National Cancer Institute Initiative Research Articles

Carboplatin dosing in the treatment of ovarian cancer: An NRG oncology group study

ObjectiveTo determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl). MethodsRetrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)—a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity were described using the area under the receiver operating characteristic curve (AUC). Sensitivity and positive predictive values described the model's ability to discriminate between subjects with/without the adverse event. ResultsAUC statistics (range, 0.52–0.64) showed log(CrClJelliffe) was not a good predictor of grade ≥3 adverse events (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). Of 3830 patients, 628 (16%) had CrCl <60 mL/min. Positive predictive values for adverse events ranged from 1.8%–15%. Using the Cockcroft-Gault, Cockcroft-Gault with NCCN modifications, and MDRD (instead of Jelliffe) formulas to estimate renal function resulted in a >10% decrease in carboplatin dosing in 16%, 32%, and 5.2% of patients, respectively, and a >10% increase in carboplatin dosing in 41%, 9.6% and 12% of patients, respectively. ConclusionThe formula used to estimate CrCl affects carboplatin dosing. Estimated CrCl <60 mL/min (by Jelliffe) did not accurately predict adverse events. Efforts continue to better predict renal function. Endorsing National Cancer Institute initiatives to broaden study eligibility, our data do not support a minimum threshold CrCl <60 mL/min as an exclusion criterion from clinical trials.

Abstract 2129: CPTAC: Biospecimen accrual for proteogenomics

Abstract The Clinical Proteomics Tumor Analysis Consortium (CPTAC) is a National Cancer Institute initiative that seeks to uncover the molecular basis of cancer using a proteogenomic approach to study prospective cancer specimens from treatment naïve patients. Leidos Biomed provides an infrastructure for supporting the collection of high quality biospecimens specific to proteogenomics and the corresponding clinical data, in addition to project and subcontract management for the program. The proportion of biospecimens so far from racial and ethnic minority patients are underrepresented, which preclude equitable research across all patient groups for cancer treatment. CPTAC program seeks diversity in the accrual cohort and an effort is ongoing to encourage the participation of tissue source sites serving racial and ethnic minorities that can contribute high quality biospecimens towards the collection. CPTAC applies the understanding of the molecular basis of cancer to identify biomarker candidates. CPTAC Phase II completed in 2016, collecting over 350 cases from breast, colon and ovarian patients. CPTAC Phase III that is in progress began to collect and analyze 200 cases from each of ten additional cancers. Analysis is close to completion for uterine corpus endometrial carcinoma, kidney clear cell renal cell carcinoma and lung adenocarcinoma while accruals are ongoing for 7 other cancer types. The study entails collection and pathology evaluation of biospecimens, high-quality clinical data and images from clinical sites from around the world. A biorepository evaluates and processes the biospecimens, sending nucleic acids to a sequencing center and tissues to proteomics groups. Data are combined and analyzed by analysis and translational centers. Genomic data are made available to the research community through the NCI Genomic Data Commons(GDC). Proteomic data are made available through CPTAC’s Data Coordinating Center(DCC). Imaging data are made available through The Cancer Imaging Archive (TCIA). The program is expanding and initiating biospecimen collection for proteogenomic analysis of ten additional rare tumor types. Citation Format: Mathangi Thiagarajan. CPTAC: Biospecimen accrual for proteogenomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2129.

An Overview of the National Cancer Institute's Initiatives to Accelerate Rural Cancer Control Research.

