Stephenson Cancer Center
Stephenson Cancer Center
News Article | May 17, 2017
WALTHAM, Mass.--(BUSINESS WIRE)--ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, today announced promising safety and efficacy data from monotherapy and combination studies with mirvetuximab soravtansine in patients with folate receptor alpha (FRα)-positive epithelial ovarian cancer (EOC). These data include results from pooled analyses of three Phase 1 expansion cohorts and from a Phase 1b/2 study, FORWARD II, evaluating mirvetuximab soravtansine in combination with Avastin® (bevacizumab), carboplatin, Doxil® (pegylated liposomal doxorubicin), or Keytruda® (pembrolizumab). These results will be presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, which is being held June 2-7, 2017 in Chicago, IL. Data from the pooled analyses demonstrate the safety and efficacy profile of mirvetuximab soravtansine in the patient population eligible for the ongoing Phase 3 registration trial, FORWARD I. These data include 113 EOC patients treated with mirvetuximab soravtansine in three expansion cohorts in the Phase 1 trial. In the subset of 36 patients meeting the key eligibility criteria for FORWARD I, which includes patients with platinum-resistant disease and medium or high levels of FRα and who have received up to three prior lines of therapy, the confirmed overall response rate (ORR) was 47 percent (95% CI 30, 65) and median progression-free survival (mPFS) was 6.7 months (95% CI 4.1, 8.3). “The data observed with mirvetuximab compare favorably with outcomes typically achieved with currently available single-agent therapies for platinum resistant ovarian cancer. Current single-agent therapies for platinum-resistant ovarian cancer have low response rates of 15 to 20% and short median progression-free survival of three to four months,” stated Kathleen Moore, M.D., Associate Professor, Department of Obstetrics and Gynecology at the Stephenson Cancer Center at the University of Oklahoma. “Based on the consistent safety and efficacy seen with mirvetuximab soravtansine reflected in these pooled analyses, particularly in those patients meeting the eligibility criteria for the pivotal study, I am very encouraged about the potential of this compound in patients with platinum-resistant ovarian cancer and look forward to continued progress with the ongoing Phase 3 FORWARD I trial.” For all 113 patients, the median number of prior regimens was 3, 85 percent had platinum-resistant disease, 67 percent had prior bevacizumab, and 22 percent had a prior poly (ADP-ribose) polymerase (PARP) inhibitor. The safety profile of the pooled population was consistent with data previously reported (2016 ASCO Annual Meeting), which consisted primarily of low grade, manageable adverse events. In this heavily pretreated group of patients, the confirmed ORR was 30 percent (95% CI 22, 39) and mPFS was 4.3 months (95% CI 3.9, 5.4). FORWARD II is a Phase 1b/2 study of mirvetuximab soravtansine in combination with Avastin®, carboplatin, Doxil® or Keytruda® in patients with FRα-positive EOC, primary peritoneal, or fallopian tube tumors. The data from these arms demonstrate mirvetuximab soravtansine may complement currently available therapies for FRα-positive EOC in a range of treatment settings, including earlier lines of therapy. The safety profiles for these combinations were manageable and as expected, based on known profiles of each agent, with no new safety signals identified. Key findings in over 60 patients from the dose escalation phase of FORWARD II are as follows: Based on the encouraging profiles of these combinations in dose escalation, ImmunoGen is moving forward with expansion cohorts for Avastin® and Keytruda® and is evaluating future studies with carboplatin combinations. “The favorable safety profile of mirvetuximab soravtansine lends itself well to combination, as evidenced by the data from FORWARD II, showing the full dose of mirvetuximab soravtansine combines with the full doses of bevacizumab (Avastin®), carboplatin, pembrolizumab (Keytruda®) and pegylated liposomal doxorubicin (Doxil®) in ovarian cancer,” stated David O’Malley, M.D., Associate Professor, Director of Gynecology Clinical Trial and Phase 1 Program, James Cancer Center and The Ohio State University Wexner Medical Center. The Phase 3 FORWARD I trial was designed based on the promising monotherapy mirvetuximab soravtansine data from the Phase 1 trial and reflects the fastest registration strategy to obtain full approval of mirvetuximab soravtansine as single-agent therapy. FORWARD