publication date: Apr. 19, 2019

NCI advisors approve eight concepts, including three Cancer Moonshot concepts

By Claire Dietz

The NCI Board of Scientific Advisors approved eight new Requests for Applications, Requests for Proposals, and PAR—a program announcement reviewed in the institute—concepts at a meeting March 25, including three new Cancer Moonshot concepts.

One Cancer Moonshot concept, “Technologies Development for Use in Next Generation Cancer Models,” was deferred at the last BSA meeting in December (The Cancer Letter, Jan. 11).

The following concepts were approved:


Cancer Intervention and Surveillance Modeling Network (re-issue RFA/Coop. Agr.)

This RFA is focused on the Cancer Intervention and Surveillance Modeling Network, CISNET, formed in 2000, which is an NCI-sponsored collaborative consortium of simulation modelers in breast, prostate, colorectal, lung, esophagus, and cervical cancers.

 

Using simulation modeling, CISNET extends evidence provided by trials and both epidemiologic and surveillance data to guide public health research and priorities. It also helps address the gap between innovation in cancer research and the “ability to efficiently harness it to improve population health.”

The RFA was submitted by project scientists from the Division of Cancer Prevention and the Division of Cancer Control and Population Sciences.

According to the RFA, in many instances, individual modeling efforts yields different results which are difficult to reconcile. CISNET created a new approach called systematic comparative modeling. This modeling uses central questions to be addressed by groups collaboratively with a common set of inputs and outputs. It aims for reproducibility across models to add credibility to the results, and differences point out areas for further study in a systematic way.

The RFA proposed components for the next round of CISNET, which included an open competition, including the continuation of current cancer sites with up to six multiple-PI U01’s. A U01 is a cooperative agreement aimed to “support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies.”

CISNET proposed the continuation of several cross-program activities including continued cross-cancer site collaborations, continued programmers interest group, and the new program: Junior Investigators Career Enhancement program, known as JUICE.

According to the RFA, CISNET can help answer questions that are becoming ubiquitous in oncology. These questions were broken up by type of cancer:

  • Cervical: Should screening recommendations change as vaccinated populations reach screening age?

  • Colorectal: What mix of screen modalities for colorectal cancer might work best in underserved populated in the U.S. and in middle- and lower-income countries?

  • Breast: Can the interface between randomized trials of active surveillance for DCIS (ductal carcinoma in situ) of the breast and modeling help us better understand and manage this condition?

  • Esophageal: Can low cost, minimally invasive mass screening serve as a cost-effective triage for upper endoscopy to detect Barrett’s esophagus?

  • Prostate: Are the strategies for PSA screen that more effectively “threading the needle” of maximizing mortality reduction while minimizing overdiagnosis? What are the most effective strategies for initiating and terminating active surveillance that can minimize the harms of overdiagnosis?

  • Lung: What strategies for the management of suspicious nodules (Lung-Rads, volumetrics) are most effective for minimizing false positives, while maximizing sensitivity? Could strategies be individualized to take into account personal preferences?

The RFA’s nine priority areas to focus their modeling efforts are:

  • Precision screening and new screening technologies

  • Prevision treatment

  • Overdiagnosis and active surveillance

  • Decision aids (individual and policy)

  • Understanding screening in real-world settings and determining the best routes to optimize the processes

  • State, local, and international cancer control planning

  • Suggesting optimal routes to reduce health disparities

  • Methods development

  • Cancer site-specific opportunities

The ongoing priorities for the RFA set by Organ Sites Specific Steering Committees:

  • Specific aims as specified in grant application and selected from the priority areas

  • New topics of timely relevance

  • Outside inquiries from other NCI staff, NCI sponsored consortia, guideline setting organizations, and other outside researchers and organizations

In keeping pace with precision treatment, CISNET will focus on evolving big data resources drawn from electronic claims, labs, and health records, and their potential linkage to population-based registry data. This would generate detailed information on first-line and salvage therapies as well as dose, recurrence, and the genomic characterization of disease.

The Junior Investigators Career Enhancement Program is aimed to address the fact that modeling-oriented data scientists are in high demand and short supply.

The program is designed to help junior investigators to get the most out of their CISNET experiences and primarily targets pre-docs, post-docs, and junior faculty across CISNET. In the last round of CISNET, there were junior investigators initiative sponsored webinars, lunch sessions at meetings, and networking opportunities—but this was still a largely underfunded mandate, according to the RFA.

The budget places strict constraints on direct costs per year for each component. This included:

  • $180k per modeling group (with three to six groups)

  • $110k for coordinating center

  • $100k for rapid response funds

  • $40k for the JUICE program.

