Starting with the nervous system to treat cancer, the Lancet sub-journal reveals six strategies

▎ WuXi AppTec content team editor

In recent years, the role of the tumor microenvironment in cancer development has received more and more attention, and recent studies have shown that the nervous system is an emerging key factor in promoting tumor growth. A review in Lancet Oncology, a sub-publication of The Lancet, took stock of progress in this area, and the authors summarized six strategies for treating cancer starting from the nervous system. Today, WuXi AppTec's content team will share the wonderful content of this review with readers, click "Read more" at the end of the article to access the original url of the review.

Inhibit tumor growth by modulating the nervous system

Innervation plays an important role in the growth of many different tumors, including gliomas, prostate cancers, pancreatic cancers, and stomach cancers. Common signaling pathways include neurochemical transmitters (glutamate, norepinephrine, acetylcholine) and growth factors (NGF, BDNF, GDNF). In addition, neurons can form tumor-nerve synapse with tumor cells. These signaling mechanisms typically activate typical carcinogenic signaling pathways that promote tumor growth. For example, in high-grade gliomas and gliomas, soluble neuromodulator 3 (NLGN3) released by neurons and oligosaptic glial precursor cells around the tumor can activate the PI3K-mTOR signaling pathway by binding to receptors on the tumor surface, leading to tumor proliferation.

▲NLGN3 released by neurons can promote tumor proliferation (Image source: Reference[1])

These mechanisms of action mean that existing neuromodulatory drugs may serve as potential anti-cancer therapies. A number of current retrospective studies and small prospective clinical trials have found that β-adrenergic blockers may improve oncology outcomes. "Old drugs and new uses" is an attractive strategy, especially for brain tumors, because many neuromodulatory drugs can cross the blood-brain barrier. However, an important clinical challenge with the use of neuromodulatory drugs as anti-cancer therapies is that these drugs are not tumor-specific and may trigger other side effects at the effective dose level. Large prospective clinical trials currently underway may provide insight into the tolerability and efficacy of neuromodulatory therapy.

Overcoming drug resistance by disrupting stress adaptation mechanisms

A common feature of invasive cancers is their ability to adapt, allowing them to proliferate in harsh environments under surgery, systemic therapy, or chemotherapy. Studies in recent years have found that multiple components of the nervous system play a role in supporting tumor growth in stressful environments. For example, pancreatic cancer cells can selectively produce NGF when they lack serine, which attracts innervation and provides foreign serine.

▲ Innervation can provide foreign serine to pancreatic cancer cells deficient in serine (Image source: Reference[1])

Interestingly, it is estimated that close to 40% of pancreatic cancers are unable to synthesize serine on their own, meaning that these patient subsets may benefit from a combination of a low serine diet and a highly selective TRK inhibitor lalotrectinib.

Remodeling the immune tumor microenvironment

Immune checkpoint inhibitors have become one of the standard treatments for many cancer types. Studies of neuroimmune signaling pathways have found that the nervous system can regulate tissue residency and the activity of immune cells in lymph nodes through a variety of mechanisms. The combination of neuroactive drugs with immune checkpoint inhibitors, cytotoxic therapies, or cancer vaccines may modulate the immune tumor microenvironment and enhance anti-cancer effects.

For example, in patients with melanoma, the use of nonspecific β-adrenergic blockers is associated with a reduced risk of recurrence and improvement in overall survival in immunotherapy. Early clinical trials found that propranolol was combined with Keytruda to achieve an initial response rate of 78% in patients with locally advanced or metastatic melanoma.

Lymph nodes are heavily innervated by adrenergic and sensory nerves, while β-adrenergic receptor signaling pathways regulate the migration of T cells away from the lymph nodes. Thus, modulating neural signaling may control the residence and release of T cells in the lymph nodes, exerting an important effect on the immune response stimulated by natural and immune checkpoint inhibitors.

▲β-adrenergic receptor signaling pathway regulates the migration of T cells from lymph nodes (Image source: Reference[1])

One of the reasons many "cold" tumors respond poorly to immune checkpoints is the scarcity of CD8-positive T cells near the tumor. Strategies for combining immune checkpoint inhibitors with radiotherapy and β-adrenergic blockers deserve further exploration. In particular, prostate and pancreatic cancers are among the most densely innervated cancer types and have high levels of nerve infiltration and sympathetic signaling.

Targeted cancer metastasis

The role of nerves in facilitating cancer metastasis is being discovered. Nerves can not only become physical channels for cancer metastasis, but also mediate the spread of cancer cells through the blood vessels and lymphatic system. The link between cancer metastasis and angiogenesis, as well as vascular permeability, has been confirmed, and the VEGF protein plays a key role in this. However, because the growth regulation of the vascular system and nerves is often closely coupled, neurotrophic factors such as NGF and BDNF are increasingly considered by scientists to be regulators of abnormal angiogenesis. In mouse breast cancer models, anti-NGF antibodies were able to reduce the formation of liver metastases and microvascular density.