I is a registration trial in which 333 patients will be randomized 2:1 and will receive either mirvetuximab soravtansine or the physicians’ choice of therapy (Doxil®, paclitaxel, or topotecan). The study is currently enrolling in North America and Europe, with more than 100 sites expected to be activated in these geographies. “The Phase 1 expansion cohort data being presented at ASCO support the potential of mirvetuximab soravtansine in the patient population eligible for FORWARD I,” said Mark Enyedy, ImmunoGen's president and chief executive officer. “With the safety and efficacy profile demonstrated by these data, we look forward to completing enrollment in FORWARD I and evaluating mirvetuximab soravtansine with other therapies, including novel agents, in earlier lines of treatment.” Title: Mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in platinum-resistant epithelial ovarian cancer (EOC) patients (pts): Activity and safety analyses in phase I pooled expansion cohorts. Presenter: Kathleen N. Moore, M.D., Associate Professor, Department of Obstetrics and Gynecology at the Stephenson Cancer Center at the University of Oklahoma Time: 1:15pm – 4:45pm CDT Location: Poster Board No.: 369, Location: Hall A Abstract: 5547 Title: Safety findings from FORWARD II: A phase 1b study evaluating the folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC) mirvetuximab soravtansine (IMGN853) in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin (PLD), or pembrolizumab in patients (pts) with ovarian cancer. Presenter: David O’Malley, M.D., Associate Professor, Director of Gynecology Clinical Trial and Phase 1 Program, James Cancer Center and The Ohio State University Wexner Medical Center Time: 1:15pm – 4:45pm CDT Location: Poster Board No.: 375, Location: Hall A Abstract: 5553 Title: FORWARD I (GOG 3011): A randomized phase 3 study to evaluate the safety and efficacy of mirvetuximab soravtansine (IMGN853) versus chemotherapy in adults with folate receptor alpha (FRα)-positive, platinum-resistant epithelial ovarian cancer (EOC), primary peritoneal cancer, or primary fallopian tube cancer. Presenter: Kathleen N. Moore, M.D., Associate Professor, Department of Obstetrics and Gynecology at the Stephenson Cancer Center at the University of Oklahoma Time: 1:15pm – 4:45pm CDT Location: Poster Board No.: 425b, Location: Hall A Abstract: TPS5607 Additional information - including presentation schedule and full abstracts - can be found www.asco.org. ImmunoGen will host a conference call on Friday, May 19 at 8:00am ET. At this briefing, ImmunoGen will discuss the data being presented at the 2017 ASCO Annual Meeting. To access the live call by phone, dial 719-325-2402; the conference ID is 4522749. The call may also be accessed through the “Investors” section of the Company's website, www.immunogen.com. Following the live webcast, a replay of the call will be available at the same location through June 1, 2017. ImmunoGen is a clinical-stage biotechnology company that develops targeted cancer therapeutics using its proprietary ADC technology. ImmunoGen's lead candidate, mirvetuximab soravtansine, is in a Phase 3 trial for FRα-positive platinum-resistant ovarian cancer, and is in Phase 1b/2 testing in combination regimens for earlier-stage disease. ImmunoGen's ADC technology is used in Roche's marketed product, Kadcyla®, in three other clinical-stage ImmunoGen product candidates, and in programs in development by partners Amgen, Bayer, Biotest, CytomX, Lilly, Novartis, Sanofi and Takeda. More information about the Company can be found at www.immunogen.com. Avastin®, Doxil®, Keytruda® and Kadcyla® are registered trademarks of their respective owners. Mirvetuximab soravtansine (IMGN853) is the first FRα-targeting ADC. It uses a FRα-binding antibody to target the ADC specifically to FRα-expressing cancer cells and a potent anti-tumor agent, DM4, to kill the targeted cancer cells. This press release includes forward-looking statements. For these statements, ImmunoGen claims the protection of the safe harbor for forward-looking statements provided by the Private Securities Litigation Reform Act of 1995. It should be noted that there are risks and uncertainties related to the development of novel anticancer products, including mirvetuximab soravtansine, including risks related to preclinical and clinical studies, their timings and results. A review of these risks can be found in ImmunoGen's Annual Report on Form 10-K for the fiscal year ended December 31, 2016 and other reports filed with the Securities and Exchange Commission.
