of 16 patients achieved a CR, while 2 patients with squamous cell carcinoma of the bladder had objective responses (1 CR and 1 PR). In the mUC cohort, 15 of 16 patients had a CR, PR or SD as their best response. Grade 3 adverse events (>5 percent of patients) observed in the doublet combination included neutropenia (17 percent), hypophosphatemia (13 percent), hypertension (10 percent), lipase increase (7 percent), fatigue (7 percent), diarrhea (7 percent) and dehydration (7 percent). Grade 3 adverse events (>5 percent of patients) observed in the triplet combination included hypertension (17 percent), hypophosphatemia (17 percent), fatigue (13 percent), hyponatremia (13 percent), lipase increase (13 percent), nausea (13 percent) and rash (6 percent). There were limited numbers of grade 4 adverse events (10 percent including thrombocytopenia and lipase increase in the doublet combination, and 6 percent (lipase increase) in the triplet combination), and no grade 5 adverse events observed in either part of the trial. “ There is a significant unmet need for treatment regimens that can slow tumor progression in advanced, intractable cancers such as metastatic urothelial carcinoma. The use of combination therapies may be a strategy that could increase anti-tumor activity in these patients,” said Andrea Apolo, M.D., Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, the principal investigator of the trial. “ Previously reported data from Part I of the trial showed that cabozantinib in combination with nivolumab provided an encouraging objective response rate and tolerability profile across a diverse range of genitourinary tumors. Data from Part II also demonstrate that using cabozantinib with two immunotherapy agents is well-tolerated with promising early activity. These results support the further evaluation of both regimens in these tumor types.” The recommended doses for the ongoing expansion cohorts were determined to be cabozantinib 40 mg daily plus nivolumab 3 mg/kg once every 2 weeks for the doublet and cabozantinib 40 mg daily, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses, then nivolumab 3 mg/kg every 2 weeks for the triplet. “ These early clinical results generated by our collaborators at the NCI-CTEP suggest that the combination of cabozantinib with either nivolumab or nivolumab and ipilimumab in patients with genitourinary malignancies is associated with an encouraging tolerability, safety and activity profile,” said Michael M. Morrissey, Ph.D., president and Chief Executive Officer of Exelixis. “ With these results in hand, we are committed to further examining the potential of cabozantinib in combination with a variety of immunotherapies to treat a broad range of genitourinary and other cancers.” The trial is sponsored by the U.S. National Cancer Institute (NCI) through Cooperative Research and Development Agreements between the NCI’s Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis, and both Bristol-Myers Squibb and Exelixis. Andrea Apolo, M.D., of the NCI’s Genitourinary Malignancies Branch, is the principal investigator. The trial is being conducted by the NCI and includes centers from its Experimental Therapeutics Clinical Trials Network. The primary endpoint of the phase 1 trial is to determine the dose limiting toxicity (DLT) and recommended phase 2 doses of the doublet and triplet combinations. The secondary endpoint is clinical response rate as assessed by RECIST 1.1. Part I of the study included four dosing levels: cabozantinib 40 mg daily plus nivolumab 1 mg/kg once every 2 weeks; cabozantinib 40 mg daily plus nivolumab 3 mg/kg once every 2 weeks; cabozantinib 60 mg daily plus nivolumab 1 mg/kg once every 2 weeks; and cabozantinib 60 mg daily plus nivolumab 3 mg/kg once every 2 weeks. Part II of the study included three dosing levels: cabozantinib 40 mg daily, nivolumab 1 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses, then nivolumab 1 mg/kg every 2 weeks; cabozantinib 40 mg daily, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses, then nivolumab 3 mg/kg every 2 weeks; and cabozantinib 60 mg daily, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses, then nivolumab 3 mg/kg every 2 weeks. Data from Part I of the study evaluating the combination of cabozantinib with nivolumab in patients with previously treated genitourinary tumors were presented by Dr. Apolo at the European Society for Medical Oncology 2016 Congress. Expansion cohorts assessing cabozantinib and nivolumab are currently being accrued with bladder, renal and rare genitourinary cancer patients. Data from these patients will be reported at a later date. Genitourinary cancers are those that affect the urinary tract, bladder, kidneys, ureter, prostate, testicles, penis or adrenal glands — parts of the body involved in reproduction and excretion — and include renal cell carcinoma and urothelial carcinoma.1 Kidney cancer is among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S., according to the American Cancer Society’s 2016 statistics.2 Clear cell renal cell carcinoma is the most common type of kidney cancer in adults.3 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.2 Approximately 30,000 patients in the U.S. and 68,000 globally require treatment.4 Prostate cancer is the second most common cause of cancer death in men, behind only skin cancer.5 There is a high survival rate for patients when prostate cancer is detected early, but once the disease has spread to other parts of the body the five-year survival rate is just 28 percent.6 Approximately 2,850,000 men were living with prostate cancer in the U.S. in 2013,7 and 180,000 new cases are diagnosed each year.5 Urothelial cancers encompass carcinomas of the bladder, ureter and renal pelvis at a ratio of 50:3:1, respectively.8 Urothelial carcinoma occurs mainly in older people, with 90 percent of patients aged 55 or older.9 Bladder cancer is the fourth most common cancer in men and accounts for about five percent of all new cases of cancer in the U.S. each year.9 In 2013, an estimated 587,426 people were living with bladder cancer in the U.S.10 CABOMETYX is the tablet formulation of cabozantinib. Its targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance. CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily. On April 25, 2016, the FDA approved CABOMETYX tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. On September 9, 2016, the European Commission approved CABOMETYX tablets for the treatment of advanced renal cell carcinoma in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland. On February 29, 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan. On December 21, 2016, this agreement was amended to include commercialization rights for Ipsen in Canada. On January 30, 2017, Exelixis and Takeda Pharmaceutical Company Limited announced an exclusive licensing agreement for the commercialization and further clinical development of cabozantinib for all future indications in Japan, including RCC. Cabozantinib is not indicated for the treatment of refractory mUC and other genitourinary tumors. Hemorrhage: Severe hemorrhage occurred with CABOMETYX. