Attach14ProjectsBackgroundandHistory.pdf

Project Background and History Information

A. Purpose

This Genome Characterization Centers (GCC) contract is in support of the Center for Cancer Genomics (CCG) and all its high-throughput genomic characterization needs. The overall purpose of CCG studies is to improve our understanding of the genomic alterations associated with the onset and progression of human cancers. This knowledge is expected to lead to novel translational approaches and, ultimately, to accelerate the development of new cancer diagnostic, prevention, and treatment strategies. It is not the intent of this project to fund translational and functional studies following the data production, but rather to enable the cancer research community to develop a new generation of studies that will leverage findings for the benefit of cancer patients.

B. Background

B.1. General Introduction

Cancer is a complex and heterogeneous disease in which mutations and other genomic and epigenomic abnormalities play a role in both its initiation and progression. Accumulated research data implicate numerous somatic mutations and a more limited number of inherited mutations in carcinogenesis. Understanding cancer-specific somatic mutations can provide important clues regarding the molecular processes underlying the development and progression of certain tumors. Given cancer’s complexity, it is generally believed that only a fraction of alterations that may be useful as characteristic markers of specific tumor types and/or potential molecular targets have been identified to date. Therefore, to be successful, comprehensive genomic analyses of cancer must overcome a broad range of challenges stemming from the biological complexity and heterogeneity of human tumors and subtypes. An important role in tumor heterogeneity is played by the genomic instability, which is inherent to the progression of cancer. The dynamic changes in tumor genomes are influenced by the cellular and biological context, genetic characteristics of individual persons, and environmental factors. Certain similarities exist across tumor types, however any effort to characterize the genomes of tumors in a comprehensive, systematic manner must address the heterogeneity across distinct cancer types and subtypes.

Many research groups are working independently to identify cancer-relevant genomic changes (e.g., alterations in expression profiles, chromosome deletions, amplifications, and/or translocations) in a relatively small number of samples. Cancer-relevant changes have been detected at diverse levels of genomic organization; they include point mutations, chromosomal deletions, amplifications, translocations, and/or changes in the number of individual chromosomes, all of which can, in principle, contribute to transcriptional aberrations. However, in terms of comprehensive cataloging, these individualized, researcher-initiated and uncoordinated approaches are limited. Such studies are inherently fragmentary (e.g., by technology and/or tumor specimens analyzed) and difficult to integrate because of data compatibility issues across studies and tumor types/sub-types.

B.2. Center for Cancer Genomics

The Center for Cancer Genomics (CCG) at the NCI was established in 2011 with a mission to lead the NCI efforts in generating critical datasets required to catalog the alterations seen in human tumors, coordinating data unification and sharing efforts, and supporting development of analytical tools and computational approaches aimed at improving our understanding of the large-scale, multidimensional data. CCG also has the goal of developing and applying cutting-edge genomic science to prevent cancer and to better treat cancer patients. An example in the context is adding comprehensive genomic characterizations to NCI-supported clinical trials. Currently, there are several large-scale cancer genome research projects initiated and managed by the CCG. In addition, the CCG performs genomic characterization in collaborative projects with other NCI Divisions, such as the Exceptional Responders and Alchemist clinical trials.

B.3. Project Backgrounds

In 2006, the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) initiated a collaboration named The Cancer Genome Atlas (TCGA) project to determine the feasibility of more comprehensively cataloging the genomic alterations associated with a number of different human cancers.

The project demonstrated that cancer-associated genes and genomic regions can be identified by combining diverse information from genome analyses (as defined in the previous paragraph), with tumor biology and clinical data, and that the sequencing of selected regions can be conducted efficiently and cost-effectively. The comprehensiveness and rate of progress of TCGA depended on both optimization of technical issues and resource availability.

The strength of TCGA was to produce unprecedented multi-dimensional data sets using an appropriate number of samples to provide statistically robust results that sets the stage for a new era in the discovery of new cancer interventions. The integrative analyses leading to the formulation of an unanticipated hypothesis on a potential mechanism of resistance highlights precisely the value and power of such project design, demonstrating how unbiased and systematic cancer genome analyses of large sample cohorts can lead to important discoveries.

Three key “lessons learned” during the TCGA Program were that, to be able to interpret the molecular characterizations generated by the various characterization platform, the Centers had to a) utilize high quality molecular analytes isolated from well characterized tissue specimens, b) perform experiments utilizing strictly standardized protocols and c) deposit the results in structured and well-described formats.

The last lesson strongly impacted the ability of the various analytical groups to extract meaningful results from the genomic data generated.