News Article | May 25, 2017
NASHVILLE, Tenn.--(BUSINESS WIRE)--Sarah Cannon announced today that it will present cancer research insights through more than 90 presentations selected by the American Society of Clinical Oncology (ASCO®) at the 2017 Annual Meeting. Hosted in Chicago, June 2-6, the meeting brings together more than 30,000 cancer experts from around the world to review the latest research to improve the diagnosis and treatment of cancer. “2017 marks the 20th anniversary of our community-based drug development program, which was the first of its kind,” said Howard A. “Skip” Burris III, MD, President of Clinical Operations and Chief Medical Officer at Sarah Cannon. “Since our program’s inception, we have conducted more than 260 first-in-human clinical trials and made countless contributions to the advancement of cancer therapies. As we look to the future, the team at Sarah Cannon remains excited about our clinical research into how novel agents can provide an even greater benefit to patients and looks forward to sharing insights with our colleagues participating in the Annual Meeting.” Highlights of Sarah Cannon’s research include a presentation in a Clinical Science Symposium by Dr. Burris, who will discuss a study of combined inhibition of IDO1 and PD-L1 in patients with locally-advanced or metastatic solid tumors. Dr. Burris’ presentation, in the symposium titled "Check" This Out: The Step Beyond PD-1 Blockade, will take place on Sunday, June 4 during the session from 9:45-11:15 a.m. in Hall D1. Dr. Burris will also participate as a discussant in a Clinical Science Symposium, Hitting the Target: Antibody-Drug Conjugates, on Monday, June 5 from 9:45-11:15 a.m. in Hall D1, at which David Spigel, MD, Chief Scientific Officer and Director, Lung Cancer Research Program, Sarah Cannon Research Institute, will moderate the discussion. Additionally, Ian Flinn, MD, PhD, Director, Blood Cancer Research Program, Sarah Cannon Research Institute, will present an Oral Abstract on results of the BRIGHT 5-year follow-up study, a first-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP, on Saturday, June 3 in the session from 3-6 p.m. in room S100BC. This abstract has also been selected as part of the Best of ASCO® program, which will be held this summer following the meeting, and highlights significant data impacting oncology research and care. Several other Sarah Cannon investigators are presenting noteworthy studies and insights at ASCO®: For a full listing of all presentations authored by Sarah Cannon investigators, visit sarahcannon.com/asco. Additional authors presenting for Sarah Cannon at the conference include: Hendrik-Tobias Arkenau, MD, PhD, FRCP, Raid Aljumaily, MD, Todd Bauer, MD, Johanna Bendell, MD, William Donnellan, MD, Professor Paul Ellis, MD, FRACP, Gerald Falchook, MD, MS, Carol Greenlees, PhD, Camille Gunderson, MD, Erika Hamilton, MD, John Hainsworth, MD, Lowell Hart, MD, Maen Hussein, MD, Jeffrey Infante, MD, Suzanne Jones, PharmD, Kathleen Moore, MD, Manish Patel, MD, DK Strickland, MD, Professor Charles Swanton, FRCP, BSc, PhD, Judy Wang, MD and Denise Yardley, MD. The researchers represent Sarah Cannon’s global network of strategic sites: Sarah Cannon Research Institute at Tennessee Oncology, Sarah Cannon Research Institute at HealthONE, Sarah Cannon Research Institute - United Kingdom, Colorado Blood Cancer Institute, The Center for Cancer and Blood Disorders - Ft. Worth, Sarah Cannon Research Institute at Florida Cancer Specialists, Sarah Cannon Research Institute at HCA Midwest Health and The Stephenson Cancer Center at the University of Oklahoma. Sarah Cannon Research Institute is the research arm of HCA Healthcare’s global cancer institute, Sarah Cannon. Focused on advancing therapies for patients, it is one of the world’s leading clinical research organizations conducting community-based clinical trials throughout the United States and United Kingdom. Sarah Cannon’s network of strategic sites includes more than 275 physicians who engage in research. The organization has led more than 260 first-in-man clinical trials since its inception in 1993, and has been a clinical trial leader in the majority of approved cancer therapies over the last 10 years. Additionally, Sarah Cannon offers management, regulatory, and other research support services for drug development and industry sponsors as well as strategic investigator sites through its contract research organization (CRO), Sarah Cannon Development Innovations. For more information, visit sarahcannon.com.
