Discovery and validation of Panx1 opens a new pathway for development of selective Panx1 blockers as novel therapeutics for cancer – Pannex Therapeutics is leading the way with its discovery platform for identifying promising drug candidates.
Panx1 is an oncogenic driver, amplifying multiple
signals in many types of cancer.
Pannexin 1 channels (Panx1) are membrane channels that are closed under normal conditions but open under pathophysiological conditions, causing detrimental effects. During the last decade, research findings from many groups around the world have implicated Pannexin 1 channels (Panx1) in cancer emergence and progression in many different types of cancer.
Once open, Panx1 channels release signaling molecules, such as ATP and Ca+2, which increase extracellular ATP (eATP) by 1000x compared to normal tissues. Very high eATP levels fuel many cancer pathways and serve as an energy source that provides survival advantages and promote cancer cell growth and spread (metastasis). Panx1 plays other detrimental roles through its linkages to the cellular cytoskeleton and to key intracellular oncogenic regulatory pathways, leading to oncogene activation.
Activation of Panx1 in tumor cells contributes to the development of important hallmarks of cancer:
• Invasion and metastasis
• Genome instability
• Sustained Proliferation
• Evading growth suppression
• Evading of cell death
Panx1 is overexpressed in tumor cells and associated with poor clinical outcome and survival.
Panx1 overexpression is associated with poor clinical outcome and survival in many tumor types, indicating broad potential for Panx1 blockers across many different tumor types. Examples include:
• Hepatocellular carcinoma
• Triple negative breast cancer
• Gastric cancer
• Human melanoma tumors
• Many other tumors
Panx1 is overexpressed in tumor cells and the tumor microenvironment (TME) but not in other tissues. Selective overexpression in tumor suggests that Panx1 blockers will not affect normal tissues or cause untoward side effects.
Blocking Panx1 is effective in animal tumor models
Carbenoxolone, spironolactone, mefloquine and other old, well-known drugs have been shown to have Panx1 blocking activity as an off-target pharmacological effect and found to be effective in in vivo animal tumor models. For example:
• Nonspecific Panx1 blockers were effective in human melanoma tumor xenografts
• Carbenoxolone and probenecid reduced lung metastasis from breast cancer cells
• Blocking Panx1 with probenecid or genetic Panx1 knock out downregulated epithelial-to-mesenchymal transition (EMT) pathway genes in breast cancer cells
PANNEX is developing first-in-class, highly effective and specific Panx1 blockers to target a wide variety of tumor types
Pannex's vision is to improve survival
by blocking multiple pathways in cancer cells.
Cancer complexity and treatment challenges
Although significant progress has been made during the last two decades, the effectiveness of current cancer treatment remains limited because it does not target the complex mechanistic pathways of tumor cells. Various pathways lead to the development of the different hallmarks of cancer, including unrelenting proliferation (increasing number of tumor cells), evasion of growth suppression signals (the body’s attempt to defend itself against cancer), resistance to apoptosis (a protective cell death mechanism in normal cells to eliminate cells when they become defective or abnormal), neovascularization (the formation by the tumor of new blood vessels to support its growth and spread) and the ability to invade and metastasize (cancer spread).
Cancer researchers and drug developers face the challenge of creating drugs that target multiple cancer pathways to stop growth, spread and survival of cancer cells.
Targeting multiple cancer
pathways
The recent discovery of pannexin 1 channels (Panx1) and their role in multiple cell pathways represents a significant advance in our understanding of cancer cell biology. It also represents an exciting opportunity to develop new effective drugs with a novel mechanism of action. Panx1 is an upstream therapeutic target that occurs early in a cancer pathway. Expression of Panx1 affects multiple downstream targets that occur later in multiple, branching pathways. Pannex’s strategy is to block Panx1 upstream in order to block multiple cancer pathways that occur downstream.
A multiple pathway mechanism of action distinguishes Panx1 blockers from typical pharmaceutical company cancer drug discovery and development, which mainly focuses on a single downstream target to block a single step in a cancer pathway.
Our mission is to translate Panx1 science into safer and more effective cancer treatments.
Selected scientific publications
Panx1 in cancer:
1. Laird, D. W., & Penuela, S. (2021). Pannexin biology and emerging linkages to cancer. Trends in Cancer, 7(12), 1119-1131.
2. Laird DW, Penuela S. Pannexin biology and emerging linkages to cancer. Trends Cancer. 2021 Dec;7(12):1119-1131.
3. Bao L, Sun K, Zhang X. PANX1 is a potential prognostic biomarker associated with immune infiltration in pancreatic adenocarcinoma: A pan-cancer analysis. Channels (Austin). 2021 Dec;15(1):680-696.
4. Shi G, Liu C, Yang Y, Song L, Liu X, Wang C, Peng Z, Li H, Zhong L. Panx1 promotes invasion-metastasis cascade in hepatocellular
carcinoma. J Cancer. 2019 Sep 7;10(23):5681-5688.
Panx1 in general:
1. Navis KE, Fan CY, Trang T, Thompson RJ, Derksen DJ. Pannexin 1 Channels as a Therapeutic Target: Structure, Inhibition, and Outlook. ACS Chem Neurosci. 2020 Aug 5;11(15):2163-2172. doi: 10.1021/acschemneuro.0c00333. Epub 2020 Jul 20. PMID: 32639715.
2. Sanchez-Arias JC, van der Slagt E, Vecchiarelli HA, Candlish RC, York N, Young PA, Shevtsova O, Juma A, Tremblay MÈ, Swayne LA. Purinergic signaling in nervous system health and disease: Focus on pannexin 1. Pharmacol Ther. 2021 Sep;225:107840.
3. Bhat EA, Sajjad N. Human Pannexin 1 channel: Insight in structure-function mechanism and its potential physiological roles. Mol Cell Biochem. 2021 Mar;476(3):1529-1540.