Tissue Targeting May Offer an Alternative Therapeutic Approach for Difficult-to-Treat Diseases

We recently received a phase II of our SBIR grant Exploiting Synthetic Lethality of Hematopoietic Lineage Cells to Develop Novel Targets from the NIH. Rather than trying to identify potential drug targets in oncogenic hematopoietic cells, much of the effort for this project focuses on trying to develop a pharmacologic approach to identify and kill off all hematopoietic cells (see recent press release). This sort of capability may offer an alternative therapeutic approach relying on tissue ablation and renewal to treat hematopoietic cancers such as leukemia and lymphoma.

Clinical approaches exist to regrow and regenerate portions of many essential tissues. For serious diseases, this capability offers a somewhat aggressive treatment possibility where affected tissues are completely eliminated and replaced by new healthy tissue. Blood is one such tissue where that can be regenerated with current clinical procedures. Though risky, a patient’s blood can be regenerated from a bone marrow cell graft through autologous hematopoietic stem cell transplantation and this is a currently a treatment of last resort for individuals suffering with life-threatening blood or bone marrow cancers. However, there is also much focus on regenerative approaches with other tissues, such as bone and skin. In addition, loss of other tissues such as thymus, prostate, and ovary do not have a significant negative impact on the quality of life. As research advances, it is reasonable to assume regenerative approaches will be available for an increasing range of cell types and tissues.

Since all cells of one tissue or lineage type are removed and replaced using this approach, the specific pathology is not particularly significant for ablative and regenerative treatments. Rather than targeting specific cells based on certain disease biology, eradication of all cells in a particular class eliminates the disorder regardless of its nature. This opens up a real opportunity to develop effective therapies for a range of diseases for which there are currently limited treatment options. As clinical technology develops, stem cell therapies improves, more tissue regeneration protocols are established, and in vitro tissue and organ culture technology becomes routine, ablative/replacement treatments may become the preferred therapeutic approach to treat any number of a broad range of disease states.

A major hurdle with this sort of therapy, however, is the in situ eradication step of the diseased cell or tissue. Currently, the principal ways to eliminate damaged cells types or tissues are through localized excision via surgery or radioactive ablation. For example, with autologous hematopoietic stem cell transplantation mentioned above, much of the toxicity of the treatment is associated with the general full-body radiation treatments to which patients are subjected to ablate an individual’s endogenous bone marrow before grafting in new healthy tissue. More precisely targeted approaches to eliminate affected cells are necessary if tissue replacement is to become a generally useful treatment option. Pharmacologicals that target and kill specific types of cells would provide a much needed solution for this problem, and may be easier to develop than drugs that specifically target only diseased, but not healthy, cells. The first step in developing these sorts of targeted molecules is identifying unique tissue-specific markers and potential drug targets as we are attempting for hematopoietic cells with this project.

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