This article is featured in Highlights of This Issue, [p. 1237][1] A recent publication by the Centers for Disease Control and Prevention (CDC; ref. [1][2]) reported that nonmetropolitan rural counties had lower 5-year annual age-adjusted cancer incidence rates (2009–2013), but higher average

The pervasive crisis of diminishing radiation therapy access for vulnerable populations in the United States—Part 4: Appalachian patients

PurposeCompared with the rest of the United States, the population of Appalachia has lower education levels, higher rates of poverty, and limited access to health care. The presence of disparities in radiation therapy (RT) access for Appalachian patients with cancer has rarely been examined. Methods and materialsThe National Cancer Institute initiatives toward addressing disparities in treatment access for rural populations were examined. An extensive literature search was undertaken for studies investigating RT access disparities in Appalachian patients, beginning with the most common cancers in these patients (lung, colorectal, and cervical). ResultsAlthough the literature investigating RT access disparities in Appalachia is relatively sparse, studies examining lung, colorectal, cervical, prostate, head and neck, breast, and esophageal cancer, as well as lymphoma, indicate an unfortunate commonality in barriers to optimal RT access for Appalachian patients with cancer. These barriers are predominantly socioeconomic in nature (low income and lack of private insurance) but are exacerbated by paucities in both the number and quality of radiation centers that are accessible to this patient population. ConclusionsRegardless of organ system, there are significant barriers for Appalachian patients with cancer to receive RT. Such diminished access is alarming and warrants resources devoted to addressing these disparities, which often go overlooked because of the assumption that the overall wealth of the United States is tangibly applicable to all of its citizens. Without intelligently targeted investments of time and finances in this arena, there is great risk of exacerbating rather than alleviating the already heavy burden facing Appalachian patients with cancer.

Abstract 400: NCI's CPTAC Phase III, proteogenomic analysis of additonal cancer types

Abstract The Clinical Proteomics Tumor Analysis Consortium (CPTAC) is a National Cancer Institute initiative that seeks to uncover the molecular basis of cancer using a proteogenomic approach to study prospective cancer specimens. Leidos Biomed provides an infrastructure for supporting the collection of high quality biospecimens and data, in addition to project and subcontract management for the program. CPTAC applies the understanding of the molecular basis of cancer to identify biomarker candidates. Phase II of CPTAC, completed in 2016, collected over 500 cases from breast, colon and ovarian patients. In early 2016, CPTAC Phase III began to collect and analyze 200 cases of each of ten additional cancers. The goal is to collect 200 qualified cases of five to six tumor types over a five-year period, although the program is currently accruing from ten. The study entails collection and pathology evaluation of biospecimens, high-quality clinical data and images from clinical sites around the world. A biorepository evaluates and processes the biospecimens, sending nucleic acids to a sequencing center and tissues to proteomics groups. Data are combined and analyzed by translational centers. Genomic data are made available to the research community through the NCI Genomic Data Commons. Proteomic data are made available through the Data Coordinating Center. We report here on progress in collection of tissues and clinical data, and use of biorepository, proteomics and genomics and analysis centers. Citation Format: Linda I. Hannick. NCI's CPTAC Phase III, proteogenomic analysis of additonal cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 400. doi:10.1158/1538-7445.AM2017-400

Defining precision: The precision medicine initiative trials NCI-MPACT and NCI-MATCH

“Precision” trials, using rationally incorporated biomarker targets and molecularly selective anticancer agents, have become of great interest to both patients and their physicians. In the endeavor to test the cornerstone premise of precision oncotherapy, that is, determining if modulating a specific molecular aberration in a patient’s tumor with a correspondingly specific therapeutic agent improves clinical outcomes, the design of clinical trials with embedded genomic characterization platforms which guide therapy are an increasing challenge. The National Cancer Institute Precision Medicine Initiative is an unprecedented large interdisciplinary collaborative effort to conceptualize and test the feasibility of trials incorporating sequencing platforms and large-scale bioinformatics processing that are not currently uniformly available to patients. National Cancer Institute-Molecular Profiling-based Assignment of Cancer Therapy and National Cancer Institute-Molecular Analysis for Therapy Choice are 2 genomic to phenotypic trials under this National Cancer Institute initiative, where treatment is selected according to predetermined genetic alterations detected using next-generation sequencing technology across a broad range of tumor types. In this article, we discuss the objectives and trial designs that have enabled the public-private partnerships required to complete the scale of both trials, as well as interim trial updates and strategic considerations that have driven data analysis and targeted therapy assignment, with the intent of elucidating further the benefits of this treatment approach for patients.

