Experimental Orally Deliverable Cancer Drug Shows Promise in Animal Models

An experimental orally deliverable drug that blocks the activity of the tumorigenic protein signal transducer and activator of transcription 3 (Stat3) was shown to block growth of cancer cells in culture and to inhibit growth of human breast and lung tumor xenografts.

The Stat protein family regulates many aspects of cell growth, survival, and differentiation. Dysregulation of this signaling pathway is frequently observed in primary tumors and leads to increased angiogenesis and enhanced tumor survival. Knockout studies have provided evidence that Stat proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance. Stat3-deficient mouse embryos cannot develop beyond embryonic day seven, when gastrulation initiates. It appears that at these early stages of development, Stat3 activation is required for self-renewal of embryonic stem cells. Constitutive Stat3 activation is associated with various human cancers and commonly suggests poor prognosis. It has antiapoptotic as well as proliferative effects.

Investigators at the University of Hawaii (Honolulu, USA) used a sophisticated computer-based molecular modeling system to guide the development of the Stat3 inhibitor BP-1-102.

The drug was tested on cancer cell cultures and in mouse xenograft models of breast and lung tumors. Results published in the May 23, 2012, online edition of the journal Proceedings of the National Academy of Sciences of the USA (PNAS) revealed that binding of BP-1-102 to Stat3 blocked this protein’s activity and selectively inhibited growth, survival, migration, and invasion of Stat3-dependent tumor cells. Intravenous or oral delivery of BP-1-102 to mice furnished micromolar or microgram levels of the drug in tumor tissues and inhibited growth of human breast and lung tumor xenografts. A unique feature of BP-1-102 is that it remained highly effective against tumor cells when administered in oral form.

“The molecular structure of the hyperactive Stat3 protein basically resembles two cars that are joined together side-by-side,” said senior author Dr. James Turkson, professor of cancer biology at the University of Hawaii. “We then utilized a computer program that creates molecular models of potential drugs engaging in binding to the Stat3 protein to craft the BP-1-102 drug which literally pulls apart the Stat3 protein rendering it ineffective in causing cancer.”

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