Specialized Programs Of Research Excellence Research Articles

Abstract 7315: Collaboration between NIDCR and NCI promotes innovative research in head and neck cancers

Abstract The Oral and Salivary Cancer Biology Program at National Institute of Dental and Craniofacial Research (NIDCR) supports research activities that improve early detection and treatment of cancers of the oral cavity, pharynx, and salivary glands. We promote basic science research on the regulatory pathways and transformation process of pre-cancerous lesions to primary and metastatic tumors, as well as translational science activities to develop novel technologies and therapeutics for the diagnosis, prognosis, and treatment of cancers. NIDCR and National Cancer Institute (NCI) have established long-term collaborations to promote and co-manage awards funded through The Immuno-Oncology Translational Network (IOTN) of the Cancer Moonshot program, Specialized Programs of Research Excellence (SPOREs), and Early Detection Research Network (EDRN) program. NIDCR and NCI have co-developed Notice of Special Interest (NOSI) and Request for Application (RFA) on Advancing Head and Neck Cancer Early Detection Research (AHEAD), which co-funded seven research projects to discover and develop molecular signatures of early detection and diagnosis of HPV positive and negative head and neck cancer (HNC). To further strengthen NIDCR and NCI collaboration, we jointly organized the symposium to promote HNC early detection and biomarker identification at the American Head and Neck Society (AHNS) 11th International Conference on Head and Neck Cancer in July 2023. In addition, NIDCR has organized a symposium to promote HNC research at the 2024 annual meeting of American Association for Dental, Oral, and Craniofacial Research (AADOCR) to celebrate the 75th anniversary of NIDCR. This AADOCR symposium will feature the collaboration between NIDCR with NCI in the Cancer Moonshot program focusing on immunoprevention and immunotherapy, HNC early detection and biomarker research in AHEAD and EDRN, and investigation of HPV positive and negative HNC and clinical translational research under SPORE. At this 2024 AACR annual meeting, NIDCR and NCI program directors will present the collaborations and funding opportunities between NIDCR and NCI, focusing on early cancer detections and biomarker discovery and validation. Collaboration between NIDCR with NCI provides a unique opportunity to promote basic, translational, and clinical research in advancing HNC early detection to benefit cancer patients. Citation Format: Zhong Chen, Wendy Wang. Collaboration between NIDCR and NCI promotes innovative research in head and neck cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7315.

MP59-10 EVALUATING EX VIVO INNATE IMMUNE TRAINING AS A PREDICTIVE MEASURE OF RESPONSIVENESS TO BCG IMMUNOTHERAPY IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 May 2022MP59-10 EVALUATING EX VIVO INNATE IMMUNE TRAINING AS A PREDICTIVE MEASURE OF RESPONSIVENESS TO BCG IMMUNOTHERAPY IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER Song Jiang, Gil Redelman-Sidi, Eugene J. Pietzak, Bernard H. Bochner, and Michael Glickman Song JiangSong Jiang More articles by this author , Gil Redelman-SidiGil Redelman-Sidi More articles by this author , Eugene J. PietzakEugene J. Pietzak More articles by this author , Bernard H. BochnerBernard H. Bochner More articles by this author , and Michael GlickmanMichael Glickman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002642.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Intravesical instillation of the live attenuated mycobacterium Bacillus Calmette-Guerin (BCG) remains the most effective adjuvant therapy for non-muscle invasive bladder cancer. An increasing body of evidence suggests that the innate immune system has characteristics that involve a heterologous memory of past insults through a process involving epigenetic reprogramming, termed trained immunity. We seek to investigate the potential for innate immune training as a pre-treatment predictor of BCG-response. METHODS: A prospective biospecimen collection was performed on venous blood from non-muscle invasive bladder cancer patients prior to receiving intravesical BCG therapy. To investigate the role of trained immunity in primary monocytes, cells were isolated from peripheral blood mononuclear cells (PBMC) by plate adhesion. In vitro training was performed via stimulation with 10:1 MOI BCG. Cells were then washed in media and allowed to rest 6 days. Subsequently, cells were stimulated with lipopolysaccharide (a TLR4 agonist). Cell free supernatant was measured for TNF-alpha production by enzyme-linked immunosorbent assay. RESULTS: In vitro training of primary monocytes induced an increase in proinflammatory cytokine production upon re-stimulation. This phenotype was dose dependent on stimulation with LPS and confined to the monocyte population. In our in vitro training experiments, there was demonstrable interpatient variability seen pre-BCG exposure in a cohort of NMIBC patients. These results will be correlated with future long term BCG response in this prospective cohort. CONCLUSIONS: We have developed a reliable assay to measure ex vivo innate immune training potential in primary monocytes collected from patient samples. These findings will be correlated with prospective clinical data on BCG responsiveness and recurrence free survival. Such insight will have potential clinical impact on the development of biomarkers and clinical assays that could predict immune responsiveness to BCG a priori, as well as identify possible immunological adjuvants that could enhance the effect of intravesical BCG. Source of Funding: NCI Specialized Programs of Research Excellence (SPORE) in Bladder Cancer P50 CA221745 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e1005 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Song Jiang More articles by this author Gil Redelman-Sidi More articles by this author Eugene J. Pietzak More articles by this author Bernard H. Bochner More articles by this author Michael Glickman More articles by this author Expand All Advertisement PDF DownloadLoading ...

