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NIH/NCI 357: Innovative Tools for Interrogating Tumor Microenvironment Dynamics

Fast-Track proposals will be accepted.

Direct-to-Phase II will be accepted.

Number of anticipated awards: 3-5

Budget (total costs, per award):

Phase I: $300,000 for 9 months;

Phase II: $2,000,000 for 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

 

Summary

Tumor microenvironment (TME) is composed of abnormal vasculature, stromal components, immune cells, all embedded in an extracellular matrix (ECM). TME plays a critical role in tumor initiation, malignant progression, metastasis and response and resistance to therapy.  Characterized by hypoxia, elevated enzymatic activities, high interstitial fluid pressure and dense stroma structure, TME creates a hostile environment for drug delivery and other forms of cancer treatments.  Research efforts and discoveries focusing on TME remediation are critical for improving cancer treatment efficacy. New drugs, molecular targets and agents that can manipulate TME are being discovered from known and novel molecular pathways, high-throughput genomics and proteomics and some of these agents are already in clinical trials.  For example antiangiogenic agents, originally designed to starve tumors, were shown to transiently normalize tumor vasculature and improve therapeutic outcome in patients with newly diagnosed and recurrent GBM and several anti-angiogenic agents have been approved for multiple cancer types. Similarly, over the past few years, a few checkpoint inhibitors modulating the immune components of the TME have been approved for multiple cancer types and many more are currently undergoing clinical trials. Recently it was discovered that antifibrosis drugs are capable of normalizing the TME and improve the delivery and efficacy of nano- and molecular medicine.  However, there are still very few new agents targeting TME that are reaching the stage of FDA approval.  The slow pace in TME-oriented therapeutic discovery can be attributed to lack of techniques capable of rapid and effective in vivo evaluation of TME-manipulating dynamics for the purpose of selecting hit compounds and demonstrating efficacy.

In addition to being good therapeutic targets, TME could also act as biomarkers to:

·         diagnose tumors at early stage

·         assess tumor prognosis

·         predict appropriate therapy to use

·         evaluate response to therapy and modulate therapy accordingly

For example, the immune components of the tumor are modulated during tumor initiation and also in response to different therapies, and thus could be used as markers to diagnose tumors early and to determine therapeutic response and modulate therapy accordingly.

Assessment of TME is mostly based on histopathological analysis of tumor biopsies. However, these methods are invasive and non-dynamic (i.e. they lack the ability to evaluate progressive changes in the same tumor over time); thus, the ability to use TME as biomarkers for tumor diagnosis, prognosis and therapy response are rather limited. Imaging methods provide non-invasive and dynamic way to assess TME, even in lesions that are difficult to biopsy, and help determine heterogeneity and obtain serial measurements of the same tissue over time. So, imaging methods could be used to diagnose tumors early and to determine if a tumor is responding to therapies.

Recent advances in sensing and imaging techniques are enabling assessment of TME with improved accuracy due to higher monitoring speed, sensitivity and resolution. For example, magnetic resonance imaging techniques, with both excellent image resolution and depth penetration, are widely used to detect abnormal TME structures and conditions:  blood oxygenation level dependent (BOLD)-MRI for hypoxic conditions, Chemical Exchange Saturation Transfer (CEST)-MRI for reduced pH, MR angiography for vascular structure and diffusion MRI for structural integrity. Positron Emission Tomography (PET) of radio-nuclei-labeled TME-associated molecular targets has been used in pre-clinical and clinical settings. There are also new developments related to designing bio-responsive sensors to monitor change in pH, oxygen levels, or enzymatic activities in TME directly through nanoparticle-based imaging modalities or indirectly through bio-fluid analyses. Biopsy-implantable chemical sensors allow to collect signals over long period of time (months) to monitor long term changes in TME. All these in vivo methods are valuable tools to dynamically examine the targeting efficiency, associated molecular events and provide insight into normalization of TME and its effect on anticancer drug delivery. ‘Bio-activatable’ delivery vehicles allow for controlled drug delivery, which is activated only with the change of a particular TME parameter. However, most of these studies still remain pre-clinical and the imaging modalities have mostly been limited to pre-clinical studies.

Identifying and monitoring TME-associated biomarkers in patient populations and effective strategies to manipulate the TME in vivo can enable early tumor detection and prognosis, provide therapy prediction and response information and also enhance effectiveness of anticancer therapies and improve treatment outcomes. To accelerate research and translational efforts focused on sensing, imaging, and manipulation of TME in real time, and TME-inspired drug delivery, the National Cancer Institute (NCI) requests proposals for the development of clinically viable in vivo probing/monitoring techniques of TME-manipulating strategies.

