MURTHA CANCER CENTER RESEARCH PROGRAM RESEARCH PROJECTS
MURTHA RESEARCH NETWORK
The Murtha Research Network, the first and one-of-a-kind tri-federal-civilian cancer research network, presently consists of 9 Military Treatment Facilities (MTF) and Medical Centers, 7 VA Medical Centers, and 2 Civilian Medical Centers. It is driving the process of discovery as a natural outgrowth of patient care and helping to transform the way evidence on clinical effectiveness is generated and used to improve health and health care for active military, dependents, veterans, and civilians. The network is designed to increase access to clinical trials; optimize federal cancer resources; increase access to translational research resources; increase access to patients’ data, tissue and oncology specialists; increase education and training opportunities; and increase recruiting and retention. The purpose of the Military Cancer Clinical Trials Network is to develop, test, and evaluate ways to increase effectiveness and efficiencies of integrated cancer care and research throughout the MHS.
The Military Cancer Clinical Trials Network continued to grow. The Network is becoming the infrastructure that the MCCRP, as the DoD Cancer CoE, will build on to meet its overall goal of an integrated cancer care and translational cancer research enterprise across the MHS.
PROJECT FOR MILITARY EXPOSURES AND TOXIN HISTORY EVALUATION IN US SERVICE MEMBERS (PROMETHEUS)
Military personnel may be exposed to possible environmental contaminants and potential toxin hazards during their service and as they deploy throughout the world in defense of our nation. There are gaps in the scientific studies that link any potential exposures to the impact on a service member’s health and future potential for development of conditions such as cancers. Arising out of President Biden’s White House Cancer Moonshot initiative in 2022, PROMETHEUS is a Cancer Moonshot 2.0 project of the Department of Defense’s Uniformed Services University of the Health Sciences (USU) Murtha Cancer Center Research Program (MCCRP). The PROject for Military Exposures and Toxin History Evaluation in US service members (PROMETHEUS) is a multi-federal and public-private partnership collaboration to study elements of these research gaps using the many different biosamples and data sets available to DoD researchers.
PROMETHEUS will integrate scientific platforms of the Department of Defense (DoD), Veterans Administration (VA), Department of Energy (DOE) and National Institutes of Health (NIH), especially the National Cancer Institute (NCI) and National Institute of Environmental Sciences (NIEHS), and other civilian and academic entities to meet some of these challenges. The effort includes creating a process and research ecosystem to integrate or link individual-level datasets of exposures and phenotypic information, conducting research studies that leverage exposure data, phenotypic data, and biospecimens, which are unique to the DoD.
PROMETHEUS will also incorporate several of the precision oncology programs that evolved from the first Cancer Moonshot. The APOLLO (Applied Proteogenomics OrganizationaL Learning and Outcomes) program now includes nine Military Treatment Facilities (MTFs), seven VA facilities, and two civilian medical centers. The central APOLLO biobank is at the Chan Soon-Shiong Institute of Molecular Medicine (CSSIOMM), Windber, Pennsylvania. APOLLO was the first DoD program to emerge from the 2016 Cancer Moonshot 1.0 program, based collaboration between DoD, VA, and NCI for translational proteogenomics research. APOLLO supports the federal government’s precision oncology initiative, with advanced technology platforms that include genomics (through The American Genome Center [TAGC] of USU) and the proteomics lab core of MCCRP. PROMETHEUS will also leverage use of the DoD Serum Repository located at the DHA Armed Forces Health Surveillance Branch, which includes over 60 million serum specimens from over ten million Service Members collected throughout their careers, which can provide valuable biospecimens collected before and after any potential toxin exposure history.
PROMETHEUS also engages the DoD Joint Pathology Center (JPC) repositories that include war-related registries with slides and/or tissue samples from more than 54,000 patients across multiple military conflicts. These registry cases are ideally suited for studying toxic exposures and their impact on Service Member and Veteran health, especially when test data are analyzed in conjunction with other relevant clinical and exposure data. The Post Deployment Health Services/Health Outcomes of Military Exposures (PDHS/HOME), a VA-Delivered Core Service, assesses the impact of deployment and environmental exposures on Veterans and develops related policy, research, education, and healthcare strategies. PDHS consists of interrelated programs and activities in epidemiology, environmental health, war-related illness and injury studies, centers for embedded fragments and depleted uranium, and toxicology expertise is another scientific program that may be incorporated. DoE Pacific Northwest National Laboratory (PNNL) and DoD collaborations have novel mass spectrometry (MS) capabilities that have been applied to various DOE and NCI biology questions and have identified protein biomarkers in serum that have the potential to function as early diagnostic markers or predictors of disease recurrence and will now be turned to the scientific questions being studied in PROMETHEUS.