One unique aspect of TCGA program was the development and operation of high throughput molecular characterization pipelines. These pipelines made it possible for TCGA to conduct a coordinated and comprehensive, genome-wide analysis of cancer-relevant alterations by simultaneously applying several technologies to interrogate the genome, epigenome or transcriptome in large collections of quality controlled cancer biospecimens derived from specific cancer types. The progress in understanding cancer-associated molecular alterations made in TCGA suggest that it was now possible to obtain comprehensive genomic information from multiple tumor types to catalog most, if not all, of the genomic changes associated with cancer. The TCGA Project Research Network demonstrated that a coordinated pipeline approach to investigation of cancer is the best way to avoid biases in the datasets, thus allowing for interoperability of the different projects. The Genome Characterization Centers contracts solicited here are key components of the integrated pipeline of the Center for Cancer Genomics at the National Cancer Institute.

B.4. Center for Cancer Genomics Pipeline

In view of the extensive experience gained through the TCGA project, the leadership of the CCG has decided to support genomic characterization projects with the same operational model. This model consists of a coordinated pipeline standardized to receive tissues accrued to the different projects, process analytes, perform characterizations of samples, and present the results to the community.

Components of this coordinated pipeline are:

a. Biospecimen Processing Center (BPC): The BPC serves as the tissue processing center and provides the biomolecules for GCCs. Standard operating procedures will be used for clinical data collection, sample collection, pathological examination, biomolecule (e.g., DNA and RNA) extractions, quality control, laboratory data collection, and biomolecule distribution to the GCCs.

The samples are required to have patient informed consent for the public release of data or an IRB waiver. (https://cancergenome.nih.gov/abouttcga/policies). All GCC awardees will be required to work with the BPC to establish legal framework document entitled Material Transfer Agreement (MTA) for the transfer of analytes.

b. Genome Characterization Centers (GCCs): As a part of CCG’s overall operation capacity, the GCCs will produce high quality genomic, transcriptomic, proteomic, and epigenomic data using validated technologies (e.g., DNA and RNA sequencing, methylation arrays, etc.) to reveal the spectrum of alterations in human tumors. Technologies must be optimized by each GCC to increase processing rate, sensitivity and specificity of production. List of requested characterization platforms, depth and breadth of coverage, as well as substrates to be used in the assays can be found in the requirements in specific task order statement of work.

c. Genome Data Analysis Centers (GDACs): The Genome Data Analysis Centers (GDACs) work hand-in-hand with the Genome Characterization Centers (GCCs) to perform “higher level” analyses of the data produced by the GCC and to develop state-of-the-art tools that assist researchers with processing and integrating data analyses across the entire genome. These analyses take the form of both fully automated pipelines, as well as, ad-hoc analysis performed at https://cancergenome.nih.gov/abouttcga/policies the request of NCI funded Analysis Working Groups (AWG) from each project to produce high quality publications.

d. Genomic Data Commons (GDC): The NCI's Genomic Data Commons (GDC) provides the cancer research community with a unified data repository that enables data sharing across cancer genomic studies in support of precision medicine. Data generated by CCG projects will be deposited into NCI’s GDC as soon as they are validated, in general within a few weeks of generation. The information generated by the CCG project will be centrally managed by GDC to follow developed data standards and controlled vocabularies for each new technology, to establish an informatics infrastructure for data exchange between components of the project and a central repository, to create portals for basic and clinical researchers to easily access the data, and to encourage new computational approaches to analyze the data. Another key function of the GDC is to provide a secure network and means to protect the integrity and security of research and clinical data. GCCs will submit primary data and metadata to GDC by adapting their submission pipelines to conform to the submission requirements of GDC.

(https://gdc.cancer.gov/submit-data)

B.5. Current CCG Genomics Studies

CCG conducts genomic studies on biospecimens from cancer patients for whom clinical characteristics and treatment outcome data are also available.

Several ongoing CCG studies are described below. CCG and collaborators may initiate new programs during the performance period of this contract.

B.5.a. Exceptional Responders(ER) Initiative

The focus of the Exceptional Responders Initiative (Exceptional Responders), also called “the Exceptional Cases Initiative,” is to explore the molecular basis for why 1% to 10% of patients enrolled in clinical trials of single targeted agent therapies that are otherwise deemed “failures” respond to these agents with a complete or partial remission of their disease. The goals are to decipher the molecular factors that may explain these “exceptional responses”. A pilot effort started at NCI in 2016 to determine how effectively hypotheses can be generated from this approach that lead to new therapeutic strategies. The majority of single agent cancer drugs that enter Phase I and II clinical trials fail to show adequate tumor response for continued development. However, in many of these trials there are a few (1% to 10%) patients that have a significant response to the therapy. These “failed” trials could be very informative regarding molecular markers that predict a positive response to these single agent therapies in a small subset of patients, thus making these “inactive” agents useful. Even later phase clinical trials may have a few patients that experience an exceptional response, such as a complete response, that occurs in 10% or less of patients. Examples of the utility of this approach exist already (e.g., mutations predicting sensitivity to Everolimus and EGFR tyrosine kinase inhibitors). The Exceptional Responders Initiative envisions that this genomic approach to understanding therapeutic responses may be broadly applicable in cancer. The ability of molecular technologies to stratify tumor types has resulted in many common cancers being separated into specific subtypes that respond to therapeutic agents in very different ways. Identifying additional molecular markers that are able to predict a clinical response in subsets of patients will render future cancer treatments more precise. The complete or partial “exceptional responses” observed in this cohort of patients treated on “failed” trials should provide new leads for future oncologic therapies.

