Fazlul H. Sarkar, Ph.D., professor of pathology at Karmanos Cancer Institute at Wayne State University, is profiling miRNA signatures associated with various cancers and other diseases and studying means of regulating miRNA activity by natural agents with known anticancer effects.
“We are looking at active compounds in dietary agents involved in either destroying miRNAs with oncogenic activity or augmenting the expression of miRNAs that are downregulated in diseases,” Dr. Sarkar said. The complete mechanisms of activity have yet to be characterized, but he has hypothesized that demethylation of selective promoter sites is involved in reexpression of miRNAs that suppress oncogenesis.
His lab is also exploring cancer recurrence stemming from cells that have survived in patients through past treatment regimens. “Lab findings, including our own, have shown two distinct features of such cells, including one called epithelial-to-mesenchymal transition, or EMT.
“Most epithelial tumors are epithelial-cell tumors that are morphologically and genotypically epithelial; when cancer is survived through a therapeutic insult, such cells can change their phenotype and become mesenchymal,” Dr. Sarkar explained, whereby they can opportunistically invade the vasculature to relocate to eventual metastatic sites within the body. Such cells also acquire cancer stem cell characteristics.
Dr. Sarkar’s lab is exploring the miRNAs involved in cancer recurrence and their responses to such natural agents as indoles, isoflavones, and curcuminoids. The work is yet at proof-of-principle stage. Three Phase II trials of isoflavones in prostate and breast cancer showed positive results, with one study indicating a reduction in radiation-induced toxicity.
Previous Phase I trials in prostate cancer led to a Phase II study in patients with newly diagnosed cancer. A protocol has now been completed for a Phase II trial in patients with triple-negative breast cancer (negative for estrogen, progesterone, and Her2 receptors), offering an option for a disease clearly nonresponsive to conventional hormonal treatments.
Beyond the patient compliance that blood-test diagnostics permit, plasma-based diagnostic/prognostic assessments of miRNA avoid the problems of isolating from blood serum (whereby coagulation of proteins, with which miRNAs associate, can otherwise reduce yields and thus erroneously skew conclusions about miRNA levels in the samples). Ultimately, advances in miRNA R&D may open treatment options that drastically affect prognostic outcomes.
As proof of principle, Dr. Sarkar’s laboratory has shown that the expression of specific miRNAs whose expression is lost in aggressive cancer cells (miR-200 and let7) can be upregulated by these natural agents, opening doors for novel cancer therapies.
“We and others have shown that the expression of miRNA can be prognostically related to patient survival. In pancreatic tumors, for instance, median survival can be as short as six to eight months, whereas certain patients exhibiting low expression of miR-21 have a median survival of approximately 43 months.” Dr. Sarkar stated that the application of miRNA in cancer therapy is still in its infancy, and he predicted rapid progress going forward, to the benefit of patients.