The PROMETHEUS project is established to bring federal assets together with public-private partners to further study these important questions of potential environmental and toxin exposures with a focus on future prevention and mechanisms of disease development that may enable early detection or enhanced precision treatments of cancers arising in such circumstances.
APPLIED PROTEOGENOMICS ORGANIZATIONAL LEARNING AND OUTCOMES (APOLLO)
Tri-Agency Coalition to Enhance Cancer Care – Applied Proteogenomics OrganizationaL Learning and Outcomes (APOLLO) Consortium: The DoD, VA, and the NCI formed a collaboration using state-of-the-art research methods in proteogenomics to more rapidly identify unique targets and pathways of cancer for detection and intervention. These methods examine patient’s genes that may lead to cancer and the expression of these genes in the form of proteins, with potential impact on disease formation and treatment for cancer patients. Initial collaborative efforts focused on a cohort of 8,000 lung cancer patients within the nation's two largest healthcare systems and will make data broadly available to the research community. Ultimately the effort will be expanded to additional cancer types to reach more cancer patients within the VA and DoD, providing knowledge scalable for physicians across the country treating the more than 1.60 million new patients diagnosed with cancer each year.
APOLLO 1 LUNG CANCER - 10TH HIGHEST CAUSE OF CANCER IN ACTIVE DUTY
Lung cancer is #1 cause of cancer deaths world-wide. Cost: $12 Billion in 2014. Lung adenocarcinoma is one of the most common types of lung cancer that has few biomarkers for predicting clinical outcomes and has high heterogeneity. Using a cohort of 87 lung adenocarcinomas, APOLLO 1 aims to identify the significant DNA/RNA/protein/ phosphoprotein alterations, identify the significant molecular subtypes, and determine which molecular markers or subtypes associate with clinical outcomes.
The MCCRP scientists generated the first, large proteogenomic characterization of LUAD from the United States population and corresponding smoke exposure. USU&HJF Joint Patent and Technology Review Group recommended filing a provisional patent application for “Molecular Predictors of Lung Adenocarcinoma Survival.”
APOLLO 2 GYN CANCER - 12TH HIGHEST CAUSE OF CANCER IN ACTIVE DUTY
The GYN-CoE is an integrated translational research program aimed at development of companion biomarkers and assays, clinical decision support tools, risk assessment algorithms, quality improvement initiatives, treatments, and interventions for patients with gynecologic tumors and cancers, among a growing proportion of active duty women in the Armed Services, veteran and retired populations. Molecular profiling of pre-cancerous and malignant lesions has also enabled development of diagnostic and chemo-preventive interventions across the most common pathologic uterine conditions, rare variants, and the aggressive and deadly metastatic and recurrent malignancies that affect women and corresponding readiness. The GYN-CoE has been the leading research program in the U.S. to identify clinical features, biologic etiologies, and social determinants underlying racial and ethnic disparities in gynecologic cancers using population based as well as translational research methods. APOLLO 2 aims to demonstrate that enriched tumor data will enable insights into tumor-specific biology underlying lower purity High-Grade Serous Ovarian Cancer (HGSOC) tumors. Additionally, stroma cell proteomic data will afford the opportunity to validate historic and refine tumor- specific prognostic signatures and define spatio-temporal tumor microenvironment signaling dynamics.
MCCRP researchers found that enrichment of tumor cells using laser microdissection reveals significant increases in somatic mutations and structural variants and shows significant increases in the correlation of protein and transcript abundances in comparison to whole tumor collections. Tumors with high gene and protein immune signatures exhibit longer time to progression than tumors with low immune signatures. This supports evidence that an immune micro-environment correlates with improved prognosis.
