Combined Therapy in Cancer: The Non-coding Approach

Despite the fact that the idea of personalized medicine in cancer has been accentuated in the last years of research, this concept is well rooted in the history of medicine: “It is more important to know what sort of person has a disease than to know what sort of disease a person has” (Hippocrates 450–370 BCE). We understood that the right therapy has to be administrated in the right amount, to the right patient, under the right conditions, and finally at the right time. But what if the safe amount is not necessarily the most effective one? In light of these aspects, researchers have developed combinatorial strategies of anti-cancer drugs to avoid a heavy insult in terms of toxicity and also installation of drug resistance. The question that arises at this moment is: how do we deal with the last generation forms of therapy in the name of microRNA (miRNA) modulation? miRNAs are short non-coding sequences that impair the expression of specific genes mainly by targeting the complementary transcript. The panel of targeted transcripts is now made available through a wide selection of databases that comprise the experimental validation of the interactions and also the predicted ones (e.g. miRWalk1Dweep H. Gretz N. Sticht C. miRWalk database for miRNA-target interactions.Methods Mol. Biol. 2014; 1182: 289-305Crossref PubMed Scopus (212) Google Scholar). Although this vast network of regulation is responsible for the normal function of numerous pathways inside the cell, the aberrant expression of miRNAs is becoming a central part in cancer initiation and development. We are currently aware that these small transcripts are involved in every cancer hallmark mainly through downregulated profiles for the tumor suppressor miRNAs and exacerbated expression for the oncogenic ones. These aspects were discussed over and over in the last years in the scientific literature and numerous proposals with miRNAs as therapeutic agents were published in the oncological domain.2Peng Y. Croce C.M. The role of MicroRNAs in human cancer.Signal Transduct Target Ther. 2016; 1: 15004Crossref PubMed Scopus (1270) Google Scholar, 3Berindan-Neagoe I. Monroig Pdel.C. Pasculli B. Calin G.A. MicroRNAome genome: a treasure for cancer diagnosis and therapy.CA Cancer J. Clin. 2014; 64: 311-336Crossref PubMed Scopus (417) Google Scholar, 4Braicu C. Calin G.A. Berindan-Neagoe I. MicroRNAs and cancer therapy - from bystanders to major players.Curr. Med. Chem. 2013; 20: 3561-3573Crossref PubMed Scopus (52) Google Scholar, 5Gulei D. Mehterov N. Nabavi S.M. Atanasov A.G. Berindan-Neagoe I. Targeting ncRNAs by plant secondary metabolites: The ncRNAs game in the balance towards malignancy inhibition.Biotechnol. Adv. 2017; (Published online November 10, 2017)https://doi.org/10.1016/j.biotechadv.2017.11.003Crossref PubMed Scopus (22) Google Scholar, 6Redis R.S. Berindan-Neagoe I. Pop V.I. Calin G.A. Non-coding RNAs as theranostics in human cancers.J. Cell. Biochem. 2012; 113: 1451-1459PubMed Google Scholar, 7Braicu C. Catana C. Calin G.A. Berindan-Neagoe I. NCRNA combined therapy as future treatment option for cancer.Curr. Pharm. Des. 2014; 20: 6565-6574Crossref PubMed Scopus (56) Google Scholar However, considering the complex scheme behind miRNA signaling, where the targeting takes place in a multicoordinated system—one miRNA can target multiple transcripts and one transcript can be targeted by more than one miRNA—the following statement becomes plausible: one single miRNA sequence, despite the extended role throughout entire signaling pathways, is not able to hazardously disrupt the development of cancer cells and completely eradicate the pathology within the organism in safe administrated doses. This affirmation comes from the idea that a tumor suppressor gene could be experimentally enforced through downregulation of an oncogenic complementary miRNA, but this is not necessarily a secure strategy considering that there are other miRNAs that can still target the same transcript. Still, the same miRNA can simultaneously target tumor suppressor and oncogenic genes in context-dependent situations, weakening the treatment efficiency or, even worse, producing long-term side effects. Moreover, the ability of cancer cells to develop compensatory mechanism by activating bypassing systems is also affecting the possibility of using miRNAs as single agents in preclinical and/or clinical therapeutics. The first clinical trial involving the experimental upregulation of miR-34 has underlined important safety aspects regarding this type of therapeutic approach and urged the need for other perspectives. To obtain a superior yield in terms of cancer therapy, we are proposing a novel kind of approach where miRNA modulation could be used as the first line of treatment to disrupt the cancer cell