NCIP Hub and Cancer Genomics Cloud Pilots – Two U.S. National Cancer Institute Initiatives

NCIP Hub and Cancer Genomics Cloud Pilots – Two U.S. National Cancer Institute Initiatives

The Quantitative Imaging Network: NCI's Historical Perspective and Planned Goals

The purpose of this editorial is to provide a brief history of National Institutes of Health National Cancer Institute (NCI) workshops as related to quantitative imaging within the oncology setting. The editorial will then focus on the recently supported NCI initiatives, including the Quantitative Imaging Network (QIN) initiative and its organizational structure, including planned research goals and deliverables. The publications in this issue of Translational Oncology come from many of the current members of this QIN research network.

NCI Initiative Focuses on Obesity‐Cancer Link

NCI Initiative Focuses on Obesity‐Cancer Link

Bioinformatic challenges for proteomic biomarkers of cancer

Background Proteomic biomarkers are sets of proteins that may be detected in biofluids for disease detection, prognosis, and treatment selection. Vanderbilt University is taking part in two National Cancer Institute initiatives to establish a basis for clinical biomarkers. The first, Clinical Proteomic Technology Assessment for Cancer (CPTAC), characterizes proteomic technologies for discovery and validation of biomarkers. The second, the Early Detection Research Network (EDRN), attempts to develop new sets of biomarkers and evaluate their effectiveness in clinically relevant samples. The quest for biomarkers is fraught with challenges for both “bench” experiments and bioinformatics. Here, we examine sources of discrepancy at several levels. The search engines that identify peptides from LC-MS/MS experiments differ significantly in the set of spectra that they identify from experiments. Parsimonious protein assembly may prune out proteins in one experiment and retain them in another. Protein differentiation tools may yield divergent results, even when starting from the same data sets. Verifying biomarkers through targeted proteomics has only recently been supported by tools that can work across instruments from different vendors. Translating cancer biology knowledge into clinically relevant tests for this disease will require care at all these levels.

WE-B-201B-01: NCI Initiatives to Create Public Resources to Evaluate CAD Methods: Progress to Date

The National Cancer Institute (NCI) has developed several initiatives supporting the creation of reference databases as public resources to facilitate the evaluation of CAD or image processing methods. They include the combined LungImageDatabase Consortium (LIDC) and ImageDatabase Resource Initiative (IDRI) which include both X‐ray CT and plain film or digital images of the lung, which are annotated to permit the evaluation of the performance of software tools for lungcancer detection. A second public resource is the Reference ImageDatabase to Evaluate the Response to Therapy (RIDER) that is designed to assist researchers in the evaluation of image processing methods to measure responses to therapy. This data base includes both repeat and longitudinal images of phantom s and patients for a range of organ systems and imaging modalities. Finally NCI has recently funded the Quantitative Imaging Network (QIN), the goals of which are to facilitate clinical decision making through development and validation of quantitative imaging methods, including testing of new imaging protocols and methods in early phase trials. Cooperative group members agree to share their data. These initiatives will be reviewed, along with options for AAPM members to participate and take advantage of the public resources as potential international reference standards to evaluate software tools. Specific details about the importance of the initial efforts to create the LIDC and IDRI initiative will be addressed.