APOLLO 3 PROSTATE CANCER - 3RD HIGHEST CAUSE OF CANCER IN ACTIVE DUTY
Prostate cancer remains the most common non-skin cancer of men diagnosed in United States. An estimated 248,530 new cases and 34,130 deaths will occur in 2021, despite major advancements in both cancer detection and treatment. The DHA Medical Surveillance Monthly Report* described 8,973 new cancers among active-duty members of the U.S Armed Forces between 2005-2014. Of these, 1,046 (11.7%) were prostate cancer diagnoses. In the same report prostate cancer occurred 2.5X more frequently in Black than in White non-Hispanic men. The Prostate Cancer CoE is uniquely positioned within the DoD to address military specific aspects of prostate cancer including the disease spectrum in younger men as well as cancer aggressiveness and lethality in a population with growing racial/ethnic diversity.
The APOLLO 3 team completed whole genome sequencing of DNA samples of 103 tumor/normal pairs: 52 African Americans (AA) and 51 Caucasian Americans (CA): Self-reported race matched genetically determined ancestry, Identified SPOP, TP53 and FOXA1 to be the most frequent, significantly mutated genes. Proteomics analysis revealed distinct differences between AA and CA prostate cancer proteome: Confirmed well documented difference in ERG protein expression, quantified proteins, phosphoproteins and peptide ancestry, informative markers (pAIM) that are significantly altered between, AA and CA tumors.
APOLLO 4 BREAST CANCER - 5TH HIGHEST CANCER IN ACTIVE DUTY
Women make up about 20% of the Active Force. Breast cancer is the most common cancer in active-duty women. It is the single greatest cause of cancer deaths among women under 40 and is a significant cause of loss of active-duty capability and Force Readiness for women in the United States Armed Forces. The more aggressive nature of the disease in young patients along with the attendant costs underscores the importance of prevention, screening, and early detection of breast cancer in young women (Force Readiness). When discovered at a later stage, treatment of breast cancer is expensive, aggressive and results in considerable disruption to a woman’s ability to contribute to the military and society (Force Readiness). The majority (>90%) of women in active military service are < 40 years of age. DoD, with its high percentage of young women and its commitment to health care and total health of the Force, remains particularly concerned about breast cancer. As all positions in the military, including combat positions, are now open to women, the increasing incidence of breast cancer in younger (military-age) women, coupled with the military’s critical reliance on a Total Force of all personnel including a high and increasing percentage of women), requires that the DoD Clinical Breast Care Project (CBCP) continue to engage in focused research on surveillance, screening, early detection, curative treatments, and post-treatment Return To Duty Survivorship programs. The CBCP has a 20 -year history of doing just that, and we are aligned with the MHS QUAD AIM with the central pillar of our efforts focused on READINESS of the Total Force.
The APOLLO 4 cohort is 34 matched cases of young (<40 y/o) and older (≥60 y/o) women by race and tumor IHC subtype and additional genomic & proteomic only cases (total 81 genomic and 70 proteomic cases). Clinicopathologic characterization indicated that young women strongly trended to have worse outcomes and showed minimal number of invasive lobular carcinoma (ILC) cases. Validated in public datasets of TCGA-BRCA and METABRIC. When germline DNA mutation analysis was done, young women have more BRCA1/2 mutations. Gene mutation analysis demonstrated that tumors from young women have lower tumor mutational burdens and fewer mutations in aging-associated mutational signatures, more frequent GATA3 mutations, and less TP53 mutations in luminal subtypes.
APOLLO 5 PROSPECTIVE DOD AND VA SAMPLES, ALL CANCERS
Use prospectively-collected VA, DoD, and NCI specimens and data for all organ sites to: identify and correlate integrated proteogenomic signatures to tumor response and resistance to conventional therapies, identify and correlate integrated proteogenomic signatures to patient outcomes, develop and computationally model integrated proteogenomic profiles to identify actionable pathways for novel clinical intervention, and conduct an integrated proteogenomic investigation of intra-tumoral heterogeneity and the micro-environment to identify innovative targets for intervention and to enhance the efficacy of currently available strategies. This is a prospective research study designed to utilize samples collected from all organ sites with associated de-identified clinical data. APOLLO 5 samples will undergo proteogenomic analyses at the participating APOLLO laboratories, and the resulting de-identified molecular and clinical data will ultimately be integrated in the NIH Genomic/Proteomic Data Commons and The Cancer Imaging Archive (TCIA). There were 9 Military Treatment Facilities (MTF), 7 VA Medical Centers, and 3 civilian medical centers procuring biospecimens for APOLLO 5. There are 1055 participants. Seventy nine percent of participants are associated with the military, approximately 60% of enrollments are malignant pan-cancer patients, Joint Pathology Center (JPC) has accepted 97% of cases, and approximately 99% have passed identity matching assessments and robustly passed quality assessments. TAGC has sequenced all 144 germline samples from Cohort 1.
