Existing drugs can be repurposed for the treatment of gastrointestinal tumors, blocking the interaction between a neuropeptide and its receptor.
Often referred to as the ‘second brain,’ the human gastrointestinal (GI) tract is full of nerves that help it to function by secreting neuropeptides. A growing body of evidence suggests that GI tumors can hijack these networks of nerves, using them to survive, grow, and metastasize.1–3 Now, researchers from the Olivia Newton-John Cancer Research Institute (ONJCRI) have reported how a specific neuropeptide called calcitonin gene-related peptide (CGRP) and its receptor, contribute to poor clinical outcomes in GI cancer patients. Published today in MBJ Oncology, the study demonstrates that this pathway is a potent driver of tumor growth and can be therapeutically targeted.4
“This is very impactful because we have identified a new way that tumors can manipulate their environment to sustain their growth,” said cancer researcher and coauthor Pavitha Parathan in a press release. “The good news is that there may already be drugs available to block this and halt tumor growth.”
Led by cancer biologist Lisa Mielke, the team aimed to investigate the expression and function of CGRP and RAMP1 in GI cancers. Commonly expressed by neurons in the central and peripheral nervous systems, CGRP helps to dilate blood vessels, contributing to cardiovascular function as well as the development of migraines.5 The team knew CGRP was expressed in GI tumors, but no one had really studied the expression or function of its receptor component, receptor activity-modifying protein 1 (RAMP1), in the same tissues.
To elucidate the role of CGRP and RAMP1, Mielke and her colleagues first analyzed samples of GI cancer (GC), colorectal cancer (CRC), and CRC liver metastases from 180 different patients, finding that higher expression of RAMP1 was strongly associated with decreased survival.
Next, the team wanted to investigate the function of RAMP1 and CGRP in these cancers. To do so, they cultured both tumor cell lines and patient-derived tumor organoids in vitro; when they stimulated the cells and organoids with CGRP, they found enhanced tumor growth and upregulation of genes associated with proliferation, metabolism, and migration. However, when they used CRISPR-Cas9 to delete RAMP1, tumor growth was halted.
When the researchers used staining to explore the expression and spatial distribution of CGRP in CRC and GC tissue samples, they found something rather unexpected. “We were surprised to see not only nerve fibres containing CGRP inside the tumors and potently promoting their growth, but also the tumor cells themselves producing CGRP,” said Parathan.
As drugs targeting the CGRP/RAMP1 axis that have been approved for the treatment of migraine exist, “the next phase of our research will involve testing existing migraine therapies that inhibit CGRP to repurpose these drugs as cancer treatments,” remarked Mielke in the press release. “In the future, we hope to incorporate the existing CGRP inhibitors in clinical trials alongside conventional colorectal cancer therapies.”
