Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities

Diana D Shi¹, Jimmy A Guo², Hannah I Hoffman³, Jennifer Su⁴, Mari Mino-Kenudson⁵, Jaimie L Barth⁵, Jason M Schenkel⁶, Jay S Loeffler⁷, Helen A Shih⁷, Theodore S Hong⁷, Jennifer Y Wo⁷, Andrew J Aguirre⁸, Tyler Jacks⁹, Lei Zheng¹⁰, Patrick Y Wen¹¹, Timothy C Wang¹², William L Hwang¹³

Affiliations

¹ Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.
² Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA; School of Medicine, University of California, San Francisco, San Francisco, CA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Biological and Biomedical Sciences Program, Harvard University, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
³ Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Harvard-MIT Health Sciences and Technology Program, Harvard Medical School, Boston, MA, USA.
⁴ Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁹ Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹² Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY, USA.
¹³ Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: whwang1@mgh.harvard.edu.

PMID: 35114133
PMCID: PMC9516432
DOI: 10.1016/S1470-2045(21)00596-9

Review

Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities

Diana D Shi et al. Lancet Oncol. 2022 Feb.

. 2022 Feb;23(2):e62-e74.

doi: 10.1016/S1470-2045(21)00596-9.

Authors

Affiliations

¹ Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.
² Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA; School of Medicine, University of California, San Francisco, San Francisco, CA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Biological and Biomedical Sciences Program, Harvard University, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
³ Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Harvard-MIT Health Sciences and Technology Program, Harvard Medical School, Boston, MA, USA.
⁴ Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁹ Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹² Division of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY, USA.
¹³ Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: whwang1@mgh.harvard.edu.

PMID: 35114133
PMCID: PMC9516432
DOI: 10.1016/S1470-2045(21)00596-9

Abstract

With increasing attention on the essential roles of the tumour microenvironment in recent years, the nervous system has emerged as a novel and crucial facilitator of cancer growth. In this Review, we describe the foundational, translational, and clinical advances illustrating how nerves contribute to tumour proliferation, stress adaptation, immunomodulation, metastasis, electrical hyperactivity and seizures, and neuropathic pain. Collectively, this expanding knowledge base reveals multiple therapeutic avenues for cancer neuroscience that warrant further exploration in clinical studies. We discuss the available clinical data, including ongoing trials investigating novel agents targeting the tumour-nerve axis, and the therapeutic potential for repurposing existing neuroactive drugs as an anti-cancer approach, particularly in combination with established treatment regimens. Lastly, we discuss the clinical challenges of these treatment strategies and highlight unanswered questions and future directions in the burgeoning field of cancer neuroscience.

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Conflict of interest statement

Declaration of interests MM-K reports personal fees from H3 Biomedicine and AstraZeneca; grants from Novartis; and royalties from Elsevier, outside the submitted work. TSH reports personal fees from Synthetic Biologics, Novocure, and Merck; equity in PanTher Therapeutics; and grants from Taiho, AstraZeneca, Bristol Myers Squibb, Tesaro, Ipsen, and Puma, outside the submitted work. AJA reports personal fees from Merck, Arrakis Therapeutics, and Oncorus; grants from Mirati Therapeutics, Deerfield, Novo Ventures, National Cancer Institute, Lustgarten Foundation, Pancreatic Cancer Action Network, Doris Duke Charitable Foundation, and Dana-Farber Cancer Institute Hale Center for Pancreatic Cancer Research; and grants and personal fees from Syros Pharmaceuticals, outside the submitted work. TJ reports grants from Lustgarten Foundation; stock in Amgen and Thermo Fisher Scientific; and membership of the Board of Directors of Amgen and Thermo Fisher Scientific, outside the submitted work. LZ reports grants from Merck, during the conduct of the study; and grants from iTeos, Bristol Meyers Squibb, Merck, AstraZeneca, Amgen, NovaRock, Inxmed, and Halozyme; personal fees from Biosion, NovaRock, Akrevia/ Xilio, Datarevive, QED, Natera, Ambrx, Snow Lake Capital, and Tempus; personal fees from Alphamab and Mingruizhiyao; and shares in Alphamab and Mingruizhiyao, outside the submitted work. PYW reports research support from Agios, AstraZeneca/Medimmune, Beigene, Celgene, Eli Lily, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Oncoceutics, Vascular Biogenics, and VBI Vaccines; and membership on the advisory board of Agios, AstraZeneca, Bayer, Boston Pharmaceuticals, CNS Pharmaceuticals, Elevate Bio Immunomic Therapeutics, Imvax, Karyopharm, Merck, Novartis, Nuvation Bio, Vascular Biogenics, VBI Vaccines, and Voyager, outside the submitted work. All other authors declare no competing interests.

Figures

**Figure 1:. Six therapeutic avenues of cancer neuroscience**
TCA=tricyclic antidepressant. SSRI=selective serotonin reuptake inhibitor. GFRα=glial cell line-derived neurotrophic factor family receptor alpha. ADC=antibody–drug conjugate. BDNF=brain-derived neurotrophic factor. NGF=nerve growth factor.

**Figure 2:. Example mechanisms of therapeutic avenues of cancer neuroscience**
NGF=nerve growth factor. DRG=dorsal root ganglia. PDAC=pancreatic ductal adenocarcinoma.

See this image and copyright information in PMC

References

1. Young HH. On the presence of nerves in tumours and of other structures in them as revealed by a modification of Ehrlich’s method of “ vital staining “ with methylene blue. J Exp Med 1897; 2: 1–12. - PMC - PubMed
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Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities

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Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities

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Conflict of interest statement

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