In addition, the nervous system also plays an important role in the brain metastasis of cancer. Recent studies have shown that when breast cancer cells metastasize to the brain, they can bind to the synapses in the brain to form pseudo-tripartite synapse, which can hijack glutamate released in normal synapses and assist tumor growth.

▲ Breast cancer cells can hijack glutamate released in normal synapses to assist tumor growth (Image source: Reference[1])

These findings imply that the use of neuroactive drugs in the early stages of cancer may prevent or delay tumor metastasis. The results of a Phase 2 clinical trial conducted in patients with in situ resectable breast cancer showed that receiving propranolol prior to surgery reduced the level of biomarkers associated with metastatic potential. If brain metastases of cancer have already occurred, the use of NMDA receptor modulators to target the growth mechanisms of metastases may be a pathway worth exploring.

Control tumor growth and seizures by disrupting electrical nerve activity

The electrical activity of neurons is essential for neurodevelopment, and evidence of neuronal electrical activity assisting cancer hyperplasia, particularly brain tumors, is emerging. Similar to the development of the normal nervous system, glioma cells are also affected by electrical activity and release growth-stimulating factors, including glutamate, into the surrounding environment, improving neuronal activity in the microenvironment. Due to the presence of AMPA receptor-dependent synapses on glioma cells, gliomas and surrounding neurons form a two-way positive feedback loop, resulting in highly active nerves and tumors and proliferation of tumors.

▲Neurons and gliomas that release glutamate form positive feedback loops (Image source: Reference[1])

The phenomenon of integrating the electrical activity of brain tumors into brain neural networks has also led scientists to re-examine the clinical symptoms of gliomas. For example, seizures are often thought to be a by-product of the tumor and the edema compression around it. However, they may also be caused by tumors secreting glutamate causing neural networks to become overactive. Previous studies have also found that gliomas with greater synaptic potential are associated with increased epileptic frequency and increased tumor invasion. These findings raise the question of whether anti-epileptic drugs have oncological therapeutic effects.

At present, how the electrical activity of the nervous system affects cancer growth still needs more research. For example, while preclinical evidence suggests that glutamate has carcinogenic effects, therapies targeting glutamate receptors have not yet shown positive results in prospective clinical trials.

Control neuralgia by targeting the sensory nervous system

Many cancer patients report severe pain at the site of the tumor in situ and metastases. This is often associated with neuroinfiltration, with the role of neurotrophic factors and neuromodulatory proteins being one of the main causes. For example, NGF can activate the sensory fibers of the dorsal root ganglia and is an important cause of pain in many pancreatic cancers. Although treatment of cancer-related pain is usually aimed at controlling symptoms, targeting neuralgia may also play a role in controlling tumors.

▲NGF secreted by pancreatic cancer causes neuralgia (Image source: Reference[1])

Since signaling proteins that regulate neuralgia also have the effect of promoting tumor growth, these neural signaling pathways are attractive therapeutic targets. For example, antibody therapies that target NGF may bring anti-cancer benefits while treating cancer-associated neuralgia. Currently, the monoclonal antibody tanezumab, which targets NGF, is being used in Phase 3 clinical trials to treat pain-inducing bone metastases.

In addition, a high-affinity capsaicin analogue, resiniferatoxin, was able to kill nerve fibers in sensory neurons in mice. It also significantly hinders tumor progression and is currently being evaluated in a Phase 1 clinical trial for severe or refractory pain in patients with advanced cancer.

The opportunities and challenges of the future

The review authors note that cancer neuroscience has exploded in recent years, enhancing our understanding of the mechanisms of communication between tumors and nerves, and promising clinical applications for molecularly targeted therapies. However, three major questions remain unanswered: (1) whether the tumor-nerve axis can be specifically targeted, resulting in broad clinical benefits; (2) whether neuromodulation synergizes with existing therapies and integrates into existing treatment regimens; and (3) whether histopathology or other concomitant diagnostics can identify patients most likely to benefit from these treatment strategies.

Several prospective clinical trials targeting tumor-nerve axis nodes are currently underway, reflecting a combined effort by academia and industry. In addition to the development of innovative therapies, the "new use of old drugs" for existing neuromodulatory drugs with good tolerance characteristics represents more opportunities. The authors say the experience of tumor microenvironment studies suggests that disrupting communication between tumors and nerves may eventually become one of the pillars of clinical oncology, as can anti-angiogenesis and immunomodulatory therapies.

Resources:

[1] Shi, et al., (2022). Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities. The Lancet Oncology, https://doi.org/10.1016/S1470-2045(21)00596-9

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