NTCP Modeling of Late Effects for Head and Neck Cancer: A Systematic Review.

NTCP Modeling of Late Effects for Head and Neck Cancer: A Systematic Review.

Treatment with a 5-day versus a 10-day schedule of decitabine in older patients with newly diagnosed acute myeloid leukaemia: a randomised phase 2 trial

Hypomethylating agents, such as decitabine, are the standard of care for older patients with newly diagnosed acute myeloid leukaemia. Single-arm studies have suggested that a 10-day schedule of decitabine cycles leads to better outcomes than the usual 5-day schedule. We compared the efficacy and safety of these two schedules. Eligible patients were aged 60 years or older with acute myeloid leukaemia but unsuitable for intensive chemotherapy (or <60 years if unsuitable for intensive chemotherapy with an anthracycline plus cytarabine). The first 40 patients were allocated equally to the two treatment groups by computer-generated block randomisation (block size 40), after which a response-adaptive randomisation algorithm used all previous patients' treatment and response data to decide the allocation of each following patient favouring the group with superior response. Patients were assigned to receive 20 mg/m2 decitabine intravenously for 5 or 10 consecutive days as induction therapy, every 4-8 weeks for up to three cycles. Responding patients received decitabine as consolidation therapy on a 5-day schedule for up to 24 cycles. We assessed a composite primary endpoint of complete remission, complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete haematological recovery (CRi) achieved at any time and assessed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01786343. Between Feb 28, 2013, and April 12, 2018, 71 patients were enrolled. 28 received decitabine for 5 days and 43 for 10 days, and all were assessable for efficacy and safety. The primary endpoint was achieved in similar proportions of patients in the two treatment groups (12 [43%] of 28 in the 5-day schedule group, 95% credible interval 26-60, and 17 [40%] of 43 in the 10-day schedule group, 26-54, p=0·78; difference 3%, -21 to 27). Total follow-up was 38·2 months, during which the median duration of overall survival was 5·5 months (IQR 2·1-11·7) in the 5-day group and 6·0 months (1·9-11·7) in the 10-day group. 1-year overall survival was 25% in both groups. Complete remission, CRp, CRi, and overall survival did not differ between groups when stratified by cytogenetics, de-novo versus secondary or therapy-related acute myeloid leukaemia, or TP53mut status. The most common grade 3-4 adverse events were neutropenic fever (seven patients [25%] in the 5-day group and 14 [33%] in the 10-day group) and infection (five [18%] and 16 [37%], respectively). One patient (4%) died from sepsis in the context of neutropenic fever, infection, and haemorrhage in the 5-day group, and in the 10-day group six patients (14%) died from infection. Early mortality was similar in the two groups. In older patients with newly diagnosed acute myeloid leukaemia, efficacy and safety did not differ by the 5-day or the 10-day decitabine schedule. University of Texas MD Anderson Cancer Center and National Cancer Institute Specialized Programs of Research Excellence.

