Pannexin-1 channels, a new key target
for novel cancer drug development

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 (Panx1) is a membrane channel, overexpressed in various tumors, including triple-negative breast cancer, where it remains open for longer than usual durations.

Once Panx1 is open:

Extracellular Pathways Engagement: Intracellular ATP leaves the cell leading to a surge of extracellular ATP (eATP) by up to a thousandfold (compared to normal tissue), which is a critical signaling event that can activate and amplify a multitude of eATP-dependent signaling pathways as illustrated in blue in the lower section of the illustration.

Intracellular Pathway Engagement: Concurrently, there is an activation of various intracellular pathways, mediated by the direct interaction with Panx1 channels and the consequent influx of calcium ions (Ca2+), shown in blue in the upper section of the illustration.

Stimulation of Tumor Functions: These extracellular and intracellular activations culminate in the stimulation of several tumor functions, highlighted in red in the illustration.

Panx1 is pivotal in suppressing the immune response, enabling tumor growth, and enhancing metastatic spread.

Consequently, the inhibition of Panx1 presents a targeted strategy to regulate numerous cancer pathways specifically in cancers with pronounced Panx1 overexpression, such as triple-negative breast cancer (TNBC), offering a novel and hopeful avenue for therapeutic intervention.

Extracellular ATP, a major biochemical constituent of the tumor microenvironment (TME)

Extracellular ATP significantly influences theTME by fostering an immunosuppressive milieu that aids tumor cell survival and growth, largely through its conversion to ADP, AMP, and adenosine. This process engages P2Y receptors to support tumor proliferation. Additionally, ATP drives the recruitment and activation of immune cells, including the activation of dendritic cells (DCs), which then release pro-inflammatory cytokines. Through the activation of P2X7 receptors (P2X7R), ATP also triggers the release of enzymes like metalloproteinases (MMPs) and cathepsin, facilitating tumor cell migration through vessel walls via P2Y receptors (P2YR).

This multifaceted role of ATP underscores its critical impact on tumor progression and the immune landscape within the TME.

Through its intracellular pathway engagement Panx1 plays an important role in metastasis.

Mechanosensitive Panx1 activation mediates microvascular metastatic cell survival.

*Furlow, Paul W., et al. Nature cell biology 17.7 (2015): 943-952

Gain-of-function mutations in the Panx1 gene have been associated with variable effects on metastasis. Specifically, mutants with decreased activity were observed to exhibit reduced metastatic potential, whereas those with heightened activity demonstrated an increased capacity for metastasis.

This differential impact underscores the critical role of Panx1 activity levels in modulating metastatic behavior.

Significance of adenosine signaling in Triple Negative Breast Cancer (TNBC)

Panx1 channels and enzymes responsible for converting extracellular ATP to Adenosine are found in high levels in TNBC. This leads to an increase in Adenosine which can suppress the immune system, allowing cancer cells to avoid being detected and destroyed by the immune system. Blocking Panx1 channels could be a more efficient way to reduce Adenosine levels, thereby boosting the immune response against cancer cells.

Safety of this new drug class

Clinical experience involving drug that inadvertently block Panx1 have not indicated any Panx1-associated adverse effects. Similarly, mouse models lacking Panx1 have not displayed significant abnormalities, underscoring the potential safety of Panx1-targeted therapies. This safety is further supported by the specific overexpression and activation of Panx1 in tumors, as opposed to normal tissues, making it an attractive target for cancer therapy. Additionally, the presence of alternative mechanisms for ATP release ensures that physiological levels of extracellular ATP remain unaffected by Panx1 inhibition, highlighting the therapeutic strategy’s specificity and minimal impact on normal
physiological processes.