NIH funding opportunities (2) - Neural Regulation of Cancer (R01, R21)

The purpose of this FOA is to encourage collaborative, transdisciplinary research with both neuroscience and cancer elements to advance current understanding of the nervous system contribution to cancer. It is anticipated that leveraging the current advances in neuroscience research, including knowledge, tools, experimental models and reagents, to uncover novel mechanisms used by the nervous system to promote central and non-central nervous system tumor initiation, progression and metastasis will ultimately inform key areas of cancer research. It is anticipated that understanding of how the nervous system and molecules typically associated with the nervous system, including neuropeptides, neurotransmitters and axon guidance molecules contribute to these cancer processes will ultimately inform improved strategies for cancer prevention and treatment of both central and non-central nervous system cancers.

A major function of the nervous system is to maintain peripheral organ homeostasis which it achieves via neuronal circuitry conveying information between the organs and the central nervous system and ultimately regulated by the brain. Whether this regulatory function of the nervous system is altered in the context of cancer however, has not yet been addressed, despite evidence for many years that the nervous system in many peripheral organs acts as a cancer promoter. For example, recent studies demonstrate that in the bone marrow, the nervous system may play an important role not only in the development and maintenance of the immune system and inflammatory response under steady-state conditions, but also contributes to blood cell cancers, most notably in chronic myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). The nervous system has recently been implicated in many aspects of cancer development, progression and therapeutic resistance, most notably in: (i) the regulation of cancer stem cell renewal, proliferation and differentiation; (ii) cancer development and metastasis and (iii) the escape of cancer cells from immune surveillance.

In addition, increasing evidence also points to a role for nerves in the etiology and evolution of solid tumors, including prostate, breast and pancreas. Solid tumors were once believed to lack innervation, but new data shows that nerves infiltrate primary tumors in a process termed neoneurogenesis, and at least in breast and prostate cancers, increasing nerve densities are associated with more aggressive disease and poor patient survival. Moreover, cancer cells have been shown to invade the neural spaces of nerves surrounding salivary, prostate and pancreatic tumors in a process known as perineural invasion. Perineural invasion is most prominent in patients with late stage, metastatic cancers and recent studies suggest that the neural niche may offer disseminating cancer cells protection from immune surveillance and exposure to therapeutic drugs, while providing an unobstructed conduit for cancer cell migration and dissemination.

Signaling molecules traditionally associated with nervous system function have also been implicated in cancer and may play an important role in promoting cancer by mediating the reciprocal cross-talk between nerves and cancer cells, particularly in the context of the tumor microenvironment. These molecules include: (i) neurotrophins, neuropeptides and axon guidance molecules, many of which are critical in vertebrate nervous system development and (ii) neurotransmitters, or the molecules responsible for conveying information across synapses between neurons, between neurons and muscles or between neurons and glands. Many neurotrophins, neuropeptides and axon guidance molecules are aberrantly expressed in cancer cells or tumor stroma cells where they have been implicated in regulating cell proliferation, cancer cell migration and de-differentiation of normal cells. Well-known examples of neurotrophins produced by cancers include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and their corresponding receptors. Additionally, axon guidance molecules were also implicated in cancer when a cohort of pancreatic tumors was sequenced and frequent and diverse somatic alterations in axon guidance genes were observed. Neurotransmitters were first shown to promote the migration of cancer cells in culture and a recent landmark study using genetically engineered mice revealed that sympathetic nervous system signaling through the neurotransmitter norepinephrine, promoted early prostate cancer development, while the parasympathetic branch of the nervous system, signaling through the acetylcholine neurotransmitter promoted a metastatic phenotype. Importantly, blocking neurotransmitter activity in this study inhibited prostate cancer development and progression.

Together, these studies point to an emerging, potentially critical role for the nervous system in cancer and suggest that in the long term, understanding the neural regulation of cancer and the mechanisms used by nerves to modulate cancer formation, progression and metastasis could prove essential in developing or improving the prevention and treatment of cancer.

Opportunity

The past two decades have seen a substantial focus on understanding the mechanisms associated with angiogenesis and lymphangiogenesis in tumor progression and metastasis, yet the neurobiology of cancer has remained comparatively understudied. However, in light of recent studies implicating the sympathetic and parasympathetic components of the autonomic nervous system in the regulation of cancers, including blood cell, prostate, gastric and pancreatic cancers, a renewed effort to assess the mechanisms that dictate the neurobiology of cancer is warranted. This FOA is intended to leverage relevant technologies and knowledge currently used in neuroscience research to accelerate our understanding of the neural regulation of cancer.

Specific Challenges

Projects suitable for this FOA are expected to be transdisciplinary and leverage current neuroscience expertise, experimental models, reagents and tools to address significant questions that advance our knowledge of cancer. Studies considered appropriate for this FOA include, but are not limited to, the following:

Studies that advance current understanding of neural invasion in cancer progression and metastasis, the signaling networks that mediate this process and the consequences of inhibiting this process.
Studies that help elucidate the mechanisms of neoneurogenesis in solid tumors, the molecules mediating this process and the impact on cancer progression when neoneurogenesis is inhibited.
Studies defining the role of nerves in the tumor microenvironment that advance the understanding of the reciprocal cross-talk between nerves and the tumor and/or between nerves and other components of the tumor microenvironment that result in cancer progression and metastasis.
Studies building on current knowledge of the role of nerves in the bone marrow niche that promote the initiation and progression of hematologic malignancies and advance the understanding of cross-talk between the nerves and the cell components of the immune system.
Studies to enhance the understanding of the influence of nerves on crucial cancer modulators including stem cells, blood vessels, immune surveillance and inflammation.
Studies to elucidate the specific components of the nervous system that contribute to cancer processes, including the nerve types and neurotransmitters, neuropeptides or axon guidance molecules and the mechanisms that underlie their role in cancer.
Studies that develop tools and protocols that enhance manipulation and analysis of tumor-associated nerves.
Studies to determine if neural networks between normal and tumor tissue differ.
Studies that include the identification or assessment of inhibitors or drugs used in neuroscience to determine their ability to prevent or treat cancer in a preclinical setting.
Studies investigating biobehavioral influences on cancer progression and metastasis and identification of the neural signaling pathways that mediate these influences on cancer.

Deadlines for both: October 26, 2016; February 22, 2017; June 27, 2017; October 26, 2017; February 22, 2018; June 27, 2018; October 25, 2018; February 22, 2019; June 27, 2019

URLs for both:

Filed Under: Funding Opportunities

NIH funding opportunities (2) – Neural Regulation of Cancer (R01, R21)