Drug Combination to Treat Lung Cancer Metastasis

Application

Combination product co-targeting PDH and GLUT1 to inhibit lung cancer metastasis.

Key Benefits

Combination of drugs exhibits greater synergism in cancer cell lines (H1299, 4T1, H1792).
Has potential to prevent metastasis in a variety of cancers.
Decreases both cell viability and invasive area.
Repurposed drugs.

Market Summary

Metastatic disease is the primary cause of cancer patient death. Numerous studies show that it is not a single metastatic cell but rather collective packs of invasive cells, that can be further divided into leaders and followers. Compared to follower cells, leader cells have shown to be resistant to common chemotherapeutic agents, suggesting that leader cells cannot be targeted using standard therapeutics, underscoring the need to identify actionable targets regulating cell invasion.

Technical Summary

Emory inventors used Spatiotemporal Cellular and Genomic Analysis (SaGA) to deconstruct the collective invasion pack and determine whether leader and follower cells exhibited differential cellular metabolism. The aim of this study was to identify metabolic vulnerabilities unique to the follower vs leader cells that could be co-targeted for disrupting collective invasion and limiting metastasis. These data revealed metabolic heterogeneity within invasive chains. Leader cells rely on active pyruvate dehydrogenase (PDH) to sustain mitochondrial respiration whereas follower cells exhibit elevated glycolysis, glucose metabolism, glucose transporter 1 (GLUT1) expression, and reduced dependency on oxidative phosphorylation (OXPHOS).

Based on these findings, Emory researchers treated cancer cells with a combination of Alexidine dihydrochloride or CPI-613/devimistat (PDH inhibitors) and BAY-876 (GLUT1 inhibitor). This drug combination showed an efficient inhibition of the collective invasion of heterogenous cellular subtypes (leader and follower cells).