Abstract IA01: Recent advances in studying EGFR and its ligands in colorectal cancer

Abstract At Vanderbilt, we have fashioned a three-pronged approach to study colorectal cancer (CRC): from in vitro studies to those both in mouse and humans. In vitro, we have analyzed trafficking and cell-surface delivery of EGFR and its ligands in a battery of CRC cell lines that retain the ability to form uniform polarizing monolayers on Transwell filters. In the mouse, we have discovered that the pan-ERBB inhibitor, LRIG1, marks a largely quiescent population of colonic stem cells distinct from LGR5 and that administration of tamoxifen to Lrig1-CreET2;Apcfl/+ mice eliminates one allele of Apc and results in highly penetrant, multiple, histologically advanced adenomas in the distal colon 50-100 days later; these adenomas show the expected loss of the 2nd Apc allele. Later this month, we will submit the 4th renewal of our GI Specialized Programs of Research Excellence (SPORE) that focuses on CRC. An advance in each of these areas will be discussed. Based on our trafficking studies, we have discovered that EGFR ligands can be released in endosome-derived small vesicles called exosomes. The ligands are signaling competent and bind to EGFR on recipient cells. We have termed this new mode of signaling, Exosomal Targeted Receptor Activation (ExTRAcrine). We have recently advanced this work to studying EGFR in exosomes isolated from mouse and human plasma using a method we have developed, fluorescence-based vesicle sorting (FAVS). Second, a limitation to studying EGFR in the mouse is the lack of robust reagents to monitor EGFR by immunohistochemistry. To circumvent this limitation, we have used CRISPR gene editing to target the endogenous mouse locus to create a chimeric EGFR-Emerald (green) reporter mouse. We will present data showing the value of this mouse in monitoring EGFR in the normal colon and in colonic tumors generated in our Lrig1-CreERT2;Apcfl/+ mouse model. Finally, we have developed a new 3D system to study CRC. Using this system, we have discovered a novel mode of cetuximab resistance and will show its relevance to human CRC. 1. Singh B, Coffey RJ. Trafficking of epidermal growth factor receptor ligands in polarized epithelial cells. Annu Rev Physiol 76: 275-300, 2014. PMC4180094. 2. Higginbotham JN, Demory Beckler M, Gephart JD, Franklin JL, Bogatcheva G, Kremers GJ, Piston DW, Ayers GD, McConnell RE, Tyska MJ, Coffey RJ. Amphiregulin exosomes increase cancer cell invasion. Curr Biol 21: 779-86, 2011. PMC3417320. 3. Higginbotham JN, Zhang Q, Jeppesen DK, Scott AM, Manning HC, Ochieng J, Franklin JL, Coffey RJ. Identification and characterization of EGF receptor in individual exosomes by fluorescence-activated vesicle sorting. J Extracell Vesicles 5: 29254, 2016. PMC4921784. 4. Powell AE, Wang Y, Li Y, Poulin EJ, Means AL, Washington MK, Higginbotham JN, Juchheim A, Prasad N, Levy SE, Guo Y, Shyr Y, Aronow BJ, Haigis KM, Franklin JL, Coffey RJ. The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 149: 146-58, 2012. PMCPMC3563328. 5. Powell AE, Vlacich G, Zhao ZY, McKinley ET, Washington MK, Manning HC, Coffey RJ. Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis. Am J Physiol Gastrointest Liver Physiol 307: G16-23, 2014. PMC4080164. 6. Wang Y, Shi C, Lu Y, Poulin EJ, Franklin JL, Coffey RJ. Loss of Lrig1 leads to expansion of Brunner glands followed by duodenal adenomas with gastric metaplasia. Am J Pathol 185: 1123-34, 2015. PMC4380843. 7. Poulin EJ, Powell AE, Wang Y, Li Y, Franklin JL, Coffey RJ. Using a new Lrig1 reporter mouse to assess differences between two Lrig1 antibodies in the intestine. Stem Cell Res 13: 422-430, 2014. PMC638408. 8. Kondo J, Powell AE, Wang Y, Musser MA, Southard-Smith EM, Franklin JL, Coffey RJ. LRIG1 Regulates Ontogeny of Smooth Muscle-Derived Subsets of Interstitial Cells of Cajal in Mice. Gastroenterology 149: 407-19 e8, 2015. PMC4527342. Citation Format: Robert J. Coffey. Recent advances in studying EGFR and its ligands in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA01.