The total cost per year for six awards (with an average of four modeling groups per cancer site) was about $1.66 million for each award, or $10 million for all six awards. From fiscal year 2020 to fiscal year 2024, the total budget would be $50 million.

 


AIDS Malignancy Consortium (re-issue RFA/Coop. Agr./Ltd. Competition)

Approximately 36.7 million people live with HIV worldwide, with approximately 1.8 million new infections per year. Cancer is a prominent manifestation of HIV/AIDS and is a leading cause of morbidity and mortality in HIV-infected people.

The AIDS Malignancy Consortium’s mission is to:

  • Develop and evaluate clinical interventions for the treatment and prevention of malignancies in people with HIV

  • Conduct phase I, II, and III clinical trials of HIV-related malignancies

  • Investigate the biology of these malignancies in the context of clinical trials

  • Contribute specimens and clinical data to the AIDS and Cancer Specimen Resource.

 

In this grant cycle, the past 36 months, the consortium has developed 15 protocols, with 14 protocols having completed enrollment. Almost 2,900 patients have been accrued, with 2,350 in the ANCHOR study, and 537 non-ANCHOR participants. Fourteen protocols are actively accruing patients and approximately 63% of accrued U.S. participants are African American or Hispanic in origin. In the past 3 years, approximately 39 papers have been published in peer-reviewed journals.

The ANCHOR study, Anal Cancer HSIL Outcomes Research study, is a randomized controlled trial to establish whether treatment of anal high grade squamous intraepithelial lesions is an effective strategy in preventing anal cancer and will evaluate whether screening for HSIL is warranted.

Over 5,000 patients with HSIL will be randomized to two arms, treatment or active monitoring. To date, more than 7,000 have been screened and 2,804 have been randomized. The study will establish a bank of blood, anal swabs, and tissue specimens to study the molecular pathogenesis of progression from HSIL to cancer.

The consortium’s accomplishments this grant cycle include:

  • Evaluating immunotherapy approaches to solid tumors in HIV patients, using ipilimumab and nivolumab in advance solid tumors and brentuximab vedotin, or nivolumab for Hodgkin lymphoma

  • Developing and the assessment of new approaches for the front-line treatment of AIDS lymphoma (ibrutinib and R-DA-EPOCH and vorinostat and R-DA-EPOCH)

  • Investigating treatments with novel mechanisms of action for Kaposi sarcoma (bortezomib, lenalidomide, sEphB4-HAS)

  • Conducting Kaposi sarcoma international trials that defined standard of care in limited resource settings

  • Providing evidence for efficacy of the HPV vaccine in preventing HSIL among HIV-infected individuals naïve to the vaccine type

  • Assessing a therapeutic vaccine directed to E6/E7 HPV types 16/18 genes using electroporation

  • Establishing a network of clinicians trained in high resolution anoscopy and treating anal HSIL. These treatments and platform are being used for the conduct of the ANCHOR study

  • Completing a feasibility study in Africa of the safety, toxicity, and compliance of concomitant chemotherapy and radiotherapy for HIV-associated locally-advanced cervical cancer

  • Examining pharmacokinetic interactions of antiretroviral agents and novel anti-cancer agents (sunitinib, cabozentinib) in HIV subjects with solid tumors

The consortium’s “Practice-Changing Accomplishment[s]” include:

  • Establishing the standards for chemotherapy in aggressive CD20+ AIDS-related lymphomas, including the use of combination anti-retroviral therapy with rituximab-CHOP

  • Helping establish treatment standard for drug-resistant severe Kaposi sarcoma (paclitaxel) and assessing the relative merits of the two most efficacious drugs (paclitaxel vs liposomal doxorubicin)

  • Establishing infrared coagulation as the leading method of treatment of anal high grade squamous interepithelial lesions

  • Establishing the superiority of paclitaxel over etoposide or bleomycin/vincristine (the previous standard of care) for treating Kaposi sarcoma in Africa

  • Demonstrating that HIV-associated aggressive lymphoma patients who meet standard eligibility criteria for autologous or allogenic stem cell transplant responds well to transplantation (This is now the standard of care)

  • Developing and initiating the ANCHOR trial, they said it will likely define standard for anal cancer screening. The study is more than half accrued

The consortium’s current scientific needs are:

  • Cancer continues to be among the leading causes of death among HIV-infected patients in the U.S., and in some studies, it is the leading cause

  • The standards of care for progressive Kaposi sarcoma and NHL have not been optimized

  • Non-AIDS-defining cancers (especially lung, liver, head and neck, and anal) are increasing in areas where cART is widely available

  • The impact of AIDS and cART on anti-cancer chemotherapy, on toxicity profiles, and on response to treatment are not sufficiently studied

  • Need to optimize treatment in resource-limited countries

The total proposed budget for the RFA 5 years is $113,730,523.