APOLLO 6 PANCREATIC CANCER - 13TH HIGHEST CAUSE OF CANCER IN ACTIVE DUTY
APOLLO 6 is performing the proteogenomic analysis of pancreatic cancer. It’s leveraging the unique Perthera Tissue-Outcomes-Clinicopathologic and Epidemiologic Data Set for Predictive/Prognostic Biomarker Discovery. It’s aims are: proteogenomic profiling of tumor epithelium and tumor stroma/immune cells to identify biomarkers that associate with early recurrence and longer survival, proteogenomic profiling of tumor epithelium and tumor stroma-immune cells to identify biomarkers that differentiate between primary vs metastatic tumors, proteogenomic profiling of tumor epithelium and tumor stroma-immune cells to identify biomarkers that predict/associate with response to therapy, and correlative comparison of CAP/CLIA-based NGS targeted exome immunohistochemical protein panel data with APOLLO 6 generated proteogenomic data.
APOLLO 7 TESTICULAR GERM CELL TUMORS - HIGHEST CAUSE OF CANCER IN ACTIVE DUTY
This APOLLO 7 protocol will leverage the DoD Joint Pathology Center’s (JPC), world’s largest collection of human repository specimens, to identify genetic markers and aberrant protein expression in testicular germ cell tumors, the most prevalent malignancy in active duty service members. In addition, racial disparities in prognosis outcomes have been reported in this cancer type, with African Americans displaying as much as 17% poorer survival despite no differences in tumor type, with over 100% increased relative risk of mortality within the first 10 years after diagnosis. APOLLO 7 is performing a comparative proteogenomic analysis of testicular germ cell tumors in African Americans and Caucasians. It has been determined that testicular germ cell tumors (TGCT) in African Americans are associated with the worse prognosis than tumors in Caucasians. The primary focus of APOLLO 7 is to perform proteogenomic analysis of TGCTs from the JPC archives to look for molecular markers that help explain the disparities between these two groups.
APOLLO 8 GLIOBLASTOMA - 7TH HIGHEST CAUSE OF CANCER IN ACTIVE DUTY
APOLLO 8 is a retrospective study of existing glioblastoma (GBM) tissue samples and associated data utilizing the APOLLO genomic and proteomic analysis platforms available through The American Genome Center (TCGA) and the MCC Clinical Proteomics Platform. This study aims to perform comprehensive neuropathologic examination of the available military GBM cases, and any available ante-mortem neurosurgical material (i.e., biopsy and resection material) for each decedent in the study. Examination may include but not be limited to: gross examination, extensive sampling, microscopic examination using modern special staining, immunohistochemical preparations, and bright field in-situ hybridization studies on blocked tissue samples, and digitization of slides for state-of-the-art Artificial Intelligence/Deep learning-based image analysis. The study will also perform genetic and proteomic characterization of the available military GBM cases to investigate potential associations with clinical outcome (e.g., young versus old onset, rapid versus slow progression, survival, response to therapy, etc.) and differences in various tumor histologic characteristics or differing tumor components.