Liao C.,University of Vermont |
Zhang Z.,The University of Oklahoma Health Sciences Center |
Kale J.,Sunnybrook Research Institute |
Kale J.,McMaster University |
And 6 more authors.
Scientific Reports | Year: 2016
Helix α9 of Bax protein can dimerize in the mitochondrial outer membrane (MOM) and lead to apoptotic pores. However, it remains unclear how different conformations of the dimer contribute to the pore formation on the molecular level. Thus we have investigated various conformational states of the α9 dimer in a MOM model-using computer simulations supplemented with site-specific mutagenesis and crosslinking of the α9 helices. Our data not only confirmed the critical membrane environment for the α9 stability and dimerization, but also revealed the distinct lipid-binding preference of the dimer in different conformational states. In our proposed pathway, a crucial iso-parallel dimer that mediates the conformational transition was discovered computationally and validated experimentally. The corroborating evidence from simulations and experiments suggests that, helix α9 assists Bax activation via the dimer heterogeneity and interactions with specific MOM lipids, which eventually facilitate proteolipidic pore formation in apoptosis regulation.
News Article | December 5, 2016
What if a smartphone app could help you avoid relapsing back to smoking even before you knew you were at risk? A researcher from the Oklahoma Tobacco Research Center at the Stephenson Cancer Center is developing smartphone-based technology to help people receive real-time tobacco cessation treatment when they are most at risk. Michael Businelle, Ph.D., Associate Professor of Family and Preventive Medicine, and Director of the Mobile Health core at the Oklahoma Tobacco Research Center, has published a paper in the Journal of Medical Internet Research that demonstrates that real-time estimation of risk for imminent smoking relapse is possible. Most tobacco cessation research in underserved communities has been conducted in clinical settings where patients are commonly asked to recall thoughts and emotions that triggered tobacco use days, or even weeks, after a smoking lapse. This data collection method can be vulnerable to errors in memory and subject to bias. Businelle enlisted socioeconomically disadvantaged smokers seeking smoking cessation treatment and asked them to use smartphones to answer questions multiple times each day. The aim was to determine whether the number of reported lapse-risk factors was greater when smoking lapse was imminent compared with moments when a lapse was not imminent. Results indicated that a lapse risk estimator that combined just six questions (i.e., urge to smoke, stress, recent alcohol consumption, interaction with someone smoking, cessation motivation, and cigarette availability) identified 80 percent of all smoking lapses within 4 hours of the first lapse. "This research may pave the way for development of smartphone-based smoking cessation treatments that automatically tailor treatment content in real-time based on presence of specific lapse triggers," said Businelle. "For instance, if a person indicates a higher than usual urge to smoke and slightly lower motivation to remain smoke free, an app could automatically address relapse risk by delivering a tailored message such as: Remember that the urge WILL pass! Even though it might seem like smoking would be pleasant right now, it will only make you feel worse later." "Interventions that identify risk for lapse and automatically deliver tailored messages or other treatment components in real-time could offer effective, low cost, and highly disseminable treatments to individuals who do not have access to other, more standard, cessation treatments," said Businelle. According to a survey by the Pew Research Center, smartphone ownership among American adults has nearly doubled since 2011, including among low-income Americans. A recent study of Businelle revealed that of 610 homeless adults in Oklahoma City 72 percent owned active mobile phones.