Abstract LB-183: Metformin use does not increase survival of pancreatic cancer patients: A cautionary lesson

Abstract Background: Epidemiologic studies have suggested that metformin use is associated with cancer death reduction. The results for pancreatic ductal adenocarcinoma (PDAC) are inconsistent. Retrospective studies of cancer survival may potentially have unintended biases; due to complexities of diabetes management, metformin use exposure is commonly categorized as simply “yes/no.” Nevertheless, in part based on epidemiologic studies, there are at least 20 open cancer clinical trials that include metformin in a treatment arm. We aimed to study metformin use and survival of patients with PDAC, addressing potential inherent biases. Methods: A retrospective cohort study for the years 2000-2011 was conducted using the patient database of the Mayo Clinic Specialized Programs of Research Excellence (SPORE) in Pancreatic Cancer. 1,360 PDAC patients (59% male; mean age 67) with diabetes were studied; overall survival was the primary outcome. Initiation and duration of metformin use was carefully abstracted from medical records. Patients were categorized into 5 groups based on metformin initiation: (A) Never used, n = 908 (reference group); (B) Metformin started &amp;gt;1 year prior to PDAC diagnosis, n = 84; (C) Metformin started within 1 year prior to PDAC diagnosis, n = 212; (D) Metformin started &amp;lt;30 days post-PDAC diagnosis, n = 104; (E) Metformin started &amp;gt;30 days post PDAC diagnosis, n = 34. Hazard ratios (HR) and 95% confidence intervals (C.I.) for survival differences between groups were computed using Cox proportional hazards models, adjusting for age, sex, disease stage, body mass index, and diagnosis year group. Results: Median survival of patients in Groups B-E was 292 days compared to 308 for Group A; this was not significantly different. However, among 413 resectable patients, metformin users appeared to survive longer than non-users (782 vs. 612 days, p = 0.07). Survival in each group was 308, 245, 249, 243 and 818 days, respectively. Because Group E had already survived &amp;gt;30 days, a bias existed. With Group E excluded, there was no survival difference among the other 4 groups (p = 0.18). Compared to Group A, HR and 95% C.I. for metformin use were 1.08 (0.85-1.37), 0.99 (0.85-1.17), 1.04 (0.83-1.31) and 0.49 (0.33-0.74), for Group B-E, respectively. Conclusions: Our thorough analysis suggests that metformin use does not improve survival of patients with PDAC. The benefit of metformin was observed only in patients who started metformin post-PDAC diagnosis; however, there is an inherent survival bias in this group of patients. Studies of medication exposure and cancer survival warrant very careful and detailed data collection. Researchers should exercise caution when initiating clinical trials based on retrospective epidemiologic studies. Citation Format: Roongruedee Chaiteerakij, David B. Zhen, Patrick A. Burch, Kari G. Chaffee, William R. Bamlet, Ann L. Oberg, Lewis R. Roberts, Gloria M. Petersen. Metformin use does not increase survival of pancreatic cancer patients: A cautionary lesson. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-183. doi:10.1158/1538-7445.AM2015-LB-183

The 6-item CAPRA-S score predicted cancer recurrence after radical prostatectomy

Source Citation Punnen S, Freedland SJ, Presti JC Jr, et al. Multi-institutional validation of the CAPRA-S score to predict disease recurrence and mortality after radical prostatectomy. Eur Urol. 2013;S0302-2838:00352-7. 23587869

