Potential Opportunities for Collaboration with Pancreatic U01s

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Dayna Short
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1 Potential Opportunities for Collaboration with Pancreatic U01s Sudhir Srivastava, PhD, MPH Chief, Cancer Biomarkers Research Group Division of Cancer Prevention

2 Background Recalcitrant Cancer Research Act 2012 Calls on NCI to develop a scientific framework for research on recalcitrant cancers Pancreatic ductal adenocarcinoma (PDAC) is a recalcitrant cancer as defined by its 5-year relative survival rate of <5% that translates into the loss of almost 40,000 lives per year NCI s 2014 Scientific Framework for PDAC Recommended evaluating longitudinal screening protocols concomitant with development of new molecular and imaging biomarkers for patients at high risk for PDAC

Pancreatic Cancer: Moving from 4 th to 2 nd Place Pancreatic cancer is the only one of the top 5 deadliest cancers for which deaths are projected to INCREASE As early as 2015, pancreatic

3 Pancreatic Cancer: Moving from 4 th to 2 nd Place Pancreatic cancer is the only one of the top 5 deadliest cancers for which deaths are projected to INCREASE As early as 2015, pancreatic cancer is projected to surpass breast and colorectal cancers and become the 2 nd leading cause of cancer death lung pancreas colorectal prostate breast Copyright 2013 Pancreatic Cancer Action Network

4 Challenges for Screening Early PDAC and PanINs Not detectable by current imaging methods Current biomarkers lack sufficient sensitivity and specificity IPMNs and MCNs Difficult to distinguish benign from precancerous lesions Increasingly identified by abdominal imaging for nonspecific symptoms

5 Challenges with Current Biomarkers for Early Detection Current biomarkers lack sufficient sensitivity and specificity to accurately detect early stage PDAC and PanIN-3 CA19-9 lacks sensitivity and specificity for early stage PDAC, but is considered a gold standard for pancreatic cancer diagnosis Current biomarkers cannot accurately distinguish benign from precancerous lesions Lack of longitudinal specimens on targetable lesions

6 History: Validation of Cancer Markers is Disappointing (not reproducible) Non-invasive markers: Holy Grail of cancer diagnosis carcinoembryonic antigen (CEA) CA125 CA19-9 magnetic resonance imaging of blood Lessons from CEA initial results (PNAS): ~100% sensitivity, specificity for colon cancer high expectations followed by disappointment experience led to rules of evidence to evaluate diagnostic tests (Ransohoff and Feinstein. NEJM 1978)

reporting Lack of appropriate specimens and reagents Variations in interpretation Bias, chance and overfitting Lack

7 Pancreatic Cancer Biomarkers: Missing the Mark Biology of early disease not fully explored Differences in analytical techniques Differences in statistical methods (study designs) Unintentional selective reporting Incomplete protocol reporting Lack of appropriate specimens and reagents Variations in interpretation Bias, chance and overfitting Lack of appropriate controls Lack of knowledge in translation of laboratory tests into clinical tests Lack of Collaboration 7

8 Models of Collaborations 1. One-to-One (abundant in R01, R21, PO1, etc) 2. One-to-Many (abundant in R01, R21, PO1, etc.) 3. Many-to-Many (Cooperative Groups, U01s)

Existing NCI Programs on Pancreatic Cancer EDRN Alliance of Glycobiologists MCL/CIB CPDPC/ PCDC PCA

Prospective Screening Cancer Control MCL Molecular and Cellular Characterization of Screen-Detected

Early Detection Research Network BiomarkerBase Commercial database of biomarkers tested in a

9 Existing NCI Programs on Pancreatic Cancer EDRN Alliance of Glycobiologists MCL/CIB CPDPC/ PCDC PCA Preclinical Exploratory Clinical Assay & Validation Retrospective Longitudinal/ Cross-sectional Prospective Screening Cancer Control MCL Molecular and Cellular Characterization of Screen-Detected Lesions CIB - Consortium for Imaging and Biomarkers (no associated computational platform) EDRN - Early Detection Research Network BiomarkerBase Commercial database of biomarkers tested in a late-stage clinical trial SEER - Surveillance, Epidemiology, and End Results Adapted from: Pepe et al., J Natl Cancer Inst

10 Organization of EDRN Division of Labor Discovery Assay Development Validation inform Discovery Validation Modeled after drug development pipeline

11 Rigor and Reproducibility: Study Designs for Biomarker Development PRoBE Study Design: Prospective- Specimen- Collection, Retrospective- Blinded- Evaluation Phases of Biomarker Discovery and Validation Preclinical Exploratory Clinical Assay and Validation Retrospective Longitudinal Prospective Screening Cancer Control PHASE 1 PHASE 2 PHASE 3 PHASE 4 PHASE 5 Promising directions identified Clinical assay detects established disease Biomarker detects preclinical disease and a screen positive rule defined Extent and characteristics of disease detected by the test and the false referral rate are identified Impact of screening on reducing burden of disease on population is quantified Phases of Biomarker Development for Early Detection of Cancer Margaret Sullivan Pepe et al. J Natl Cancer Inst, Vol. 93, No. 14, July 18, 2001 Pivotal Evaluation of the Accuracy of a Biomarker Used for Classification or Prediction: Standards for Study Design Margaret Sullivan Pepe et al. J Natl Cancer Inst 2008; 100:

12 EDRN Associate Membership Program Purpose A mechanism through which non-edrn investigators can become members of the Network to pre-validate and/or validate their biomarkers. EDRN Associate Members can establish active collaborations with EDRN investigators and utilize available EDRN support, resources and infrastructure. Associate Members can attend EDRN SC Meetings and monthly Collaborative Group teleconferences.