APOLLO 9 KRUKENBERG Tumors - Related to GYN CANCER 12TH HIGHEST CAUSE OF CANCER IN ACTIVE DUTY
Krukenberg tumors are a specific type of metastasis involving spread to the ovaries from a primary adenocarcinoma of another location. The molecular profile of patient's primary and metastatic Krukenberg tumors will be studied to learn what are the features that underlie the capacity to spread to the ovary, and possible mechanisms to stop that spread. Due to the relative rarity of this type of metastasis, there are ongoing questions regarding Krukenberg and how and why they develop and how to manage them. Through this project, the investigator hopes to gain better insight into Krukenberg tumors, specifically with regards to how they have evolved from the primary and how that may impact their spread or any other prognostic factors. Additionally, this study assesses DNA, RNA and protein molecules of cancer tissues and the ovarian tissues to enhance our understanding of dysregulated pathways in pathogenesis and proliferation of metastatic cancer. De-identified slides are provided from the Department of Pathology at the Stanford University Medical Center to the Gynecologic Cancer Center of Excellence at the John P. Murtha Cancer Center to assess the material needed for analysis. After receiving sufficient material for analysis from Stanford, the Gynecologic Cancer Center performs proteomics analysis as well as distribute slides to the MCC Research Pathology Center for immunoscore analysis and The American Genome Center at the Uniformed Services University (USU) for genomic analysis. All analytic centers provide data to the Data Science Core at the USU. Stanford will also share basic clinicopathological data to the Data Science Core.
APOLLO ADVANCED TECHNOLOGIES
The molecular laboratories and a core biobank established under the National Cancer Moonshot 1.0 has grown. They house the advanced technologies required to execute the research aspects of the various studies. The cancer research studies across the network have acquired a total of over half a million cancer specimens which have been and are being used in hundreds of other research projects, both DoD and with partners. All of these laboratories and capabilities are operated and funded by the DoD, ensuring data and tissue security as well as allowing the MCCRP to set the priorities for research, which is to study and impact cancer as a readiness issue.
The American Genome Center for APOLLO, part of the MCCRP research network of laboratories, is located at USU. It conducts both whole genome and RNA sequencing. The state-of-the art genome sequencers and high performance analysis workflow systems have the capability to analyze 8,000 cancer genomes per year, 20,000 transcriptomes per year and provides genomics data generation, computational in support of informative value to APOLLO biomedical research investigators.
Technologies at Chan Soon-Shiong Institute of Molecular Medicine at Windber (CSSIMMW) are in direct support of APOLLO. The CSSIMMW is a biorepository with 12 minus 80 degree mechanical and 17 liquid nitrogen freezers. It coordinates all biospecimen qualification pathology and molecular quality control activities for APOLLO. The CSSIMMW has also developed data tracking systems to monitor laboratory operations, patient registration and APOLLO protocol assignment, clinico-pathologic data capture and QC, case credentialing with secondary pathology review, sample identity matching and QC, remote tumor review and mark-up for LMD processing, molecular extraction and sample processing for molecular centers, and the capture of experimental results.
The MCCRP proteomics lab is located at Inova in Northern, VA. It uses high-performance mass spectrometry to profile human cancer tissue to identify and validate protein biomarkers to prevent, diagnose, and treat cancer. It supports all MCCRP network proteomics sample research, including but not limited to APOLLO. It also houses the APOLLO Research Pathology Center (RPC) that utilizes laser microdissection for histology resolved proteogenomics. The RPC uses industrialized workflows and standard operating procedures to prepare cancer tissues for histology review and analysis.
The Apollo Program has continued to hold its biannual Retreats virtually to report scientific advances made throughout the COVID-19 pandemic. Researchers shared the remarkable research progress they made while following the strict rules imposed during the pandemic. An indication of the Retreats success was the number of individuals who attend each event. 174 scientists attended the last Retreat in September 2023.
DOD FRAMINGHAM LONGITUDINAL MOLECULAR CANCER PROGRAM
Framingham --The MCCRP launched a groundbreaking longitudinal study to revolutionize precision oncology – it established a new longitudinal study to transform our understanding of the biological underpinnings of cancer. Using the vast amount of data housed in the DoD Cancer Registry housed at the Joint Pathology Center (JPC) and the Active Duty Service Members (ADSM) sera from the DoD Serum Repository (DoDSR) at the Armed Forces Health Surveillance Branch (AFHSB) researchers are working to identify new linkages between pre-diagnostic biological markers and various types of cancer. Four different serum specimens (two before, one during, and one after cancer diagnosis and treatment) from every ADSM who developed certain types of cancer over a ten-year period of time are sent to the DoE Pacific Northwest National Laboratory (PNNL) for proteomic analysis. Approximately 1,000 new cases of cancer occur annually in active duty personnel, and there are approximately 250,000 samples from the last 25 years available to undergo protein signature analysis for pre-incident cancer markers. These results will lead to clinical trials for cancer prevention, diagnosis, and advanced treatments.
