Abstract B46: A fundamental vulnerability of tumor cells

Abstract

Abstract Available means of multicellular organisms are incapable of fully preventing or repairing damage to the genetic material and aging is associated with genetic and epigenetic changes in somatic cells. An age-associated increase in tumorigenesis is one of the various consequences of such changes. It is also a fact that cellular proliferation increases probability of mutations and certain alterations of chromatin structure with cellular differentiation adversely affect genetic stability. An evolutionarily conserved strategy at the face of this situation is to have infrequently dividing stem cells that are kept in an undifferentiated state and to maintain soma through transiently proliferating and differentiating progenitor cells. I described previously a vulnerability of the tumorigenic cells and a treatment strategy directed to it. Here I will present and discuss data showing that the developed treatment can provide elimination of tumors in human subjects independent of localization, histopathological classification and stage. Normal stem cells reside at particular tissue sites, niches, where the niche support cells contribute to regulation of proliferation and differentiation of stem cells and of their progeny. Tumor cells having stem cell features, on the other hand, have become independent of an anatomically defined niche as a result of the genetic and epigenetic changes they have acquired during tumorigenesis and this represents a vulnerability or disadvantage in comparison to the normal stem cells enjoying support of a niche when the critical signals relied upon are reduced. After testing on normal human skin a selective inhibitor of a signaling deemed critical in niche, Hedgehog/Smoothened (Hh/Smo) signaling, and noting evidence for decrease of Hh gradually with distance from niche to provide dose-dependent variation of Hh effects on stem cells and on their differentiating progeny, a treatment program was initiated. Topical application of a selective inhibitor of Hh/Smo signaling (cyclopamine) to skin tumors in doses previously determined to be safe on human skin showed dose-dependent induction of differentiation and apoptotic elimination of the cancer cells while sparing the normal stem cells and progenitor cells, consistent with above-mentioned hypothesis. In accord with the dose-dependent regulation of transcription of Hh target genes, a dose of inhibitor far beyond the dose sufficing to inhibit tumor cell proliferation is required for tumor cell apoptosis and the normal stem cells exposed to such a dose are well preserved structurally and functionally as determined with human subjects followed up long term. Similarly, intratumoral/intrabronhial cylopamine administrations to a man who had become bed-ridden due to an inoperable adenocarcinoma of lung obstructing one of the main bronchi resulted in rapid restoration of the airway in less than a week with no evidence of an adverse effect on the normal bronchial tissue and on normal mediastinal structures visualized by bronchoscopy and MRI, respectively. The patient was mobilized to resume manual labor and did not show evidence of an adverse effect during follow up. Conclusion: Although a niche supports normal stem cells in many respects, including by reducing likelihood of oxidative and other damage to the genetic material, doses of genotoxic agents required to kill tumor cells necessarily cause irreversible harm to the normal cells. A drug treatment not relying on exertion of genotoxicity and designed to take advantage of an essential difference identified between the normal and tumorigenic cells having stem cell features, on the other hand, can provide safe and selective elimination of cancer cells. Conflict of Interest Statement: I have patents and pending applications related to the described subject matter. I declare otherwise no conflict of interest. Citation Information: Clin Cancer Res 2010;16(7 Suppl):B46