Introduction: Evidence-based, Problem-oriented Medicine

“Precision” trials, using rationally incorporated biomarker targets and molecularly selective anticancer agents, have become of great interest to both patients and their physicians. In the endeavor to test the cornerstone premise of precision oncotherapy, that is, determining if modulating a specific molecular aberration in a patient’s tumor with a correspondingly specific therapeutic agent improves clinical outcomes, the design of clinical trials with embedded genomic characterization platforms which guide therapy are an increasing challenge. The National Cancer Institute Precision Medicine Initiative is an unprecedented large interdisciplinary collaborative effort to conceptualize and test the feasibility of trials incorporating sequencing platforms and large-scale bioinformatics processing that are not currently uniformly available to patients. National Cancer Institute-Molecular Profiling-based Assignment of Cancer Therapy and National Cancer Institute-Molecular Analysis for Therapy Choice are 2 genomic to phenotypic trials under this National Cancer Institute initiative, where treatment is selected according to predetermined genetic alterations detected using next-generation sequencing technology across a broad range of tumor types. In this article, we discuss the objectives and trial designs that have enabled the public-private partnerships required to complete the scale of both trials, as well as interim trial updates and strategic considerations that have driven data analysis and targeted therapy assignment, with the intent of elucidating further the benefits of this treatment approach for patients.

Discovery and Characterization of Macrocyclic Thiopeptide Proteasome Inhibitors for Hematologic Malignancies

The ubiquitin proteasome pathway comprises a coordinated, dynamic cellular system critical to cellular metabolism, signaling and proliferation. The expanding clinical utility of the peptide boronate, bortezomib, in the treatment of patients with multiple myeloma and other hematologic malignancies has established the human 26S proteasome as a validated target in cancer. Still, only one FDA-approved proteasome inhibitor presently exists. Restricted activity against one enzymatic function of the proteasome and dose-limiting toxicities associated with bortezomib warrant further discovery efforts aimed at the identification of structurally and functionally distinct protein degradation inhibitors (PDIs). Here, we report a novel family of natural product proteasome inhibitors discovered by high-throughput, high-content screening at the National Cancer Institute Initiative for Chemical Genetics. A primary screen of 14,000 small molecules was performed in 384-well plate format using a cell line stably transfected with a destabilized fluorescent protein chimera. Assay positives were retested in the primary screen in dose-response format. Thiostrepton was selected for further characterization due to its unique macrocyclic chemical structure, the recent publication of its total synthesis, reports of anticancer properties and the lack of prior annotation as a PDI. First, thiostrepton was linked to previously characterized molecules acting on the protein degradation pathways by transcriptional small molecule connectivity mapping (CMAP). Subsequent cell-state analyses confirmed strong induction of functional and annotated gene sets associated with misfolded protein stress and proteasome inhibition. Mechanism of action was confirmed by biochemical profiling of human 20S proteasome active site inhibition and specificity using homogeneous assays and selective substrates for each of three catalytic active sites. Importantly, inhibitory activity of thiostrepton differs from bortezomib by blocking both the chymotryptic-like and PGPH active sites with sub-micromolar potencies. Dose-dependent inhibition of multiple myeloma cell growth was observed, with a concomitant increase in polyubiquitinated protein stress and induction of apoptosis. Inhibition of conferred proliferation by bone marrow stroma was confirmed using a novel miniaturized high-content assay modeling the bone marrow stroma-multiple myeloma microenvironment. Structurally related compounds to thiostrepton, nosiheptide and siomycin, were confirmed also as proteasome inhibitors as above. Our discovery of this class of natural products as proteasome inhibitors and a recent report of siomycin inhibition of Sonic Hedgehog (Shh) signaling begged the question whether established proteasome inhibitors would inhibit Shh signaling in human cancer. This hypothesis was confirmed in a set of reporter-gene assays. In sum, these studies identify thiopeptide macrocycles as a class of naturally-occurring proteasome inhibitors poised for clinical development in hematologic malignancies, establish novel high-throughput assays for modeling MM-stroma microenvironment interactions and pave the way for the development of proteasome inhibitors in disease states where Shh signaling is central to pathogenesis.