News Article | October 31, 2016
Nearly 7 in 10 cigarette smokers are looking for a way to quit - and many smokers have turned to e-cigarettes for help. A researcher at the Oklahoma Tobacco Research Center at the Stephenson Cancer Center has received a 5-year, $3 million R01 grant from the National Cancer Institute to study the impact of e-cigarette usage on smoking rates. The grant was awarded to Theodore Wagener, PhD, assistant professor of pediatrics, associate director for training at the Oklahoma Tobacco Research Center, and an Oklahoma TSET Research Scholar. National Cancer Institute R01 grants are the oldest and most prestigious type of cancer research grants. Wagener's research will assess how effective different types of e-cigarettes are in helping smokers switch from cigarettes to these vaping products and what impact switching has on smokers' exposure to harmful carcinogens and cancer risk. "We know that traditional combustible cigarettes, when used as intended kill one out of three smokers and is the leading cause of preventable death," Wagener said. "There may be a potential benefit if smokers switch to e-cigarettes completely, but we need additional research to understand to what extent." Since e-cigarettes have emerged on the market, the design and nicotine delivery has evolved. The newest generation of high-powered e-cigarettes is able to deliver nicotine much more like a cigarette, but with much lower levels of cancer-causing agents and no carbon monoxide. Early research demonstrates that an e-cigarette user may see some health benefit if they switch completely to the newer generation of e-cigarettes and reduce their exposure to combustible cigarette smoke. "Missing from the current literature is a long-term randomized trial assessing differences between earlier, low-powered e-cigarette devices and newer, high-powered devices on affecting smoking behaviors, nicotine addiction, and users' exposure to harmful chemicals and the resulting changes in cancer risk," said Wagener. Wagener's study will monitor levels of chemicals and toxicants in an e-cigarette user's body and inform the developing research base about the health impacts of e-cigarettes. Through this improved understanding, the study hopes to better inform the Food and Drug Administration as it considers any product-specific regulations. Historically, the e-cigarette market has been unregulated. As a TSET Research Scholar, Wagener, a clinical psychologist, has used a grant from TSET to fund research into the evolving field of e-cigarette use for more than four years. These pilot studies allowed Wagener to gather the necessary data to apply for the National Cancer Institute grant. "[E-cigarettes are] a new and evolving field for tobacco addiction, and it's important that those working to end tobacco use, regulators and consumers have the best information needed to make informed decisions," said TSET Executive Director Tracey Strader. "While the science on e-cigarettes is developing, wedo know that nicotine is not good for the developing brains of youth and young adults, and that children, pregnant women, and nonsmokers should not be exposed to the secondhand aerosol from e-cigarettes. Dr. Wagener's research will certainly benefit Oklahomans, and should have relevance for the nation, and across the globe." According to the Centers for Disease Control and Prevention, cigarette smoking is responsible for more than 480,000 deaths each year in the United States alone. The e-cigarette research is funded by NCI grant R01 CA204891.
