Novel Anti-Cancer Stem Cell Agents

The cancer stem-like cell (CSC) hypothesis explains the shortcomings of current anti-cancer therapeutics and posits a paradigm-shifting direction for the discovery of new anti-cancer drugs. The major shortcomings of the current anti-cancer chemotherapy are the primary and acquired resistances to cytotoxic agents, which lead to disease recurrence. This phenomenon is thought to arise from the very small population of CSCs that possesses the ability to self-renew, differentiate and reconstitute the entire tumor after initial treatment. Clearly, a therapeutic that selectively targets CSCs to inhibit their self-renewal and differentiation potential is key to preventing relapse and thereby greatly enhancing survival.

The technology

Researchers at Virginia Commonwealth University have designed, synthesized and shown that distinct and unique novel sulfated flavonoids inhibit CSC self-renewal and differentiation, thereby preventing cancer relapse. The unique sulfated flavonoids modulate the interaction of glycosaminoglycans (GAGs) with cell surface receptors that are involved in growth and/or differentiation signaling, resulting in the reduction of the incidence of cancer recurrence due to CSCs. The sulfated flavonoids are easy to synthesize, easy to transform into formulations, and easy to monitor in vivo for PK/PD. The efficacy of these novel sulfated flavonoids has been demonstrated in several murine models of colorectal cancer. A series of patent applications have been filed to protect the technology platform. 

A lipidic quercetin dimer, labeled as G5C, prevents relapse of cancer in nearly 100% of animals when xenografts are induced with cells previously treated with anti-cancer agents (5-fluorouracil and oxaliplatin (FUOX)). Likewise, G5C and other specific analogs significantly reduce xenograft growth alone and in combination with FUOX. G5C is a lipidic analog of a sulfated quercetin dimer, which potently and selectively inhibits colorectal, pancreatic, and lung CSCs. G5C exhibits strong anti-CSC activity (~50 – 100 mg/kg) without any significant toxicity (at ~3-times the effective dose); has a half-life of > 6 h; oral bioavailability 20 – 30%, and a shelf-life of > 3 months. G2C and G8C are two other unique analogs of G5C that are currently being studied in multiple models of cancer and therapeutic efficacy.