13 Types of Associate Membership Type A Pre-clinical evaluation of novel biomarkers and development of novel technologies, study designs or statistical methodologies to enhance the early detection of cancer ($50,000/yr for 2 years; one time only) Type B Sharing of available resources with EDRN, contributing specimens, or making available high-risk registries and cohorts in conjunction with pre-validation and validation studies ($100,000 for 1 yr; can reapply for additional years). Type C Scientists, clinicians, patient advocates, and ethicists from academic and industrial fields with no financial involvement with EDRN. All Associate Members types A and B, whose funding has ceased

14 Introduction to CPDPC Consortium on Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC)) Joint RFA Initiative: NIDDK, NCI and NIAAA

15 Purpose of CPDPC-1 Identify fibrosis markers in patients with acute or recurrent pancreatitis who progress to chronic pancreatitis Detect and quantify pancreatic fibrosis and pancreatic cancer Trials to determine efficacy of treatment strategies to improve symptoms and outcome (anti-fibrosis for (early) chronic pancreatitis); metformin for prevention of diabetes and pancreatic cancer in patients with chronic pancreatitis Determine which combination(s) of genetic and/or environmental factors give rise to pancreatic cancer

16 Purpose of CPDPC-2 Epidemiological studies to establish the incidence and prevalence of T3cDM Studies to establish the risks of acute/chronic pancreatitis and pancreatic cancer in patients with T2DM treated with incretinbased therapies Studies of high risk patients to evaluate genomic, proteomic, and hormonal markers of early pancreatic cancer Conduct pilot surveillance studies and generation of survivorship registries; and identification of factors that may contribute to disparity in incidence of pancreatic cancer among populations

17 NCI Initiative: Screening for High Risk and Early Detection Pancreatic Cancer Detection Consortium (PCDC)

18 Research Topics Being Pursued by the Consortium Evaluation of longitudinal screening protocols using patients at high risk of developing pancreatic cancer Development of novel methods to obtain and interrogate pancreatic tissues containing preneoplastic lesions Development and validation of biomarkers to detect early stage PDAC, PanIN-3s, IPMNs or MCNs Development of imaging methods to detect early stage PDAC, PanIN-3s, IPMNs, or MCNs Development and integration of imaging approaches and multiplexed biomarker panels Development of imageable biomarkers yielding 3D localization of PDAC and high-grade precursor lesions

19 Molecular and Cellular Characterization of Screen-Detected Lesions (MCL) Consortium Division of Cancer Prevention Division of Cancer Biology

20 MCL Consortium: Underlying Scientific Theme Phenotypically distinguishing between lesions that are likely to progress and those that are indolent and require no immediate treatment Predicting whether lesions that are detected by sensitive screening tests are indolent (hence, not requiring immediate treatment) or progressive and potentially life-threatening

21 Biospecimen Collections and Sharing Requirements Biospecimens from patients with early stage PDAC and precursor lesions Plasma, serum, DNA Stool, urine Duodenal / pancreatic aspirates Diagnostic biopsies, pancreatic resections Imaging EUS, secretin MRCP Uniform data collection, common data elements, protocols, and analyses for serial sample collection and clinical annotation Reproducibility of data collection including verification and auditing Specimens will be collected by U01 grantees

22 Alliance of Pancreatic Consortia Recent Experience with Biomarkers Solicited collaborative proposals from multiple consortia for a bake-off study on pancreatic cancer biomarkers for early detection To our surprise, only a few proposals turned (failed to meet the EDRN guidelines) This indicates that we need to focus on developing robust, reproducible biomarkers We have a formed a Virtual Consortium Alliance of Pancreatic Consortia comprising of the NCI-funded programs and others funded by foundations

23 Strategic Collaboration: It Takes a Village Federal Partnerships National Institute of Standards and Technology Center for Prostate Disease Research, DOD Pacific Northwest National Laboratory, DOE Jet Propulsion Laboratory (JPL), NASA Non-Profit Foundations Leveraging Resources PanCan Lustgarten Foundation funded 20-hybridoma cell lines for pancreatic candidate markers Kenner Foundation International Partnerships Cancer Research UK (in progress; pancreatic, lung) 23

24 Program Contacts Dr. JoAnn Rinaudo Dr. Sharmistha Ghosh Dr. Mat Young

25 NCI s Major Programs Addressing Early Detection Early Detection Research Network; Alliance of Glycobiologists: Chronic Pancreatitis, Diabetes, Pancreatitis and Cancer Consortium (CPDPC): Molecular and Cellular Characterization of Early Lesions Pancreatic Cancer Detection Consortium 25

26 Thank You! Q and A

ACG Clinical Guideline: Diagnosis and Management of Pancreatic Cysts

ACG Clinical Guideline: Diagnosis and Management of Pancreatic Cysts Grace H. Elta, MD, FACG 1, Brintha K. Enestvedt, MD, MBA 2, Bryan G. Sauer, MD, MSc, FACG (GRADE Methodologist) 3 and Anne Marie Lennon,