Perspective: Opportunities in recalcitrant, rare and neglected tumors

The ‘Recalcitrant Cancer Research Act of 2012’ defines recalcitrant cancers as having a 5-year survival rate of <20% and estimated to cause the death of at least 30,000 individuals in the US each year. Cancers specifically mentioned in the act are lung and pancreatic cancers. In addition to recalcitrant tumors, rare tumors are often neglected in the drug discovery arena. Sarcomas are ~1% of cancers. The NCI Specialized Programs of Research Excellence (SPOREs) provide disease-focused cancer center grants specifically to accelerate the impact of laboratory research on the treatment of patients. There are 3 SPOREs focused on pancreatic cancer, 7 SPOREs focused on lung cancer and 1 SPORE focused on sarcoma. Through the Developmental Therapeutics Program (DTP), NCI maintains the infrastructure and expertise for the operation of cell-free and cell-based high-, medium- and low-throughput assays. The current effort is on sarcoma, SCLC and pancreatic lines. The DTP functional genomics laboratory provides molecular analyses including gene expression microarrays, exon arrays, microRNA arrays, multiplexing gene assays, plus others as tools to identify potential drug targets and to determine the role of selected genes in the mechanism(s) of drug action and cellular responses to stressors. The DTP tumor microenvironment laboratory focuses on the discovery of targets and the development of therapeutic strategies targeting the tumor microenvironment and physiological abnormalities of tumors resulting from environmental factors or alterations in metabolic enzymes. The DTP maintains a group focused on determining the mechanism(s) of action and identifying potential surrogate markers of activity for select compounds integrating proteomics, transcriptomics and molecular biology platforms. In conclusion, the NCI has active SPORE programs and an internal effort focused on recalcitrant, rare and neglected cancers which are generating data toward improving treatment of these difficult diseases.

Synthetic Lethal Interactions Between EGFR and PARP Inhibition in Triple Negative Breast Cancer

ACKNOWLEDGMENTS *Corresponding author (ESY, eyang@uab.edu). This work was supported by a career development award from the UAB Specialized Programs of Research Excellence (SPORE) in breast cancer (5P50CA089019-10), a Translational Scholar Award from Sidney Kimmel Foundation, the State of Alabama Investment Pool for Action (IMPACT) Award from the University of Alabama at Birmingham School of Medicine, and developmental support from the Comprehensive Cancer Center and Department of Radiation Oncology at the University of Alabama at Birmingham School of Medicine (to ESY). CONCLUSIONS

Accelerating Identification and Regulatory Approval of Investigational Cancer Drugs