The feasibility of the Exceptional Responders paradigm will be assessed in 100 patients for whom reliable outcome data from patients treated on clinical trials both with generic and targeted monotherapies or combinations. Tumor biopsy material will be obtained from these patients as well as germline tissue, if available. The tissue will undergo next generation whole exome resequencing and, if practical, whole transcriptome resequencing. If this proves feasible, the project can be expanded to include other therapy regimens. The success of the endeavor depends on having adequate tissue for analysis, robust analytical techniques/platforms, and reliable outcome data for patients who have been treated on defined and consistent drug regimens. Tissue and clinical data could be obtained from either NCI-supported or pharmaceutical industry trials where there is reliable outcome data, and perhaps from other sources. In addition, the Exceptional Responders initiative will collect publicly available sequencing and clinical data from patients with exceptional therapeutic responses

B.5.b. Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (Alchemist)

The Alchemist Clinical Trial seeks to capitalize on a number of events that have converged to create an opportunity for significant clinical advances in the treatment of subsets of adjuvant lung cancer and to take the next step in biological characterization of lung cancer on a national level. Recently, two of the NCI-supported US Cooperative Clinical Trials groups have brought study proposals forward for evaluation in the NCI Thoracic Malignancy Steering Committee. Each proposal would select patients according to a biomarker validated in the metastatic setting and test for a large clinical effect. The two markers, EGFR mutation and ALK-positivity, each have an incidence of about 5%- 10% in the general lung adenocarcinoma population, so each study design would require screening over 7,000 patients. These two markers are mutually exclusive, so there is particular efficiency in screening one set of patients to identify those positive for one marker or the other. Surgical specimens will be available from this trial, providing adequate tissue for extensive analysis. While most of this tumor tissue obtained from a cooperative group clinical trial would be formalin-fixed, technical advances now allow extensive sequence characterization of this material. Although this project would launch based on the EGFR and ALK biomarkers, it is envisioned that Alchemist serves as an open platform, and it is likely that if the infrastructure were put in place, additional studies could tap into the stream of biomarker-classified patients. In particular, tissues from all patients screened for the Alchemist trial would be available for comprehensive genomic analyses, for which the patients would be consented. Patients testing negative for the EGFR and ALK biomarkers will be given standard treatment and followed as a prospective cohort, with repeat biopsies obtained upon tumor relapse.

B.5.c. Cancer Driver Discovery Project (CDDP)

The TCGA project seeks to characterize 500 cases per tumor for most tumor types. However, with 500 cases at a background mutation rate of 10 mutations/Mb, only mutations that occur in at least 5 percent of the cases can be identified. Analysis of more of tumors is needed to discover less common oncogenes and tumor suppressors. The pilot phase of the Cancer Driver Discovery Project (CDDP), seeks to identify these lower frequency cancer drivers in lung, and colorectal cancers. Up to 2000 cases from each disease will be characterized and analyzed to discover genes mutated at low frequency between 2% to 5%. For the most part, CDDP cases will have the same qualifying metrics as TCGA. However, in order to collect more cases, CDDP will accept cases with only formalin-fixed paraffin-embedded (FFPE) tumor tissues in addition to cases with frozen tumor tissues. Since FFPE tumor tissues tend to be smaller, the minimal yield requirements for DNA and RNA in CDDP will be lower than has been typically been used in TCGA.

B.5.d. Human Cancer Models initiative (HCMI)

The Human Cancer Models Initiative (HCMI) is an international consortium that is generating novel human tumor-derived culture models, which are annotated with genomic and clinical data. In an effort to advance cancer research and more fully understand how in vitro findings are related to clinical biology, HCMI-developed models and related data will be available as a community resource for cancer research. The National Cancer Institute (NCI) is contributing to this international consortium by providing funding and support to two Cancer Model Development Centers (CMDCs).

The CMDCs will develop next-generation cancer models from patient tissue. Visit the Cancer Model Development Centers page (https://ocg.cancer.gov/programs/hcmi/cancer-model-development-centers) for an introduction to the NCI's CMDCs.