 


Cancer Trials Support Unit contract renewal proposal (re-issue RFP)

The Cancer Trials Support Unit is a service of the NCI that supports clinical trial management and conduct. It “provides services to NCI-sponsored programs such as the National Clinical Trials Network, the Experimental Therapeutics Clinical Trials Network, and the NCI Community Oncology Research Program,” as well as other programs.

CTSU was established in 1999 to “streamline and harmonize support services for Phase III Cooperative Group cancer clinical trials funded by the NCI.” The scope of the unit has expanded to include support of multiple NCI-funded networks and clinical trials in the realm of cancer treatment, prevention and control, advanced imaging, and correlative science studies.

Their objectives are:

  • Providing centralized operational support activities for NCI Clinical Trials conducted by the NCTN, ETCTN, NCORP, and other multi-center organizations

  • Facilitating investigator/research staff participation in NCI multi-center programs/clinical trials

  • Increasing investigator and patient awareness and enrollment

  • Providing standardized, integrated, and comprehensive support services

  • Identifying best practices and streamline or eliminate redundant processes

  • Improving operational efficiency, enhance productivity and deliver products offering measurable business value

 

CTSU helps provide 24/7 operational support for the entire lifecycle of a clinical trial. It also supports an NCI Grant portfolio with a combined FY2019 funding level of about $343 million per year. CTSU’s budget only takes up about $23 million a year, which is approximately 5-6% of the entire grant portfolio budget.

 

The program helps streamline the pre-enrollment process, subject enrollment—­a process which has multiple checks to ensure compliance—and study conduct and monitoring.

The unit’s accomplishments include:

  • Supporting transition to NCTN/NCORP/ETCTN

  • CDMS Integration across networks

  • Supporting precision medicine trials (MATCH, Exceptional Responders, LUNG-MAP)

  • Implementing biospecimen navigator

  • Safety database integration

  • Implementing data standardization across networks

  • Supporting increased regulatory compliance

    • Registration and credential repository

    • Delegation of tasks log

    • CDISC compliance

  • Site support for Electronic Medical Record/National Coverage Analysis

The program’s future goals include optimizing their current services and integrations in order to increase efficiency, including by:

  • Maintaining and enhancing operational, administrative, regulatory support of current Grant portfolios and new Grantees as identified

  • Maintaining and enhancing integration activities/standardization

  • Leveraging multiple contractors as opposed to a single contractor

    • They plan to divide contract service areas into smaller units, which gives them flexibility to address new needs/regulations/requirements, and emerging technologies.

  • Increasing Contract awardee pool

    • Current contract includes: 2 awardees, Future contract: 4-8 awardees

The budget request for the contract reissue is for a 10-year contract period, with a requested budget of $23 million per year, which represents a small decrease over the average expenditure of current contract. It also includes an allowance for cost-of-living adjustments.


Small Business Innovation Research Proposed FY2020 Contract Topics (new RFP)

The Small Business Innovation Research and Small Business Technology Transfer programs are housed in the Office of the Director at NCI.

Under the SBIR program, the contract mechanism is primarily used to fund awards in targeted areas of research and development that are “ripe for development by the small business community,” said Andrew Kurtz, program director and team leader at NCI’s SBIR and STTR programs.

 

“These tend to be areas that the NCI has identified as being priorities for the institute. In a lot of cases they are intended to fill in technology gaps, areas that the private sector hasn’t adequately addressed on its own or things that are intended to support some of the broader research goals of the institute,” Kurtz said to The Cancer Letter.

The NCI’s SBIR and STTR programs take a small portion of NCI’s overall extramural research and development funding. The SBIR program is required to spend 3.2% of NCI’s extramural research and development budget on projects at U.S. small businesses.

 

“A majority of our SBIR funding goes toward funding investigator-initiated grant awards, where the companies bring their best ideas to the NCI,” Kurtz said. 

The portion of the SBIR budget used to fund contracts in targeted areas may fall anywhere from 10-20%, though it varies by year.

One case Kurtz gave as an example included MagArray Inc., whose goal was to develop sensors with improved sensitivity and specificity of genomic and proteomic signatures for early detection and post-treatment monitoring.

A Stanford spin-out, MarArray worked with ultra-sensitive multiplex immunoassay systems, which ultimately resulted in REVEAL Blood Test for Lung Nodule Characterization, which launched in 2018, after receiving the Phase I contract in 2007.