THE DEVELOPMENT OF NEW DRUGS IS BECOMING INCREASingly expensive—and oncology drugs, in particular, have a high clinical failure rate. The current return on capital investment in drug development by US public companies was recently reported as less than 0.3%. The low probability of success, coupled with rapidly accelerating expenses, means that drug development is increasingly the purview of only 2 organization types: a few large companies and myriad small, venture capital–funded start-up firms. At an estimated cost of $1.0 billion to $1.8 billion for developing a successful new drug, funding for such risky ventures, particularly for oncology drugs, may diminish. The high cost of oncology drug development is not only an issue of finance but also occurs because many cancers are heterogeneous. The inability (or lack of explicit effort) to identify and incorporate specific disease subtypes into trial design inhibits the development of more cost-effective drugs that target specific populations. The major losers in this inefficient approach are the patients who would benefit from new treatments. This dilemma necessitates new clinical trial designs that account for the heterogeneity and complexity of the specific disease at the outset and fully recognize that the problem is better solved through collaboration vs competition. Precompetitive collaborations will serve to advance these goals and enable a more efficient model of drug discovery. At a recent workshop entitled “The Role of Precompetitive Collaborations in Advancing Regulatory Science and Enabling Evidence-Based Review,” stakeholders representing various constituencies involved in new drug development discussed the benefits of precompetitive collaboration in creating pathways for regulatory approval for drugs that successfully demonstrate a significant improvement in surrogate end points in screening phase 2 trials. Precompetitive collaboration involves cooperation among traditionally competitive stakeholders, who work together on projects that advance mutual interest without providing a competitive advantage for any single organization. Such collaboration can allow institutions to pool resources and expertise for the multidisciplinary research necessary to accelerate drug development and allow more rapid sharing of successes and failures, furthering progress toward a shared goal of identifying classes of agents and the subtypes of diseases for which they are effective. Asanexample,theI-SPY2TRIAL(InvestigationofSerialStudies to Predict Your Therapeutic Response With Imaging and MolecularAnalysis)modelwasdevelopedasaprecompetitive collaborationamongmultiple academic,pharmaceutical, biotechnology,governmental, andadvocate stakeholders. I-SPY2 uses an adaptive design, modular trial process for the purpose of concurrently screening phase 2 agents in women with stage 2 and 3 breast cancer who are at increased risk for cancer recurrence and death despite standard adjuvant treatment. In this setting, pathologic complete response (pCR), measuring thecompletedisappearanceof tumor in response to treatment prior tosurgical excision,maypredict recurrence-free survival (RFS)—a current regulatory standard for Food and Drug Administration(FDA)approval.Thetrialevaluatesdrugs,byclass, in the context of standard and emerging biomarkers to determinewhetherthosedrugscanimprovethechanceofpCRcompared with standard therapy. The trial is powered to detect a doubling of the log odds of pCR within a biomarker signature. Drugs that are considered successful when they complete the trial are predicted to have an 85% likelihood of success in a confirmatory randomized neoadjuvant trial of 300 patients with tumor that have the drug’s newly identified biomarker signature. I-SPY2wasbasedonearlierworkinI-SPY1(CALGB150007 and 150012/ACRIN 6657), a collaboration of the Specialized Programs of Research Excellence (SPOREs) and the National Cancer InstituteCooperativeGroups.Prior to starting I-SPY2, the consortium worked for several years to refine the clinical approach and surrogates for RFS at 3 years. The group also developed an infrastructure for data sharing and the methods to miniaturize molecular assays and maximize the number of assays that could be performed on small amounts of tissue. The consortiumbaseditscriteria foreligibilityontheresultsofI-SPY 1, which shows that, in biologically high-risk palpable breast cancer, pCR differs by subset and is more predictive by subset than it isoverall, demonstrating that theextentofoutcomeadvantage conferred by pCR is specific to tumor biology.

Patient Advocacy in Research

Patient Advocacy in Research

Melanoma biomarker expression in melanocytic tumor progression: a tissue microarray study

The elucidation of protein biomarkers that are differentially expressed in human melanocytic tumors during tumor progression may lead to the identification of therapeutic targets and novel diagnostic tests. In a meeting chaired by Dr Mihm, a list of biomarkers of interest in melanoma was compiled. The specialized programs of research excellence (SPORE) in skin cancer developed a melanocytic tumor progression tissue microarray (TMA) to evaluate these candidate biomarkers. In addition to markers reported elsewhere, we evaluated c-Kit, MITF, MART1, HMB-45 and bcl-2. The TMA contains 480 cores of benign nevi, primary cutaneous melanoma and melanoma metastases. Immunohistochemical detection of melanoma biomarkers, including c-Kit, MITF, MART-1, HMB-45 and bcl-2 was performed. Intense nuclear staining for MITF protein was observed in 83% of nevi, 56% of primary melanomas and 23% of metastases. Bcl-2 expression was reduced with progression to metastasis (detected in 86, 89 and 52% of nevi, primaries and metastases, respectively), contrary to MART-1, which showed no differential expression (74, 85 and 84%). HMB-45 was observed in 18% of nevi and most (72 and 75%) primary melanomas and metastases. c-Kit protein increased with progression from nevi to primary tumor (10 and 77% of cases, respectively) and was decreased in metastases (26% of cases). Through a collaboration of the Skin SPOREs sponsored by the Organ Systems Branch of the National Cancer Institute (NCI), we identified a list of melanoma biomarkers of interest, developed a melanocytic tumor progression TMA and completed a coordinated analysis of these biomarkers. This TMA has served as a powerful validation tool for newly identified and known melanoma biomarkers by revealing trends in expression during tumor progression and by confirming the heterogeneity of biomarker expression in cutaneous melanocytic tumors.