B.5.e. Clinical Trials Sequencing Project (CTSP)

The Clinical Trials Sequencing Project (CTSP) will promote the use of genomics to explain the molecular basis of response and resistance to therapies studied in National Cancer Institute (NCI)-sponsored clinical trials of the National Clinical Trials Network (NCTN). This project is a collaborative effort of the NCI’s Center for Cancer Genomics (CCG) and Division of Cancer Treatment and Diagnosis (DCTD) that has accepted six completed clinical trials in the initial calls for proposals. These trials include the following tumor types: diffuse large B-cell lymphoma, breast carcinoma, lung adenocarcinoma, cervical and renal cell carcinomas. The CTSP will use whole genome and/or whole exome sequencing along with transcriptome sequencing to attempt to identify recurrent genetic alterations and/or gene expression signatures of biospecimens collected from these clinical trials.

B.6. Other Collaborating NCI Programs information

The NCI has established several strategic initiatives that involve collaborations between CCG and other NCI Divisions in the realm of precision medicine. These major institutional efforts also take advantage of CCG’s integrated pipelines for genome characterizations.

https://www.cancer.gov/ https://ocg.cancer.gov/programs/hcmi/cancer-model-development-centers https://ocg.cancer.gov/programs/hcmi/cancer-model-development-centers https://ocg.cancer.gov/programs/hcmi/cancer-model-development-centers https://ocg.cancer.gov/programs/hcmi/cancer-model-development-centers http://www.cancer.gov/research/areas/clinical-trials/nctn http://www.cancer.gov/about-nci/organization/ccg http://dctd.cancer.gov/ http://dctd.cancer.gov/

B.6.a. Division of Cancer Treatment and Diagnosis

The Division of Cancer Treatment and Diagnosis (DCTD) takes prospective detection and treatment leads, facilitates their paths to clinical application, and expedites the initial and subsequent large-scale testing of new agents, biomarkers, imaging tests, and other therapeutic interventions (radiation, surgery, immunotherapy) in patients.

DCTD, like all of NCI, supports many programs that could not be done without government funding.

Investigators supported by the division engage in scientifically sound, high-risk research that may yield great benefits for patients with cancer, but are too difficult or risky for industry or academia to pursue. This includes a particular emphasis on the development of distinct molecular signatures for cancer, refined molecular assays, and state-of-the-art imaging techniques that will guide oncologic therapy in the future.

The division has eight major programs, including the Cancer Therapy Evaluation Program, that work together to bring unique molecules, diagnostic tests, and therapeutic interventions from the laboratory bench to the patient bedside.

B.6.b. Cancer Trials Support Unit

NCI developed the Cancer Trials Support Unit (CTSU) in 1999 as an integral support system for NCI’s cancer clinical trials. The CTSU streamlines and harmonizes support services for NCI-sponsored trials in cancer treatment, cancer prevention and control, advanced imaging and correlative science studies. As the NCI launched new programs in 2014, including the NCI’s National Clinical Trials Network (NCTN) and the Experimental Therapeutics Clinical Trials Network, (ETCTN), the CTSU will continue to play a key support role including to:

1) enhance the integration of information technology services supporting NCI’s national cancer clinical trials program,

2) streamline and standardize processes, including patient enrollment and data collection services,

3) reduce regulatory and administrative burden on investigators participating in NCI-sponsored clinical trials, and

4) facilitate physician and patient access to NCI-sponsored clinical trials.

B.6.c. Cancer Therapy Evaluation Program

The mission of the Cancer Therapy Evaluation Program (CTEP) is to improve the lives of cancer patients by finding better ways to treat, control and cure cancer. CTEP accomplishes this mission by funding an extensive national program of cancer research and by sponsoring clinical trials to evaluate new anti-cancer agents, with a particular emphasis on translational research to elucidate molecular targets and mechanisms of drug effects.

CTEP uses a scientific process to accomplish its mission:

1) Promising basic science findings are identified and translated into clinical research, both by identifying new agents for evaluation and by identifying biologic characteristics of tumors that may be clinically exploited.

2) Identifying novel anti-cancer agents with distinctive molecular targets, mechanisms of action, or properties are introduced into clinical trials, with prioritization of agents based on scientific criteria and therapeutic needs.

3) Evaluating anti-tumor activity of new anti-cancer agents in clinical trials.

4) Promising new cancer treatments are rigorously compared to best available treatments in hypothesis-driven clinical trials to reliably define superior treatments for specific types of cancer.

CTEP attempts to forge broad collaborations within the research community and works extensively with the pharmaceutical/biotechnology industry to effectively develop new cancer treatments. CTEP also seeks to involve outside experts and patients or their advocates in the formulation of research priorities. In the selection of clinical research for NCI sponsorship, CTEP attempts to fill critical gaps in the national cancer research effort and to avoid duplication of ongoing private sector efforts. In further efforts to control cancer, active new anticancer agents are made available as rapidly and widely as possible for patients.