Clinical characterization of cancer therapy-induced adverse sequelae and mechanism-based interventional strategies (new PAR)

Cancer treatments can result in acute, chronic, or progressive toxicities with adverse effects persisting after completion of therapy or developing as late effects. Cancer survivorship and adverse effects will significantly increase in the next couple of decades, but little is known about the rates of adverse events related to new therapies.

Currently, the development of biomarkers and the mitigation and prevention strategies are limited by:

  • Lack of mechanistic understanding of adverse events

  • Lack of accurate reporting and archiving of adverse event data

  • Difficulties in objectively measuring treatment-related toxic effects

  • Insufficient characterization of the clinical phenotypes

  • Insufficient studies validating pre-clinical biomarkers in the clinical setting

The purpose of the program announcement with special review was to:

  • Support preclinical and clinical research projects which seek to:

    • Clinically characterize adverse sequelae

    • Translate the mechanistic understanding into therapeutic approaches to prevent or minimize the development of long-term sequelae

    • Identify mechanisms of new therapy-induced adverse sequelae

  • Applications should prospectively identify the specific adverse effects and/or cluster of effects under evaluation

  • Collaborations between clinical and non-clinical investigators are encouraged to couple the Mechanistic knowledge with the clinical phenotype

  • Emphasizing should be on translating mechanistic knowledge into approaches or interventions to prevent or mitigate adverse sequelae

The PAR would:

  • Stimulate clinical and translational research related to adverse-effects with strong mechanistic underpinnings that:

    • Go beyond single adverse-effects to look at clusters of effects

    • Address newly identified adverse-effects related to treatment

    • Characterize clinical phenotypes of adverse-effects

    • Evaluate and/or validate new biomarkers

    • Evaluate the trajectory of chronic or progressive adverse-effects and their relationship with cancer treatments and other comorbid conditions

    • Develop intervention strategies

  • Applications that evaluate clinical characteristics and mechanisms of adverse sequelae tend to be poorly reviewed in NIH standing study sections (which lack expertise in treatment relative adverse effects)

The PAR would also:

  • Leverage NCI investment to:

    • Clinically characterize adverse sequelae

    • Translate the mechanistic understanding into therapeutic approaches to prevent or minimize the development of long-term sequelae

    • Identify mechanisms of new therapy-induced adverse sequelae

    • Specific review panels are critical

 Three Cancer Moonshot concepts were approved:


Activities to Promote Human Immune-Representing Oncology Models (RFA)

The RFA aims to support “new model development research projects proposing to recapitulate innate and adaptive components of the human immune system without the use of human fetal tissue, in a manner that addresses the needs of immuno-oncology research.” These models must demonstrate recapitulation of human immune function.

The RFA proposes research projects that focus on “recapitulation of the human immune system in their proposed cancer model using human cells or tissues to regenerate and recapitulate the human immune system in in-vivo or in-vitro immuno-oncology models in a manner that matches or exceeds representation of the human immune system achieved with murine models developed using human fetal tissue.”.

The award would have a single receipt date, anticipating support for two to three R33 projects with a maximum budget of $250,000 direct costs per year for up to 4 years (which is adequate to support multi-PI teams). It accounts for up to $4 million in total cost. The anticipated schedule:

  • April 2019: Issue “Notice of Intent to Publish”

  • June/July 2019: Publish RFA

  • Nov/Dec 2019: Application Due Date

  • June 2020: Award Date/Project Start Date

The outcome measures include both development and dissemination measures. The development measures include exhibiting capabilities that support replacement of models developed using human fetal tissue, the number of projects that meet their proposed performance measures, publications demonstrating progress towards proposed aims, and evidence of subsequent investment to pursue dissemination.

The dissemination measures include: the number of new collaborations explored by supported model developers and investigators associated with immuno-oncology research and the number of models that are adopted by immuno-oncology research groups– especially those replacing models developed using human fetal tissue.


Next Gen Technology for Next Gen Cancer Models (RFA)

This Cancer Moonshot concept was a reissue from a previous BSA meeting in December 2018.

The Human Cancer Models Initiative is an international consortium with approximately 1000 “next generation human cancer models” with clinical and molecular data. This consortium includes NCI’s Moonshot initiative, Wellcome Sanger Institute, and Hubrecht Organoid Technology.

 

Some of the technologies for model development include organoids and conditionally reprogrammed cells.

The challenge of the concept rationale was: functional genomic technologies are not optimized for efficient use in next-gen cancer models. Successful completion of this concept will fill gaps, as well as answering several questions:

  • What is the impact of cellular polarity in 3D structures on the results from perturbagen screens?