What Is the Future of Oncology? National Cancer Institute Initiatives to Improve Research, Development, and Implementation in Cancer Prevention and Treatment

To improve the efficiency and effectiveness with which we bring novel cancer treatment and prevention strategies into routine clinical use, the National Cancer Institute has commissioned the Clinical Trials Working Group to restructure its activities related to clinical trials. A total of 22 initiatives have been developed and are being implemented under the rubrics of Coordination, Prioritization/Scientific Quality, Standardization, Operational Efficiency, and Integrated Management. A similar model was recently applied to the newly formed Translational Research Working Group, which will focus on more efficient translation of scientific discoveries arising from the laboratory, clinic, or population into early phase clinical testing.

Small Molecules, Big Players: the National Cancer Institute's Initiative for Chemical Genetics

In 2002, the National Cancer Institute created the Initiative for Chemical Genetics (ICG), to enable public research using small molecules to accelerate the discovery of cancer-relevant small-molecule probes. The ICG is a public-access research facility consisting of a tightly integrated team of synthetic and analytical chemists, assay developers, high-throughput screening and automation engineers, computational scientists, and software developers. The ICG seeks to facilitate the cross-fertilization of synthetic chemistry and cancer biology by creating a research environment in which new scientific collaborations are possible. To date, the ICG has interacted with 76 biology laboratories from 39 institutions and more than a dozen organic synthetic chemistry laboratories around the country and in Canada. All chemistry and screening data are deposited into the ChemBank web site (http://chembank.broad.harvard.edu/) and are available to the entire research community within a year of generation. ChemBank is both a data repository and a data analysis environment, facilitating the exploration of chemical and biological information across many different assays and small molecules. This report outlines how the ICG functions, how researchers can take advantage of its screening, chemistry and informatic capabilities, and provides a brief summary of some of the many important research findings.

National Cancer Institute initiatives for international and AIDS-related cancer research

National Cancer Institute initiatives for international and AIDS-related cancer research

598 The cancer therapy evaluation program, National Cancer Institute initiative to enhance combination investigational agent clinical trials

We have designed microfluidic devices with the aim of coupling isotachophoresis (ITP) with zone electrophoresis (ZE) as a method to increase the concentration limit of detection in microfluidic devices. We used plastic multi-channel chips, designed with long sample injection channel segments, to increase the sample loading. The chip was designed to allow stacking of the sample into a narrow band by discontinuous ITP buffers and subsequent separation in the ZE mode. In the ITP–ZE mode, with a 2-cm long sample injection plug, sensitivity was increased by 400-fold over chip ZE and we found that the separation performance after the ITP stacking was comparable to that of regular chip ZE. We report sub-picomolar limits of detection of fluorescently labeled ACLARA eTag reporter molecules electrokinetically injected from cell lysate sample matrixes containing moderate salt concentrations. We evaluated sample injections from buffers with varied ionic strengths and found that efficient stacking and separations were obtained in both low and high conductivity buffers, including physiological buffer with at least 140 mM salt. We applied ITP–ZE to the analysis of a cell surface protease (ADAM 17) which used live intact cells in physiological buffers with detection limits below 10 cells/assay.

From knowing to controlling: a path from genomics to drugs using small molecule probes.

The National Cancer Institute Initiative in Chemical Genetics is designed to encourage the development of small molecular probes. The probes are useful for activating or inactivating protein functions, thereby providing resources that help discern the functions of gene products in normal and disease cells, as well as in tissues. This initiative includes "ChemBank," a suite of informatics tools and databases aimed at promoting the development and use of chemical genetics by scientists worldwide. The information generated with such tools should provide a critical link from genomic discovery to drug development.

National Cancer Institute Initiative: Lung Image Database Resource for Imaging Research