New foundation focused on the early detection of cancer

New foundation focused on the early detection of cancer

NIH Grant Watch

BioTechniquesVol. 44, No. 3 NIH Grant WatchOpen AccessNIH Grant WatchD. McCormick† & B. Perry†D. McCormick††D. McCormick is editorial director ofBioTechniques. B. Perry is president of NIH Sales, Rockville, MD.Search for more papers by this author & B. Perry††D. McCormick is editorial director ofBioTechniques. B. Perry is president of NIH Sales, Rockville, MD.Search for more papers by this authorPublished Online:16 May 2018https://doi.org/10.2144/000112774AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInRedditEmail EpigeneticsThis month, BioTechniques and NIH Sales reviewed the 67,648 grants made by the NIH during 2007 to see how many planned epigenetic studies. Of the abstracts searched, 484 included discussions of epigenesis; these proposals won $195 million in funding. Unsurprisingly, the National Cancer Institute awarded 44% of the funds, followed at a distance by the National Institute of General Medical Sciences (10.1%), the National Institute of Child Health and Development (7.5%), and the National Institute of Environmental Health Sciences (6.1%). Five of the grants, including three of the ten largest, proposed Specialized Programs of Research Excellence (SPOREs). Featured here are recipients of the largest grants.Cancer Center Support Grant $3,387,817.00(5P30CA030199-27, National Cancer Institute, 5/1/2007)Kristiina Vuori (Burnham Institute for Medical Research, La Jolla, CA)Goal: To continue progress in the Center's six program areas: 1) cell adhesion and extracellular matrix; 2) glycobiology; 3) oncodevelopmental biology; 4) cancer genetics and epigenetics; 5) signal transduction research; and 6) apoptosis and cell death. To encourage the use of small molecules as probes for studies of normal and cancer cell biology, and to develop lead compounds that might serve as candidates for further development as anticancer drugs.Barrett's Esophagus: Predictors of Progression $2,428,948.00(2P01CA091955-06, National Cancer Institute, 8/13/2007)Brian J. Reid (Fred Hutchinson Cancer Research Center, Seattle, WA)Goal: To investigate Barrett's esophagus (BE), a unique in vivo model of human epithelial neoplasia and the only established precursor to esophageal adenocarcinoma (EA), a highly lethal malignancy whose incidence has increased more than 600 percent in three decades.University of Texas M.D. Anderson Cancer Center SPORE in Leukemia $2,363,102.00(5P50CA100632-05, National Cancer Institute, 6/19/2007)Jean-Pierre J. Issa (University of Texas M.D. Anderson Cancer Center, Houston, TX)Goal: In collaboration with the University of Texas Southwest Medical Center, to cultivate significant translational research into the biologic, genetic, and clinical aspects of leukemia to improve understanding and therapy. The program includes projects in: epigenetics of drug resistance in acute leukemia; adoptive cellular therapy for myeloid leukemia; concerted blockade of oncoprotein activity; PPAR-gamma nuclear transcription factor, a novel target for leukemia therapy; molecular epidemiology of AML risk and progression; and response of AML patients to FLT3 inhibitors.Johns Hopkins SPORE in Lung Cancer $2,359,850.00(5P50CA058184-13, National Cancer Institute, 6/21/2007)Stephen B. Baylin (Johns Hopkins University, Baltimore, MD)Goal: To provide new means for preventing, detecting, and treating lung cancers of all types. The program includes studies of epigenetic molecular markers with promise in risk assessment, early detection, gauging, and prognosis.University of Texas Southwest Medical Center SPORE in Lung Cancer $2,353,640.00(5P50CA070907-10, National Cancer Institute, 9/17/2007)John D. Minna (University of Texas Southwest Medical Center, Dallas, TX)Goal: In collaboration with the University of Texas M.D. Anderson Cancer Center, to identify and understand the molecular “hallmarks of lung cancer” and translate this information into the clinic. The program includes: identification and exploitation of key lung cancer tumor suppressor genes; identification of inherited and acquired factors that increase risk; identification of abnormalities in apoptosis and invasion during lung cancer pathogenesis; understanding of signaling pathways presenting new targets for chemoprevention and therapy; and development of therapies directed against telomerase.Center for Genomic Experimentation and Computation $2,336,126.00(5P50HG002370-05, National Human Genome Research Institute, 8/16/2007)Roger Brent (Molecular Sciences Institute, Berkeley, CA)Goal: To establish a center that combines functional genomic and computational research to model a prototype signal transduction pathway. The program will focus on gaining the ability to predict the behavior of a well-studied biological regulatory system (the G-protein receptor coupled signal-transduction pathway governing the response of haploid MATa S. cerevisiae to the mating pheromone, a factor) at the level of individual cells.FiguresReferencesRelatedDetails Vol. 44, No. 3 Follow us on social media for the latest updates Metrics Downloaded 136 times History Published online 16 May 2018 Published in print March 2008 Information© 2008 Author(s)PDF download