FRAMINGHAM 1 OROPHARYNGEAL CANCER - 2.8 % OF ALL NEW CANCER CASES IN THE U.S.
Head and neck squamous cell carcinomas, including oropharyngeal squamous cell carcinoma (OPSCC), are the 6th most common cause of cancer worldwide. While five-year survival rates of those diagnosed with early stages of the disease are good, there are currently no clinically accepted screening tests for this cancer, leading to long-lasting negative effects of more advanced treatments, and poorer clinical outcomes. In this study, cutting-edge proteomics research will be utilized to identify serum biomarkers indicative of disease states to develop early diagnostic tools and prognostic indicators, which may be used to inform treatment decisions and improve survival. The primary objective of this study is to compare serum markers of OPSCC patients to cancer-free controls at points prior to diagnosis, during the course of treatment (or just after), and during post-treatment surveillance, including targeting HPV16 biomarkers and other known proteins of the OPSCC mutanome. This study is a retrospective analysis of longitudinal serum samples collected over the course of the subjects’ military active component service. Subjects from whom serum samples will be utilized from service members diagnosed with different sub-locations of OPSCC while on active component between the years of 2003-2013, as well as their age- and gender-matched active component cancer-free controls. A set of approximately 200 biomarkers thought or known to be associated with HPV-positivity, OPSCC, or the immune inflammatory response will be analyzed for incidence and prevalence and their ability to differentiate between cases and controls, especially when considered in aggregate. Given that serum samples will be taken from as early as four years prior to diagnosis, there is the potential for identification of a set of biomarkers capable of successfully distinguishing disease from healthy states early enough to enable preventive care, or at least significant improvement in treatment decisions and outcomes.
Using a Random Forest machine learning approach, a 13-protein signature was derived that distinguishes cases versus controls based on longitudinal changes in serum protein concentration. The abundances of each of the 13 proteins remain constant over time in control subjects. The conclusion that can be drawn from these data is that this 13-protein classifier is highly promising for detection of OPSCC prior to overt symptoms. The results also indicate that the use of longitudinal samples has significant potential to identify biomarkers for detection and risk stratification.
FRAMINGHAM 2 LYMPHOMA - 4TH HIGHEST CAUSE OF CANCER IN ACTIVE DUTY
Proteomic Serum Analysis of Biomarkers in Diffuse Large B-Cell Lymphoma (DLBCL). Lymphoma is the most common blood cancer. The two main forms of lymphoma are Hodgkin lymphoma and non-Hodgkin lymphoma (NHL). Lymphoma occurs when cells of the immune system called lymphocytes, a type of white blood cell, grow and multiply uncontrollably. Cancerous lymphocytes can travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood, or other organs, and form a mass called a tumor. From 2000 through 2011, non-Hodgkin lymphoma was one of the top ten cancers diagnosed among active duty service members. Leukemia and lymphoma cases have been related hypothetically to exposure to depleted uranium, which has several military applications and has been utilized in combat by the U.S. military. Given lymphoma’s relevance to U.S. military service members, additional investigation is warranted into methods that promote early detection, prognosis, and therapeutic response.
The hypothesis of Framingham 2 is that proteomic analysis of serum samples from patients ultimately diagnosed with DLBCL obtained in the months to years prior to diagnosis will reveal protein aberrations within the serum that are present at least one year prior to diagnosis that will ultimately inform and predict a diagnosis of DLBCL. The specific aim is to conduct an exhaustive analysis of pre-diagnostic serum samples in patients ultimately diagnosed with DLBCL, consisted of global discovery mass spectrometry and targeted protein mass spectrometry. The availability of longitudinal samples from active component service members at points before their incident diagnosis of cancer and during the period of illness when combined with the highly innovative mass spectrometric techniques available at PNNL will enable the identification of markers and mutations predictive of cancer diagnosis.
