Fast-Track proposals will be accepted.
Number of anticipated awards: 3-5
Budget (total costs, per award):
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Evolution of cancer is complex: from the early lesion to the development of primary tumor to widespread metastasis, numerous and complex interactions occur among normal and malignant cells, as well as their microenvironment. Studies on cancer progression and treatment have mostly focused on molecular underpinnings and pathways associated with these interactions at a single point in time under the assumption of a homogenous cell population. Within the last decade, researchers have found that tumor and its environment (TME) consist of a multitude of cell types. It’s believed this heterogeneity contributes to unpredictable tumor behaviors and poses significant therapeutic challenges. We have limited knowledge in how the characteristics and interactions of a tumor and TME change in time during tumor progression and cancer treatment.
Tracking and understanding the dynamic evolution of heterogeneous cell populations and molecular characteristics within the tumor and its microenvironment (TME) would add significant knowledge on cancer progression and could lead to the development of novel therapeutics and more efficacious treatment strategies. The TME has an abnormal vasculature, stromal components, and immune cells, which are embedded in an extracellular matrix (ECM). The TME, which plays a critical role in tumor initiation, malignant progression, and metastasis and response, has been shown to hamper drug delivery and contribute to drug resistance. For this reason, research efforts and discoveries focusing on both tumor-killing and TMEremediation can synergistically improve cancer treatment efficacy. Concurrently, administration of anti-angiogenic or antifibrotic agents during chemotherapy has been shown to improve therapeutic outcome by curtailing TME-imposed barriers to drug delivery to tumor sites. Over the recent years, immunotherapies utilizing checkpoint inhibitors to modulate the immune components of tumor cells and TME have been approved for multiple cancer types, and more are currently undergoing clinical trials; however, immunotherapies are only effective in a restricted group of patient populations.
The evaluation of tumor and TME at the molecular and cellular level is often based on histopathological analysis of tumor biopsies. However, these methods are invasive and lack spatial and temporal information; thus, the ability to use tumor and TME-associated molecular and cellular signatures for tumor prediction, diagnosis, prognosis, and therapy response are rather limited. Techniques capable of temporal in vivo molecular characterization and cell mapping of the tumor and its TME, in its physical location and over time, can accelerate lead compound identification, assist in patient stratification, monitor therapeutic response and modulate therapy accordingly.
Recent advances in imaging techniques are enabling assessment of tumor and 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 pre-malignant, tumor and 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 tumor or TME-associated molecular targets has been used in pre-clinical and clinical settings. All these in vivo methods are valuable tools to spatiotemporally examine the targeting efficiency and associated molecular events, and provide insight into the normalization of tumor and TME and its effect on anticancer drug delivery. ‘Bio-activatable’ delivery vehicles allow for controlled drug delivery, which is activated only by the change of tumor and TME parameters. However, most of these studies are pre-clinical, and the imaging modalities have mostly been limited to pre-clinical studies.
Dynamic or longitudinal evaluation of the molecular characteristics and cell populations in tumor and its TME within an individual patient is an effective and personalized strategy for early detection of cancer, the prognosis of tumor progression as well as prediction of treatment outcome. To accelerate research and translational efforts focused on dynamic profiling of tumor and TME in real time, the National Cancer Institute (NCI) requests proposals for the development of clinically viable in vivo technologies that can enable enhanced mapping of human tumors. This topic is in line with the Cancer Moonshot Blue Ribbon Panel’s Recommendation to support Generation of Human Tumor Atlases.
Tumor diagnosis at an 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 tumor response to treatment is essential to prevent the use of ineffective treatment options and allow alternative treatment options. As such, the ability to characterize the dynamic changes in tumor and TME at the molecular and cellular levels in an individual patient for early diagnosis and during treatment is critical. 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 goal of this topic is to develop non-invasive, in vivo imaging-based platforms that can repeatedly generate threedimensional molecular and cellular maps of the tumor and its TME at different time points for diagnosis and treatment prediction/response. With the emergence of promising immunotherapies, technologies and molecular imaging approaches to track immune response to immunotherapies are of particular interest. The proposed technology should be focused on interrogating one or more of the following tumor and TME parameters across time via in vivo imaging techniques with cellular resolution. The proposed imaging technology should provide three-dimensional information at any given time point. Potential molecular, cellular and physiological parameters to be measured may include but are not limited to the following:
This contract topic is agnostic to the imaging modality proposed. 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, optical, photoacoustic and ultrasound. Novel or currently existing imaging agents or probes (targeting certain molecular or cellular signatures) may be developed and optimized to enable molecular, cellular, and physiological measurements. The goal of the topic is to develop imaging tools for tumor and TME in the clinic; hence, the tools developed need 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 funded. Examples of inappropriate proposals 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), chemical constructs or linkers that are inherently toxic or immunogenic, and agents/probes that focus on molecular targets that do not have human equivalent. Image-based companion diagnostics that do not incorporate mapping of the tumor or TME are not appropriate for this topic and may better address the topic “Diagnostic Imaging for Cancer Immunotherapies.”
Phase I activities should generate scientific data to confirm clinical potential of the proposed agent and imaging capability with cellular resolution. Expected activities and deliverables should include but are not limit to:
Phase II activities should support commercialization of the proposed agent for clinical use. Expected activities and deliverables may include:
Closing date: October 20, 2017, 5:00 PM Eastern Daylight Time
Apply for this topic on the Contract Proposal Submission (eCPS) website.
Full FY18 Contract Solicitation is available HERE.