Novel holistic approaches for overcoming therapy resistance in pancreatic and colon cancers

Gastrointestinal [GI] cancers, such as of the colon and pancreas, are highly resistant to both standard and targeted therapeutics. Therapy-resistant and heterogeneous GI cancers harbor highly complex signaling networks [the resistome] that resist apoptotic programming. Commonly used gemcitabine or platinum-based regimens fail to induce meaningful [i.e. disease-reversing] perturbations in the resistome, resulting in high rates of treatment failure. The GI cancer resistance networks are, in part, due to interactions between parallel signaling and aberrantly expressed microRNAs [miRNAs] that collectively promote the development and survival of drug-resistant cancer stem cells with epithelial-to-mesenchymal transition [EMT] characteristics. The lack of understanding of the resistance networks associated with this subpopulation of cells as well as reductionist, single protein-/pathway-targeted approaches have made 'effective drug design' a difficult task. We propose that the successful design of novel therapeutic regimens to target drug-resistant GI tumors is only possible if network based drug avenues and agents, in particular 'natural agents' with no known toxicity, are correctly identified. Natural agents [dietary agents or their synthetic derivatives] can individually alter miRNA profiles, suppress EMT pathways and eliminate cancer stem-like cells that derive from pancreatic cancer and colon cancer, by partially targeting multiple yet meaningful networks within the GI cancer resistome. However, the efficacy of these agents as combinations [e.g. consumed in the diet] against this resistome has never been studied. This short review article provides an overview of the different challenges involved in the understanding of the GI resistome, and how novel computational biology can help in the design of effective therapies to overcome resistance

Role of bioresponse 3,3'-diindolylmethane in the treatment of human prostate cancer: clinical experience

Castration-resistant prostate cancer [CRPC] progression after androgen deprivation therapy shows upregulated expression of androgen receptor [AR] splice variants, induced epithelial-to-mesenchymal transition phenotypes and enhanced stem cell characteristics, all of which are associated with resistance to enzalutamide. Since there is no curative treatment for CRPC, innovative treatments are urgently needed. In our recent study, we found that resistance to enzalutamide was partly due to deregulated expression of microRNAs such as miR-34a, miR-124, miR-27b, miR-320 and let-7, which play important roles in regulating AR and stem cell marker gene expression that appears to be linked with resistance to enzalutamide. Importantly, we found that Bio-Response 3,3' -diindolylmethane [BR-DIM] treatment in vitro and in vivo caused downregulation in the expression of wildtype AR. The AR splice variants, Lin28B and EZH2, appear to be deregulated through the re-expression of let-7, miR-27b, miR-320 and miR-34a in human prostate cancer [PCa]. BRDIM administered in clinical trials was well tolerated, and 93% of patients had detectable prostatic DIM levels. The inhibitory effects of BR-DIM on AR and AR target gene such as prostate-specific antigen were also observed in the clinical trial. Our preclinical and clinical studies provide the scientific basis for a 'proof-of-concept' clinical trial in CRPC patients treated with enzalutamide in combination with BRDIM. This strategy could be expanded in future clinical trials in patients with PCa to determine whether or not they could achieve a better treatment outcome which could be partly mediated by delaying or preventing the development of CRPC

The biological complexity of RKIP signaling in human cancers

The Raf kinase inhibitory protein (RKIP) has been demonstrated to modulate different intracellular signaling pathways in cancers. Studies have shown that RKIP is frequently downregulated in cancers; therefore, attempts have been made to upregulate the expression of RKIP using natural and synthetic agents for the treatment of human malignancies. Moreover, various regulators such as specific proteins and microRNAs (miRNAs) that are involved in the regulation of RKIP expression have also been identified. RKIP mechanistically modulates the apoptotic regulators of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling. Because of its critical role in human cancers, RKIP has drawn much research attention, and our understanding is expanding rapidly. Here, we summarize some of the biological complexities of RKIP regulation. However, we restrict our discussion to selected tumors by focusing on TRAIL, miRNAs and natural agents. Emerging evidence suggests a role for natural agents in RKIP regulation in cancer cells; therefore, naturally occurring agents may serve as cancer-targeting agents for cancer treatment. Although the literature suggests some advancement in our knowledge of RKIP biology, it is incomplete with regard to its preclinical and clinical efficacy; thus, further research is warranted. Furthermore, the mechanism by which chemotherapeutic drugs and novel compounds modulate RKIP and how nanotechnologically delivered RKIP can be therapeutically exploited remain to be determined.