A novel strategy to overcome drug resistance in cancer

摘要

ABSTRACT The major obstacle to successful cancer therapy is the rapid development of drug resistance. While targeted therapies often extend overall survival in the subset of patients with sensitizing mutations, their effects are short-lived. Patients who initially respond to these drugs generally develop resistance within a few months. Single-cell sequencing of tumors has revealed significant genetic heterogeneity; tumor cells without the sensitizing mutation survive therapy and re-populate the tumor. At the same time, compensatory epigenetic and genetic changes relieve dependence on the targeted pathway, also contributing to resistance. There is thus a critical unmet need for new therapeutic strategies capable of providing more robust cancer control. A robust system continues to function even when an individual component fails. In the context of drug development, a robust therapy would produce parallel, redundant anti-cancer effects, each of which is sufficient to inhibit tumor growth. One approach to achieving such redundancy is to embrace the pleiotropic actions of natural compounds. Endogenous signaling molecules produce coordinated and complex responses by targeting multiple signaling nodes in parallel. For example, endogenous sphingolipids exhibit potent tumor suppressor activity by producing multifaceted and incompletely characterized changes in signaling pathways that trigger proliferative arrest in normal cells and death in cancer cells. SH-BC-893 (893), a synthetic sphingolipid with improved drug properties, retains the anti-neoplastic activity of these natural compounds. In a rigorous, genetically-engineered mouse model for aggressive prostate cancer, 893 reduces autochthonous tumor growth by 82%. In a related subcutaneous isograft model, 893 produces tumor regressions in >50% of mice. 893 is also effective against patient-derived prostate tumor organoids that are resistant to standard-of- care therapies. The major argument against pleiotropic agents has been that toxicity will be unacceptably amplified relative to more specific drugs. However, natural sphingolipids induce quiescence in normal cells as part of an adaptive, homeostatic response to stress. Indeed, 893 does not cause organ toxicity or disrupt the proliferation of normal cells in the bone marrow or intestinal crypts even after 3 months of treatment with the anti-neoplastic dose. Normal cells are more resistant to 893, but 893’s pharmacokinetic properties also likely contribute to its safety margin. Our preliminary data showing that 893 engages multiple, high-value oncology targets results raise the possibility that 893 will be less susceptible to drug resistance and could overcome resistance to FDA-approved therapies. This proposal will test this provocative hypothesis. The expected results would have a significant positive impact by changing thinking in the field and providing a novel therapeutic strategy that would be effective in patients with late-stage, lethal prostate cancers.