2A: The discovery analysis has been completed. 1502 samples were received; 2500 proteins were identified; and 150 surrogate peptides were identified. Additionally, a differential signal was detected for 104 proteins. The team will review additional protein candidates and decide if they would like to include them in the analysis.
FRAMINGHAM 3 MELANOMA - 2ND HIGHEST CAUSE OF CANCER IN ACTIVE DUTY
Skin cancer is the most common cancer type in the United States, with melanoma being the third most common skin cancer type and causing the most deaths. Melanoma risk is higher among active duty personnel than the general population, and from 2000-2011 malignant melanoma was the most highly incident diagnosis of cancer in active component service members. This project represents a unique opportunity to leverage the DoD’s cancer registry and serum repository to identify linkages between pre-diagnostic biological markers and melanoma. The DoDSR, is a biological repository 60,000,000 serum specimens collected from members of the active duty service members. The availability of longitudinal samples from active component service members at points before their incident diagnosis of cancer, during the period of illness, and after resolution, when combined with the highly innovative mass spectrometric techniques available at PNNL and the multi-omics profiling capabilities of TAGC, will enable the identification of markers predictive of melanoma diagnosis.
The DoD JPC’s Automated Central Tumor Registry (ACTUR) was queried for patients with stage T2 or higher melanoma diagnosed while on active duty between the period of 1 January 2001 to 31December 2016. This query returned a total of 592 patients receiving a primary diagnosis of melanoma while on active duty during this period. JPC will send the list of identified patients to the AFHSB in order to requisition serum. The JPC will also provide information on the staging of the tumor at the time of diagnosis for each of the identified subjects and report any instances of recurrence in these cases. The JPC will work directly with the AFHSB to keep study investigators blinded to identifiers. Date of diagnosis for each patient will be provided to the AFHSB. Serum from the year of diagnosis (+1 year), two years pre-diagnosis (+/- 1 year), four years pre-diagnosis (+/- 1 year), and two years post-diagnosis (+/- 1 year) will be requisitioned. Serum from the year of diagnosis should be obtained post-diagnosis, within up to one year following the date of diagnosis. Of the 592 cases identified, 200 cases will be selected based on the availability of serum samples. Cases with all four requested samples will be prioritized first, then those with three available, etc. Each of the 200 patients with melanoma will be matched by age (+/- one year) and sex to 200 controls who were cancer free for the duration of their active component service, as well as free of autoimmunity, transplant, or immune suppression.
PNNL will perform comprehensive quantitative proteomics measurements on 100uL aliquots of serum sent from DoDSR. PNNL has established state-of-the-art liquid chromatography-tandem mass spectrometry (LC-MS/MS) based proteomics pipelines that provides deep, quantitative proteome characterization for unbiased biomarker discovery, or precise, sensitive and multiplexed quantification of target proteins in high-throughput fashion for biomarker verification. The availability of longitudinal specimens from the patients (pre-diagnosis and at diagnosis) and controls collected under well-defined protocols, as well as the cutting-edge proteomics platforms, provides an opportunity to explore the detailed temporal profiles in protein concentrations and verify promising biomarker candidates for early detection of the disease.
390 samples (73 pairs) have been received. From these, 1,700 proteins and 16,310 peptides were retained having had achieved 70% valid values. Differential signals were detected for 75 proteins and 812 peptides (combined total = 301). Next steps are to conduct a literature review for possible additional candidates (up to 200 can be analyzed) and for team to decide which ones they want included.
FRAMINGHAM 4 PANCREATIC DUCTAL ADENOCARCINOMA - 13TH HIGHEST CAUSE OF CANCER IN ACTIVE DUTY
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death with a five-year survival rate of less than 10%, greatly due to its indolent nature during early stages, and its subsequent late diagnosis. Unfortunately, there are currently no optimal screening markers in the asymptomatic population. Utilizing the unique resources of the DoD’s cancer registry and DoDSR this project, “Proteomic Serum Analysis of Biomarkers in Pancreatic Ductal Adenocarcinoma,” or “DOD Framingham-4,” seeks to identify serum markers for PDAC that may be used to screen the asymptomatic population and/or surveille for early detection of recurrence. Serum from active Armed Forces members diagnosed with pancreatic adenocarcinoma before, during, and after their diagnosis will be analyzed with sophisticated mass spectrometric techniques available at PNNL, identifying potential biomarkers predictive of this highly lethal disease.