Preliminary clinical studies suggest that spiral computed tomography (CT) of the lungs can improve early detection of lung cancer in high-risk individuals. More clinical studies are needed, however, before public health recommendations can be proposed for population-based screening. Spiral CT generates large-volume data sets and thus poses problems in terms of implementation of efficient and cost-effective screening methods. Image processing algorithms such as computer assisted diagnostic (CAD) methods have the potential to assist in lesion (eg, nodule) detection on spiral CT studies. CAD methods may also be used to characterize nodules by either assessing the stability or change in size of lesions based on evaluation of serial CT studies, or quantitatively measuring the temporal parameters related to contrast dynamics when using contrast material–enhanced CT studies. CAD methods therefore have the potential to enhance the sensitivity and specificity of spiral CT lung screening studies. Lung cancer screening studies now under investigation create an opportunity to develop an image database that will allow comparison and optimization of CAD algorithms. This database could serve as an important national resource for the academic and industrial research community that is currently involved in the development of CAD methods. The National Cancer Institute request for applications (RFA) (CA-01-001) has already been announced (April 2000) to establish and support a consortium of academic centers to develop this database, the consortium to be referred to as the Lung Image Database Consortium (LIDC). This RFA is now closed. Five academic sites have been selected to be members of the LIDC, the first meeting of this consortium is planned for spring of 2001, and a public meeting is to be held in 2002. This report is abstracted from the previously published RFA to serve as an example of how an initiative is developed by the National Cancer Institute to support a research resource. For specific details of the RFA, please access the following Internet site: http://www.nci.nih.gov/bip/NCI-DIPinisumm.htm#a11 .

NCI-Funded Small Animal Imaging Programs

The use of small animal models as surrogates for humans in the study of normal and disease states has a long history. The models used have ranged from the simplest possible to those as complex as the investigator’s imagination and skills allow. Growing opportunities to apply methods of molecular and cellular biology to the study and treatment of human disease have increased demand for the creation of animal models with more humanlike diseases. Cultures of cancer cells growing in vitro, or as tumors on the flank of a small animal, no longer suffice because treatment agents and techniques that enjoy even great success in such milieus too frequently prove to be utter failures in phase I testing in humans. These failures propel investigators to understand disease, and its progression and treatment, by better means than observations of less-faithful models, such as a growing cell line. They see more fruitful approaches in molecular and cellular manipulations of animals to model the whole disease process more faithfully. Successful creations of live, whole animals that more faithfully model human diseases led to an obvious desire for a way to image disease progression in each animal, without resort to biopsy or sacrifice to answer every question. Most early animal imaging studies used instruments and techniques designed for human use, during hours when this equipment was not in clinical use. However, systems optimized for human use frequently yield suboptimal results for small animal studies. In addition, there are other problems associated with mixing animal and patient studies on clinical instruments. The growing need for dedicated small animal imaging systems was noticed by the Biomedical Imaging Program of the National Cancer Institute (NCI) and was included among other issues explored in series of workshops held to better define the needs for cancer imaging and areas in which special NCI initiatives might provide the most impetus for change and advancement. One subgroup addressing small animal imaging—the In vivo Molecular/Functional Imaging Subgroup (MIS), chaired by Elias Zerhouni, MD—recommended that the National Institutes of Health (NIH) and NCI should support dedicated small animal imaging facilities focusing on the study of genetically engineered tumor models (http://cancer.gov/bip/ISWG3.htm). They also recommended that the greater part of the efforts of the facilities be directed toward imaging, not the creation of new instruments. Workshop participants concluded that the facilities should provide imaging by more than one technique because they did not like the prospect of limiting the range of scientific questions open to investigation by having only one modality at hand. With this workshop recommendation in mind, the Biomedical Imaging Program developed a concept for Small Animal Imaging Resource Project (SAIRP) grants, which the May 1998 NCI Board of Scientific Advisors approved enthusiastically. The concept was for the Biomedical Imaging Program to budget support for approximately four SAIRPs under the R24 mechanism, which specifies the development of research resource centers. Each grantee would be expected to provide access to at least two different imaging modalities and serve at least six funded cancer research projects by the end of the 2nd year of operation. The Biomedical Imaging Program translated the concept into a request for applications, set a receipt date of November 1998, and defined the objectives and scope as follows: (a) multiple imaging technologies for small animals, emphasizing, but not limited to those technologies that can provide biochemical, genetic or Acad Radiol 2001; 8:372–374