News Article | December 28, 2016
WALTHAM, Mass.--(BUSINESS WIRE)--ImmunoGen, Inc. (Nasdaq:IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, today announced that results from the Phase 1 expansion cohort evaluating mirvetuximab soravtansine (IMGN853) in patients with folate receptor alpha (FRα)-positive platinum-resistant ovarian cancer were published in the Journal of Clinical Oncology. The data demonstrate the potential clinical benefit of mirvetuximab soravtansine for the treatment of platinum-resistant ovarian cancer. “Standard single-agent therapy for patients with platinum-resistant ovarian cancer typically has a response rate below 20% and median progression-free survival below four months,” said Kathleen Moore, M.D., Associate Professor, Stephenson Cancer Center, University of Oklahoma, and lead author of the publication. “Mirvetuximab soravtansine generated encouraging efficacy and tolerability data in the Phase 1 trial that suggest the potential to improve clinical outcomes for this patient population.” The Phase 1 expansion cohort enrolled 46 patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer whose tumors were positive for FRα. Patients were dosed with mirvetuximab soravtansine once every three weeks. Mirvetuximab soravtansine demonstrated single-agent activity in the 46-patient cohort with a 26% confirmed response rate and median progression free survival (PFS) of 4.8 months. In a subset of 23 patients with low, medium or high FRα, who had received three or fewer prior lines of therapy, there was a 39% objective response rate (ORR) and median PFS of 6.7 months. On the basis of the study findings and additional data demonstrating the importance of FRα expression levels with mirvetuximab soravtansine, the Company has designed the Phase 3 FORWARD I study to enroll patients with platinum-resistant ovarian cancer with one to three prior therapies and with medium or high FRα. This group of patients in the Phase 1 expansion cohort exhibited a 44% ORR and a median PFS of 6.7 months.1 Mirvetuximab soravtansine exhibited a manageable safety profile. Adverse events (AEs) were generally mild with the majority being grade 1 or grade 2 (least severe grades). The most commonly observed AEs were diarrhea, blurred vision, nausea, and fatigue. “These results demonstrate that mirvetuximab soravtansine is active in platinum-resistant ovarian cancer, with encouraging response rates and progression-free survival combined with a manageable safety profile,” said Anna Berkenblit, M.D., Vice President and Chief Medical Officer of ImmunoGen. “On the basis of these findings, we have moved confidently into a Phase 3 registration study evaluating this promising agent against the standard of care in the platinum-resistant setting. In addition, we are evaluating combination regimens to assess mirvetuximab soravtansine in expanded patient populations and will begin reporting data from these combinations in mid-2017.” The publication, “Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha-Targeting Antibody-Drug Conjugate, in Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: A Phase I Expansion Study,” is available on the Journal of Clinical Oncology website. Mirvetuximab soravtansine (IMGN853) is the first FRα-targeting ADC. It uses a FRα-binding antibody to target the ADC specifically to FRα-expressing cancer cells and a potent anti-tumor agent, DM4, to kill the targeted cancer cells. Mirvetuximab soravtansine is ImmunoGen’s lead program and is now in Phase 3 testing as a single agent for the treatment of platinum-resistant ovarian cancer. The candidate is also being assessed in combination regimens for both platinum-resistant and platinum-sensitive disease in Phase 1b/2 FORWARD II trial. In 2016, approximately 22,300 new cases of ovarian cancer will be diagnosed in the U.S. and more than 14,200 women will die from the disease.2 ImmunoGen estimates that 60% of ovarian cancer cases have medium or high FRα expression. Standard first-line therapy for ovarian cancer is a platinum-based regimen. Once the cancer becomes platinum-resistant, treatment options include single-agent cytotoxic therapies such as pegylated liposomal doxorubicin, paclitaxel, or topotecan. ImmunoGen is a clinical-stage biotechnology company that develops targeted cancer therapeutics using its proprietary ADC technology. ImmunoGen’s lead product candidate, mirvetuximab soravtansine, is in a Phase 3 trial for FRα-positive platinum-resistant ovarian cancer, and is in Phase 1b/2 testing in combination regimens for earlier-stage disease. ImmunoGen’s ADC technology is used in Roche's marketed product, Kadcyla®, in three other clinical-stage ImmunoGen product candidates, and in programs in development by partners Amgen, Bayer, Biotest, CytomX, Lilly, Novartis, Sanofi and Takeda. More information about the Company can be found at www.immunogen.com. Kadcyla® is a registered trademark of Genentech, a member of the Roche Group. 1Moore KN, Martin LP, Matulonis UA et al: IMGN853 (mirvetuximab soravtansine), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC): single-agent activity in platinum-resistant epithelial ovarian cancer (EOC) patients, presented at American Society of Clinical Oncology, June 2016, abstract # 5567 This press release includes forward-looking statements. For these statements, ImmunoGen claims the protection of the safe harbor for forward-looking statements provided by the Private Securities Litigation Reform Act of 1995. It should be noted that there are risks and uncertainties related to the development of novel anticancer products, including mirvetuximab soravtansine, including risks related to preclinical and clinical studies, their timings and results. A review of these risks can be found in ImmunoGen’s Annual Report on Form 10-K for the fiscal year ended June 30, 2016 and other reports filed with the Securities and Exchange Commission.