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the cabozantinib clinical program. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage. Gastrointestinal (GI) Perforations and Fistulas: Fistulas were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated patients and 0% of everolimus-treated patients. GI perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of everolimus-treated patients. Fatal perforations occurred in the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation. Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. Venous thromboembolism was reported in 7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Events of arterial thromboembolism were reported in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication. Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension. Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of everolimus-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management. Diarrhea: Diarrhea occurred in 74% of patients treated with CABOMETYX and in 28% of patients treated with everolimus. Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to diarrhea occurred in 26% of patients. Palmar-Plantar Erythrodysesthesia Syndrome (PPES): Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated with CABOMETYX and in 6% of patients treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES occurred in 16% of patients. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS. Embryo-fetal Toxicity: CABOMETYX can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose. Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation. Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided. Lactation: Advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose. Reproductive Potential: Contraception―Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility ―CABOMETYX may impair fertility in females and males of reproductive potential. Hepatic Impairment: Reduce the CABOMETYX dose in patients with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment. Please see full Prescribing Information at https://cabometyx.com/downloads/cabometyxuspi.pdf. Exelixis, Inc. (Nasdaq: EXEL) is a biopharmaceutical company committed to the discovery, development and promotion of new medicines with the potential to improve care and outcomes for people with cancer. Since its founding in 1994, three products discovered at Exelixis have progressed through clinical development to receive regulatory approval. Currently, Exelixis is focused on advancing cabozantinib, an inhibitor of multiple tyrosine kinases including MET, AXL and VEGF receptors, which has shown clinical anti-tumor activity in more than 20 forms of cancer and is the subject of a broad clinical development program. Two separate formulations of cabozantinib have received regulatory approval to treat certain forms of kidney and thyroid cancer and are marketed for those purposes as CABOMETYX™ tablets (U.S. and EU) and COMETRIQ® capsules (U.S. and EU), respectively. Another Exelixis-discovered compound, COTELLIC® (cobimetinib), a selective inhibitor of MEK, has been approved in major territories including the United States and European Union, and is being evaluated for further potential indications by Roche and Genentech (a member of the Roche Group) under a collaboration with Exelixis. For more information on Exelixis, please visit www.exelixis.com or follow @ExelixisInc on Twitter. This press release contains forward-looking statements, including, without limitation, statements related to: the further evaluation of cabozantinib in combination with immunotherapies to treat a variety of genitourinary tumors; future data results from expansion cohorts assessing cabozantinib and nivolumab in bladder, renal and rare genitourinary cancer patients; Exelixis' commitment to the discovery, development and commercialization of new medicines with the potential to improve care and outcomes for people with cancer; Exelixis’ focus on advancing cabozantinib; and the continued development of cobimetinib. Words such as “may,” “further,” “committed,” “focused,” or other similar expressions identify forward-looking statements, but the absence of these words does not necessarily mean that a statement is not forward-looking. In addition, any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements. These forward-looking statements are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: Exelixis’ ability and the ability of its collaborators to conduct clinical trials of cabozantinib sufficient to achieve a positive completion; risks related to the potential failure of cabozantinib to demonstrate safety and efficacy in clinical testing; the availability of data at the referenced times; risks and uncertainties related to regulatory review and approval processes and Exelixis’ compliance with applicable legal and regulatory requirements; the degree of market acceptance of CABOMETYX and the availability of coverage and reimbursement for CABOMETYX; the risk that unanticipated developments could adversely affect the commercialization of CABOMETYX; Exelixis’ dependence on its relationships with Ipsen and Takeda, including, the level of their investment in the resources necessary to successfully commercialize cabozantinib in the territories where it is approved; Exelixis’ dependence on its relationship with Genentech/Roche with respect to cobimetinib and Exelixis’ ability to maintain its rights under the collaboration; Exelixis’ dependence on third-party vendors; Exelixis’ ability to protect the company’s intellectual property rights; market competition; changes in economic and business conditions, and other factors discussed under the caption “Risk Factors” in Exelixis’ quarterly report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on November 3, 2016, and in Exelixis’ future filings with the SEC. The forward-looking statements made in this press release speak only as of the date of this press release. Exelixis expressly disclaims any duty, obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in Exelixis’ expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based.