    • Does topology (e.g. 3D organoids) change the effect of gene(s) essentiality in cancer?

  • How to adapt pertubagens that were developed for classical cancer cell lines to function in other cancer models?

  • What transduction technologies should be optimized for 3D and 2D NGCM?

    • Can diffusion work efficiently for cells that are within (internal) an organoid?

The concept’s goals are:

  • The NGCMs represent a powerful tool for precision oncology

    • Clinical data, including response to treatment of donor patient

    • Genomic characterization upfront

    • This FOA aims to accelerate functional genomics using the HCMI models in screens using:

    • Cas9/gRNA (CRISPR)

    • RNAi

    • Open reading frame cDNA

    • Small molecule

The concept will address the technical challenges of “using NGCM in functional genomics experiments and applications” and will do so by developing of robust protocols and conditions when using molecular perturbagens (Cas9/gRNAs, small molecules, cDNAs) with NGCMs and rapid sharing of all data and reagents.

The methods, data and reagents generated under the FOA will allow researchers to get insight into essential pathways in cancer. The preclinical knowledge base will support precision oncology by identifying new drug targets and mechanisms of therapeutic resistance.

Advantages of the consortium include:

  • The grant awardees will use NGCMs developed through NCI’s investment in the HCMI program

  • Research in the cooperative U01 setting will:

    • Reduce excessive redundancy, thereby ensure cost efficiency

    • Promote sharing of reagents and communication

    • Standardize methods

    • Provide standardized reagents

    • Make all data publicly available

  • The contract mechanism requires deliverables and oversight

  • A single steering committee allows real-time sharing of results between the U01 Centers and contractor

The funding for this concept would include FY2020-2022. The U01 Technology Centers, which would be about three in total, would have an estimated $3.3 million per year cost. The Standardized Reagent Developer contract, which involves CRISPR reagents development and distribution, would cost roughly $700,000 per year. The total cost of the concept would be $4 million per year, or $12 million over the three years.

 


Therapeutic Target Identification to Overcome Drug Resistance (RFA)

The Drug Resistance & Sensitivity Network was funded under RFA-CA-17-009, which is composed of U54 centers, and was launched in FY18. A new FY20 initiative, “Mechanisms of Cancer Drug Resistance Competing Revisions” provides rationale for a complementary initiative, leverages the wider range of expertise in the NCI portfolio, encourages collaborative projects, as well as incentivizes and accelerates ideas not well represented in the DRSN.

DRSN’s overarching focus is to address the Blue Ribbon Panel recommendation on establishment of multidisciplinary research teams to elucidate the complex mechanistic underpinnings of drug resistance and to inform drug development efforts and future clinical trials:

  • Drug Resistance & Sensitivity Network composed of 5 x U54s, launched in FY18

  • These U54s are primarily disease-specific

  • Preference given to studies involving NCI CTEP IND agents

  • NCI-IND agents (n= >60) include a wide variety of small molecule and antibody inhibitors that impact classic oncogenic signaling, epigenetic regulators & checkpoint targets (e.g., RTK, MAPK, AR, EZH2, PDL1)

 

DSRN’s goal for the Competing Revision initiative is to accelerate evaluation of: new and/or under-explored mechanisms of drug resistance, new approaches with classical targets, and promote collaborative efforts that complement on-going DRSN studies. It also aims to:

  • Leverage active broad-based NCI research programs that have the capability to incorporate new directions and accompanying know-how/expertise;

  • Competing Revision opportunities will incentivize new collaboration, enable testing of new concepts in drug resistance, and accelerate on-going activities represented in the DRSN;

  • Identify and characterize new leads for DRSN and other NCI activities;

  • Potential to inform and accelerate the development of therapeutic targets in a synergistic manner;

  • Opportunity to expand and diversify the current DRSN

The funding structure of DSRN:

  • Variety of mechanisms are eligible (R01, U01, P01, U54, P50);

  • Programmatic expectations for responsiveness:

    • involves multi-disciplinary scientific collaborations;

    • brings together complementary expertise;

    • promotes infusion of a new cadre of investigators into DRSN efforts; and

    • accelerates ideas that align and integrate with the overarching objectives of the BRP recommendation;

  • Anticipate funding 5 to 10 new competing supplements (4 receipt dates over 2 years);

  • Budgetary requests may not exceed $250,000 D.C./year for the life of the project;

  • Applicants must have a minimum of 3 years left of funding on the parent grant (at the time of application);

The total cost of the Moonshot concept would be $4.2 million per year, and $12.6 million in total over the next three fiscal years.

Copyright (c) 2018 The Cancer Letter Inc.