Aravindan S.,The University of Oklahoma Health Sciences Center |
Aravindan S.,Annamalai University |
Aravindan S.,Stephenson Cancer Center |
Natarajan M.,University of Texas Health Science Center at San Antonio |
And 3 more authors.
PLoS ONE | Year: 2013
Recently, we demonstrated that radiation (IR) instigates the occurrence of a NFκB-TNFα feedback cycle which sustains persistent NFκB activation in neuroblastoma (NB) cells and favors survival advantage and clonal expansion. Further, we reported that curcumin targets IR-induced survival signaling and NFκB dependent hTERT mediated clonal expansion in human NB cells. Herein, we investigated the efficacy of a novel synthetic monoketone, EF24, a curcumin analog in inhibiting persistent NFκB activation by disrupting the IR-induced NFκB-TNFα-NFκB feedback signaling in NB and subsequent mitigation of survival advantage and clonal expansion. EF24 profoundly suppressed the IR-induced NFκB-DNA binding activity/promoter activation and, maintained the NFκB repression by deterring NFκB-dependent TNFα transactivation/intercellular secretion in genetically varied human NB (SH-SY5Y, IMR-32, SK-PN-DW, MC-IXC and SK-N-MC) cell types. Further, EF24 completely suppressed IR-induced NFκB-TNFα cross-signaling dependent transactivation/translation of pro-survival IAP1, IAP2 and Survivin and subsequent cell survival. In corroboration, EF24 treatment maximally blocked IR-induced NFκB dependent hTERT transactivation/promoter activation, telomerase activation and consequent clonal expansion. EF24 displayed significant regulation of IR-induced feedback dependent NFκB and NFκB mediated survival signaling and complete regression of NB xenograft. Together, the results demonstrate for the first time that, novel synthetic monoketone EF24 potentiates radiotherapy and mitigates NB progression by selectively targeting IR-triggered NFκB-dependent TNFα-NFκB cross-signaling maintained NFκB mediated survival advantage and clonal expansion. © 2013 Aravindan et al.
Ramraj S.K.,The University of Oklahoma Health Sciences Center |
Aravindan S.,Stephenson Cancer Center |
Somasundaram D.B.,The University of Oklahoma Health Sciences Center |
Herman T.S.,The University of Oklahoma Health Sciences Center |
And 3 more authors.