Do K.,Center for Cancer Research |
Chen A.P.,U.S. National Cancer Institute
Clinical Cancer Research | Year: 2013
Poly (ADP-ribose) polymerases (PARP) are a family of nuclear protein enzymes involved in the DNA damage response. The role of PARP-1 in base excisional repair has been extensively characterized. More recent in vitro studies additionally implicate a role for PARP-1 in facilitating homologous recombination and nonhomologous end-joining. The more faithful process of homologous recombination repair of doublestranded DNA breaks involves localization of BRCA-1 and BRCA-2 to sites of DNA damage, resection of the double-stranded break, and gap-filling DNA synthesis using the homologous sister chromatid as a template. Simultaneous dysfunction of both DNA repair pathways decreases the ability of cells to compensate, and forms the basis for the concept of synthetic lethality. Treatment strategies, thus far, have focused on two main principles: (i) exploitation of the concept of synthetic lethality in homologous recombination-deficient tumors, primarily in breast and ovarian cancer patients with BRCA mutation, and (ii) as radiosensitizers and chemosensitizers. BRCA deficiency accounts for only a fraction of dysfunction in homologous recombination repair. Epigenetic alterations of BRCA function and defects within the Fanconi anemia pathway also result in defective DNA repair. Rational therapeutic combinations exploiting alternate mechanisms of defective DNA repair, abrogation of cell-cycle checkpoints, and additional functions of PARP-1 present novel opportunities for further clinical development of PARP inhibitors. On the basis of the results of clinical studies of PARP inhibitors thus far, it is imperative that future development of PARP inhibitors take a more refined approach, identifying the unique subset of patients that would most benefit from these agents, determining the optimal time for use, and identifying the optimal combination partner in any particular setting. © 2012 American Association for Cancer Research.
Fojo A.T.,Center for Cancer Research |
Clinical Cancer Research | Year: 2010
We describe the development and approval of biologically targeted agents in the clinic through examples chosen from the experience with inhibitors of the epidermal growth factor (EGF) and VEGF pathways. Despite extensive biological rationale for the use of these classes of molecules, marginal clinical benefits have been observed in broad patient populations, and the agents have entered into general clinical practice.We discuss why this situation is unsatisfactory because marginal general benefit may often be at the expense of toxicity to nonbenefiting or even harmed patients. Finally, we point out that emerging technologies bring the promise of allowing the identification of patients who might potentially benefit from a therapy. However, development of this technology will not move forward without broader recognition of its need by the range of stakeholders, including patients, advocates, academic and private oncologists, drug sponsors, and those who develop drugs and diagnostic tests. ©2010 AACR.
Roschewski M.,U.S. National Institutes of Health |
Wilson W.H.,Center for Cancer Research
Best Practice and Research: Clinical Haematology | Year: 2012
Epstein-Barr virus (EBV) is a ubiquitous γ-herpes virus that infects most people but results in life-threatening diseases in only a small subset. Persons who are unable to maintain the virus in its latent state can develop uncontrolled EBV-driven lymphoproliferative disorders and lymphomas. EBV-associated lymphomas are well characterized in patients with known defects in cellular immunity as occurs post-transplantation or HIV/AIDS but are increasingly recognized in patients without overt immunodeficiencies. Improved understanding of the biology of these lymphomas and the role EBV plays in lymphomagenesis offer the opportunity for improved therapies targeted at important signaling pathways and immunotherapy specific against EBV viral antigens. © 2012 Elsevier Ltd. All rights reserved.