at multiple levels, followed by administration of small molecule inhibitors for specific cancer-driven targets in the attempt to obtain a superior effect at lower doses. This approach has a molecular level of action for both therapeutic molecules, where the suppression of a specific target by a small molecule inhibitor could be sustained by a synergistic miRNA concentrated on the same oncogenic pathway. Moreover, the ability of miRNAs to modulate multiple transcripts from the same or interconnected molecular mechanisms (e.g. apoptosis, epithelial to mesenchymal transition [EMT], angiogenesis, etc.) represents a steady advantage,8Berindan-Neagoe I. Calin G.A. Molecular pathways: microRNAs, cancer cells, and microenvironment.Clin. Cancer Res. 2014; 20: 6247-6253Crossref PubMed Scopus (87) Google Scholar, 9Gulei D. Mehterov N. Ling H. Stanta G. Braicu C. Berindan-Neagoe I. The “good-cop bad-cop” TGF-beta role in breast cancer modulated by non-coding RNAs.Biochim. Biophys. Acta. 2017; 1861: 1661-1675Crossref PubMed Scopus (36) Google Scholar, 10Gulei D. Magdo L. Jurj A. Raduly L. Cojocneanu-Petric R. Moldovan A. Moldovan C. Florea A. Pasca S. Pop L.A. et al.The silent healer: miR-205-5p up-regulation inhibits epithelial to mesenchymal transition in colon cancer cells by indirectly up-regulating E-cadherin expression.Cell Death Dis. 2018; 9: 66Crossref PubMed Scopus (60) Google Scholar where the effect of miRNA will be perceived at a more general level and the small molecule will strongly attack the principal knot from the altered oncogenic pathway (the principal knot is considered a molecule that is strongly overexpressed and functional within a oncogenic pathway; the principal knot can also be cancer specific). In this way, the tendency of cancer cells to overcome the impairing effects through activation of adaptive loops will be hampered by a well-chosen non-coding sequence able to modulate targets that could be used by malignant cells for activation of secondary paths. Importantly, the chosen signaling knot (referred to as the main targeted oncogenic molecule) will be inhibited by both agents to obtain a maximum impairing effect with smaller doses. In this way, the potential toxicity and implicit side effects will be strongly diminished, preserving or even improving the malignant inhibitory effect. In general terms, the exogenous miRNA is used for weakening of cancer cell due to its ability to target multiple transcripts, where the second line of treatment is used as a powerful targeted agent able to eradicate the cancer cell through different mechanisms (e.g. apoptosis, inhibition of cell cycle, necrosis, etc). The effect of the second therapeutic will be significantly improved due to the already weak malignant phenotype obtained after the restoration of a specific miRNA expression. This approach represents a novel perspective upon miRNA therapeutics, where the non-coding sequence is not the central part of the treatment scheme, but is contributing to the efficiency of the second type of therapy. Despite the fact that the proposed molecule for the second administration consists in a specific small molecule inhibitor, there is the possibility to replace this one with other types of therapies, even with the classical chemotherapy. One of the marked points in molecular oncology consists of the implementation of non-coding RNA sequences, partially represented by miRNAs, as important influencers of cancer-related pathways.3Berindan-Neagoe I. Monroig Pdel.C. Pasculli B. Calin G.A. MicroRNAome genome: a treasure for cancer diagnosis and therapy.CA Cancer J. Clin. 2014; 64: 311-336Crossref PubMed Scopus (417) Google Scholar Despite numerous research conducted on this type of therapy,11Christopher A.F. Kaur R.P. Kaur G. Kaur A. Gupta V. Bansal P. MicroRNA therapeutics: Discovering novel targets and developing specific therapy.Perspect. Clin. Res. 2016; 7: 68-74Crossref PubMed Google Scholar, 12Chakraborty C. Sharma A.R. Sharma G. Doss C.G.P. Lee S.S. Therapeutic miRNA and siRNA: Moving from Bench to Clinic as Next Generation Medicine.Mol. Ther. Nucleic Acids. 2017; 8: 132-143Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar, 13Shah M.Y. Ferrajoli A. Sood A.K. Lopez-Berestein G. Calin G.A. microRNA Therapeutics in Cancer - An Emerging Concept.EBioMedicine. 