 

Project Goals

Tumor diagnosis at early stage, before it has grown too big or spread, is critical to improving survival of patients with the tumor. Similarly, being able to predict if a tumor responds to certain therapy is very essential to determining what treatment option would be the best for patients. This will increase overall survival and also prevent use of ineffective treatment options. Once the patient starts treatment, it is essential to monitor the response of tumor to the therapy to determine if it’s working or if modulation in therapy is required.

As precision medicine is becoming an increasingly important area in cancer treatment, the ability to determine changes in TME in general and as related to individual patient, in particular is critical. The development of this knowledge can provide insight into effectiveness of treatment using existing drugs and enabling development of new drugs. TME studies can also further knowledge on local cellular environments and categorizing TME associated cells into small sub-groups defined by their molecular makeup.

Various components of TME can serve as a good biomarker for tumor diagnosis, prognosis, treatment prediction and therapeutic response. For example, the extent of immune cell infiltration and activation in solid tumors could be used to determine if immunotherapy is working in patients. The current methods to assess immune activation in response to immunotherapy involve biopsy procedures that are invasive and cannot be done on the same tumor over time. Thus it is important to develop methods that are non-invasive and that would enable longitudinal tracking of treatment response.

The goal of this solicitation is to develop non-invasive, in vivo platforms that can: image, assess or interrogate TME dynamics over time for tumor diagnosis and/or treatment prediction/response.

To apply for this topic, the proposed technology should be focused on interrogating one or more of the following TME parameters:

·         Tissue oxygenation Level and/or pH

·         Vasculature and/or stromal architecture

·         Tissue integrity

·         Enzymatic activities

·         Indication of immunotherapy response

·         Response in specific cell type(s) or subtype(s) at the molecular level

The goal of this contract topic is not to solicit any particular technology; so this topic is agnostic to the imaging modality used. New imaging modalities could be developed or agents targeting TME could be developed using any imaging modality currently available including X-ray, MRI, PET, SPECT, CT and ultrasound. The goal of the topic is to develop imaging tools for TME in the clinic; so the tools developed have to be clinically feasible and relevant.

Proposals with incremental improvement from the current state of art or having no immediate translational potential will not be considered responsive to this solicitation.  Examples of non-responsiveness may include, but are not limited to: imaging methods that can work only in pre-clinical imaging modalities (i.e. ultrahigh-field MRI or unconventional PET radionuclei labeling), imaging agents, chemical constructs or linkers that are inherently toxic or immunogenic (i.e. Quantum Dots, Avidin) and probes that targets molecular targets that do not have human equivalent.

 

Phase I Activities and Deliverables

Phase I activities should generate scientific data to confirm clinical potential of the proposed agent. Expected activities and deliverables may include:

·         Identification and validation of marker(s) for TME

o    Preparation of imaging agents based on the validated markers

o    Characterize the variation, reproducibility, and accuracy of the tool

o    Demonstrate that the agent produces high signal-to-noise ratio

o    Demonstrate specific binding/targeting of the agent/probe to the molecular target (TME target)

 ·         Prepare, select and demonstrate TME-targeting probes/sensors based on target specificity and minimal toxicity in vitro

 ·         Optimize detection scheme to demonstrate in vitro signal specificity and correlate signals to molecular target concentrations measured using conventional assays

 ·         Determine optimal dose and detection window through proof-of-concept small animal studies with evidence of systemic stability and minimal toxicity

 ·         Establish calibration curves correlating in vivo signal changes to concentration of molecular targets measured via conventional biological assays.

 ·         Demonstrate robust signal changes in response to in vivo perturbation

 ·         Benchmark experiments against currently state-of-the-art methodologies.

 ·         Present Phase I results and development to NCI staff

For successful completion of benchmarking experiments, demonstrate a minimum of 5x improvement against compatible methodologies.

 

Phase II Activities and Expected Deliverables

Phase II activities should support commercialization of the proposed agent for clinical use. Expected activities and deliverables may include:

·         Demonstrate fast in vivo clearance, rapid tumor accumulation, sufficient in vivo stability, good bioavailability, and low immunogenicity/toxicity of imaging agent or sensors

·         Demonstrate high reproducibility and accuracy of the imaging agent in multiple relevant animal models

·         Demonstrate superiority over currently available imaging tools

·         Perform toxicological studies

·         Demonstrate clinical utility

o    For diagnosis markers, demonstrate that the agent can detect tumors at early stages and demonstrate superiority to current diagnosis methods

o    For predictive/decision markers, validate the predictive capability of the marker by performing prospective pre-clinical animal trials: stratify the animals into treatment groups and demonstrate that the imaging agent accurately predicts appropriate therapy to use

o    For therapy response markers, demonstrate that the imaging tool can accurately visualize changes in response to therapy and validate characteristics of response and non-response

·         Collect sufficient animal and safety data in preparation for an IDE application

  ·         Submit IDE application to obtain necessary regulatory approval for clinical validation.

Posted: August 1, 2016