Approximately 100 pancreatic adenocarcinoma subjects and equivalent matched controls, each with up to seven longitudinal samples, will be analyzed using the advanced targeted proteomics platforms established at PNNL. These specimens will be first processed using immunoaffinity depletion for removing top-14 most abundant proteins which represent >95% of the protein mass from each individual serum sample; this reduces the “masking effects” of highly abundant proteins, and hence significantly increases the dynamic range of the proteomics measurements. Using the strong domain knowledge of pancreatic adenocarcinoma represented by the expert scientists and oncologists at the Murtha Cancer Center, we will then select up to 200 candidate biomarker proteins for analysis in a targeted fashion.
Utilizing these invaluable resources, this study seeks to identify sensitive and specific biomarkers for pancreatic adenocarcinoma in the asymptomatic, pre-diagnosis group, which is something that is greatly needed for early detection of this lethal cancer. The study further seeks to compare biomarker patterns to controls, compare early stage pancreatic cancer markers to late stage markers, as well as compare recurrence patterns to disease remission to better understand biomarkers in pancreatic adenocarcinoma and identify markers for surveillance of recurrence. These discoveries would greatly benefit all by increasing chances of early detection and therefore survival after pancreatic adenocarcinoma diagnosis.
FRAMINGHAM 5 METASTATIC CANCER OF ANY TYPE TO BONE
Bone metastases and surgical stabilization Metastatic bone disease results in an enormous economic impact to the MHS. For example, in this country, it is estimated that the 5.3% of cancer patients with metastatic bone disease account for a disproportionate 17% of the $74 billion NIH estimated total direct medical cost for cancer. As the retiree population increases over the coming decades, these estimates are likely to grow. The investigators seek to identify cytokines and chemokines and other protein candidates in hopes of identify biomarkers predictive of metastatic bone disease to aid in early identification of metastatic bone disease and improve an accurate personalized estimation of survival in this challenging patient population.
MILITARY CANCER BIOREPOSITORY
MCCRP biobank protocols have become the platform on which the Military Cancer Clinical Trials Network is being built. The specimens and data that are collected from volunteers at the Network’s sites will be used in MCCRP facilitated scientific collaborations to help prevent, diagnose, treat and cure cancer, in SMs and DoD beneficiaries. Recently, 1535 patients were consented to participate in MCCRP specimen collection protocols and 764 patients voluntarily donated specimens to the biobank. An additional 825 patients were consented into the APOLLO research protocol. In the past decade, it has become increasingly clear that access to highest quality of human tissue and data are the most critical component of successful biomedical research aimed at cancer detection, prevention and cure. The development of future targeted cancer interventions will require broad access to this scarce resource of uniformly collected and stored human specimens linked to a detailed epidemiological database. The MCCRP is building a military-based tissue repository of prospectively collected biospecimens that will fulfill the research needs of DoD investigators and their collaborators. A master template for implementation at participating sites in the Murtha Research Network has been developed. This protocol establishes strict guidelines and procedures for biorepository efforts and formulates the processes necessary for the highest quality tissue collection, storage and distribution. Collected biospecimens will be used in all types of research and development, such as finding the cause of disease, developing new diagnostic tests, or advanced approaches to treatments and cures. The biospecimens may also be used in genetic research or research into hereditary diseases. They will be used by DoD, VA and NCI researchers and collaborators and other DoD funded projects such as APOLLO.
The Chan Soon-Shiong Institute of Molecular Medicine (CSSIMM), at Windber Pennsylvania has been established as the MCCRP consolidated biorepository. The consolidated biobank manages sample acquisition, processing, storage and distribution for MCCRP research. The biobank is involved in the management of all biospecimens from the different Military Treatment Facilities and selected VA Medical Centers. These activities include sample receiving, storage, slide imaging for remote pathology review and annotation, nucleic acid extraction and quantitation.
The quality standard of the biobank is enhanced by its accreditation by the College of American Pathologists (CAP) and certification by the Clinical Laboratory Improvement Amendments (CLIA) with a commitment to promoting reliable molecular research by providing high quality biospecimens to the scientific community.