Promise and problems of translational research

The potential for synergistic collaboration to increase progress in the state of the science for ovarian cancer is provided by services and programs developed and supported by National Cancer Institute (NCI), the Gynecologic Oncology Group (GOG) and the Specialized Programs of Research Excellence (SPOREs). The capabilities span from drug discovery to phase III clinical trials, all of which are available for collaborative interaction with each other and with individual researchers.

An informatics model for tissue banks – Lessons learned from the Cooperative Prostate Cancer Tissue Resource

BackgroundAdvances in molecular biology and growing requirements from biomarker validation studies have generated a need for tissue banks to provide quality-controlled tissue samples with standardized clinical annotation. The NCI Cooperative Prostate Cancer Tissue Resource (CPCTR) is a distributed tissue bank that comprises four academic centers and provides thousands of clinically annotated prostate cancer specimens to researchers. Here we describe the CPCTR information management system architecture, common data element (CDE) development, query interfaces, data curation, and quality control.MethodsData managers review the medical records to collect and continuously update information for the 145 clinical, pathological and inventorial CDEs that the Resource maintains for each case. An Access-based data entry tool provides de-identification and a standard communication mechanism between each group and a central CPCTR database. Standardized automated quality control audits have been implemented. Centrally, an Oracle database has web interfaces allowing multiple user-types, including the general public, to mine de-identified information from all of the sites with three levels of specificity and granularity as well as to request tissues through a formal letter of intent.ResultsSince July 2003, CPCTR has offered over 6,000 cases (38,000 blocks) of highly characterized prostate cancer biospecimens, including several tissue microarrays (TMA). The Resource developed a website with interfaces for the general public as well as researchers and internal members. These user groups have utilized the web-tools for public query of summary data on the cases that were available, to prepare requests, and to receive tissues. As of December 2005, the Resource received over 130 tissue requests, of which 45 have been reviewed, approved and filled. Additionally, the Resource implemented the TMA Data Exchange Specification in its TMA program and created a computer program for calculating PSA recurrence.ConclusionBuilding a biorepository infrastructure that meets today's research needs involves time and input of many individuals from diverse disciplines. The CPCTR can provide large volumes of carefully annotated prostate tissue for research initiatives such as Specialized Programs of Research Excellence (SPOREs) and for biomarker validation studies and its experience can help development of collaborative, large scale, virtual tissue banks in other organ systems.

High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype

Focal adhesion kinase (FAK) is a protein tyrosine kinase expressed in invasive breast cancer that regulates antiapoptotic signaling. We have examined FAK expression by immunohistochemistry using anti-FAK 4.47 in breast tumor samples from a large population-based, case–control study of women participating in the University of North Carolina Breast Specialized Programs of Research Excellence (SPORE), Carolina Breast Cancer Study. In this population, 629 formalin-fixed, paraffin-embedded tissue sections were stained for FAK and scored as high (3+ or 4+ intensity and ≥90% positive cells) or otherwise. High FAK expression was associated with poor prognostic indicators including high mitotic index (>10 mitoses per 10 consecutive high-power fields), nuclear grade 3, architectural grade 3, estrogen and progesterone receptor negative, and HER-2/neu overexpressed using CB11 antibody. The association of high FAK expression with HER-2/neu overexpression lends further support that HER-2/neu and FAK collaborate to promote tumorigenesis. The presence of strong FAK expression in many high grade, estrogen- and progesterone-negative breast carcinomas indicates that FAK may be an attractive target for therapeutic intervention.