Oncotarget | Year: 2016
Background: Circulating miRNAs have momentous clinical relevance as prognostic biomarkers and in the progression of solid tumors. Recognizing novel candidates of neuroblastoma-specific circulating miRNAs would allow us to identify potential prognostic biomarkers that could predict the switch from favorable to high-risk metastatic neuroblastoma (HR-NB). Results: Utilizing mouse models of favorable and HR-NB and whole miRnome profiling, we identified high serum levels of 34 and low levels of 46 miRNAs in animals with HR-NB. Preferential sequence homology exclusion of mouse miRNAs identified 25 (11 increased; 14 decreased) human-specific prognostic marker candidates, of which, 21 were unique to HR-NB. miRNA QPCR validated miRnome profile. Target analysis defined the candidate miRNAs' signal transduction flow-through and demonstrated their converged roles in tumor progression. miRNA silencing studies verified the function of select miRNAs on the translation of at least 14 target proteins. Expressions of critical targets that correlate tumor progression in tissue of multifarious organs identify the orchestration of HR-NB. Significant (> 10 fold) increase in serum levels of miR-381, miR-548h, and miR-580 identify them as potential prognostic markers for neuroblastoma progression. Conclusion: For the first time, we identified serum-circulating miRNAs that predict the switch from favorable to HR-NB and, further imply that these miRNAs could play a functional role in tumor progression.
Eifler J.B.,Vanderbilt University |
Cookson M.S.,Stephenson Cancer Center
Nature Reviews Urology | Year: 2014
After biochemical recurrence following radical prostatectomy, external beam radiation therapy (EBRT) reduces the risk of prostate-cancer-specific mortality. However, many men with a detectable serum PSA level will never experience clinical progression. New definitions of biochemical recurrence could help to determine the most appropriate candidates and time points for salvage EBRT.
Khan F.H.,The University of Oklahoma Health Sciences Center |
Pandian V.,The University of Oklahoma Health Sciences Center |
Ramraj S.,The University of Oklahoma Health Sciences Center |
Aravindan S.,Stephenson Cancer Center |
And 3 more authors.
BMC Genomics | Year: 2015
Background: MetastamiRs have momentous clinical relevance and have been correlated with disease progression in many tumors. In this study, we identified neuroblastoma metastamiRs exploiting unique mouse models of favorable and high-risk metastatic human neuroblastoma. Further, we related their deregulation to the modulation of target proteins and established their association with clinical outcomes. Results: Whole genome miRNA microarray analysis identified 74 metastamiRs across the manifold of metastatic tumors. RT-qPCR on select miRNAs validated profile expression. Results from bio-informatics across the ingenuity pathway, miRCancer, and literature data-mining endorsed the expression of these miRNAs in multiple tumor systems and showed their role in metastasis, identifying them as metastamiRs. Immunoblotting and TMA-IHC analyses revealed alterations in the expression/phosphorylation of metastamiRs' targets, including ADAMTS-1, AKT1/2/3, ASK1, AURKβ, Birc1, Birc2, Bric5, β-CATENIN, CASP8, CD54, CDK4, CREB, CTGF, CXCR4, CYCLIN-D1, EGFR, ELK1, ESR1, CFOS, FOSB, FRA, GRB10, GSK3β, IL1aα, JUND, kRAS, KRTAP1, MCP1, MEGF10, MMP2, MMP3, MMP9, MMP10, MTA2, MYB, cMYC, NF2, NOS3, P21, pP38, PTPN3, CLEAVED PARP, PKC, SDF-1β, SEMA3D, SELE, STAT3, TLR3, TNFaα, TNFR1, and VEGF in aggressive cells ex vivo and in a manifold of metastatic tumors in vivo. miRNA mimic (hsa-miR-125b, hsa-miR-27b, hsa-miR-93, hsa-miR-20a) and inhibitor (hsa-miR-1224-3p, hsa-miR-1260) approach for select miRNAs revealed the direct influence of the altered metastamiRs in the regulation of identified protein targets. Clinical outcome association analysis with the validated metastamiRs' targets corresponded strongly with poor overall and relapse-free survival. Conclusions: For the first time, these results identified a comprehensive list of neuroblastoma metastamiRs, related their deregulation to altered expression of protein targets, and established their association with poor clinical outcomes. The identified set of distinctive neuroblastoma metastamiRs could serve as potential candidates for diagnostic markers for the switch from favorable to high-risk metastatic disease. © 2015 Khan et al.