2016; 12: 34-42Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar there are still major concerns related to the actual clinical effects of miRNA modulation. As is the case of any other drug, there is the need for numerous optimization protocols in order to reduce the unwanted effects and potentiate the beneficial one. Several issues related to delivery platforms—optimal dosage, unwanted toxicity, and achieving targeted administration—are still the subjects of intense studies.14Brown R.A.M. Richardson K.L. Kalinowski F.C. Epis M.R. Horsham J.L. Kabir T.D. De Pinho M.H. Beveridge D.J. Stuart L.M. Wintle L.C. Leedman P.J. Evaluation of MicroRNA Delivery In Vivo.Methods Mol. Biol. 2018; 1699: 155-178Crossref PubMed Scopus (12) Google Scholar, 15Chen Y. Gao D.Y. Huang L. In vivo delivery of miRNAs for cancer therapy: challenges and strategies.Adv. Drug Deliv. Rev. 2015; 81: 128-141Crossref PubMed Scopus (450) Google Scholar One particular situation that is quite specific for non-coding oligonucleotides-based therapies is that, compared to the usual situation, where one main target is affected, miRNAs influence numerous elements within the cell, and the assessment of the specific downstream effect becomes much more difficult to evaluate. In the moment of increased administration, when the dose is being pushed to the highest levels to obtain a clear effect, the risk of unwanted targeting is clearly potentiated. This type of toxicity is primarily divided into two categories: hybridization dependent and hybridization independent (or chemistry-related effects). For the first category, it is possible to force the modulation of the targeted genes by administering excess therapeutic compound (exaggerated pharmacology) or to determine off-target effects caused by unspecific binding. For the last case, there is also the possibility of saturation concept, when the exogenous sequence is administrated in doses that exceed the amount of target sequences present in the malignant cell and, in this way, the probability of off-target effects is majorly increased. The second primary category, chemistry-related effects, generally refers to the structure of the miRNA sequence and the biological effects that are unrelated to the hybridization action. Importantly, like any other DNA- or RNA-based regimens, miRNA therapeutics can induce an innate immune response that will trigger an entire cascade of pro-inflammatory events. Nevertheless, another important aspect—secondary related to toxicology—consists of the gradual aspects of the therapeutic efficiency, where miRNAs act on primary targets that, in their turn, modulate downstream effectors. Considering that the sum of the pharmacological effects over time is able to cause a change in the disease phenotype establishes the pharmacological activity of a compound, it is highly possible that the immediate effect observed after miRNA exogenous expression or inhibition is not completely underlying the overall preclinical or clinical changes. This is actually a crucial issue in managing the dose of administrated miRNA compound, where a specific amount of inhibitor or mimic can cause a certain effect at the present time, an effect that can be potentiated afterwards, revealing supplementary toxicity.11Christopher A.F. Kaur R.P. Kaur G. Kaur A. Gupta V. Bansal P. MicroRNA therapeutics: Discovering novel targets and developing specific therapy.Perspect. Clin. Res. 2016; 7: 68-74Crossref PubMed Google Scholar, 16van Rooij E. Purcell A.L. Levin A.A. Developing microRNA therapeutics.Circ. Res. 2012; 110: 496-507Crossref PubMed Scopus (416) Google Scholar In light of these aspects, it is crucially important to manage the doses of administrated miRNA therapeutics at highly specific levels and not lose sight of the potential side effects in favor of the beneficial and prominent ones. The switch from chemotherapy to molecular targeted agents has been implemented already in the oncological field with several successful cases: anti-estrogens and anti-androgens for the curative management of hormone driven breast and prostate cancer, all trans retinoic acid for acute promyelocytic leukemia patients that present translocation in the retinoic acid and for L. of retinoic acid in the treatment of acute promyelocytic PubMed Google Scholar, I. A. et compared with and for J. Med. PubMed Scopus Google Scholar, S. 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Full Text PDF PubMed Scopus Google Scholar However, there are also that need to be overcome in order to the most of this One issue to the of cancer cells, the where the of a cancer cell is not necessarily to the and implicit phenotype of another cell within the same malignant M.R. and the of cancer J. Med. PubMed Scopus Google Scholar, for cancer Full Text Full Text PDF PubMed Scopus (56) Google Scholar, D. The of personalized cancer medicine: underlying hallmark 2012; PubMed Scopus Google Scholar In this way, cells could in a different to the activity of the small molecule inhibitor in one particular case, the inhibitory agent is and, in the other case, the effect is or major issue is drug where the cell can to the action of the small molecule inhibitor through activation of S. E. J. S. N. inhibition regulation of 1: PubMed Scopus Google Scholar or signaling C.M. L. L.A. C.M. N. J. et to inhibition through pathway PubMed Scopus Google Scholar, R. H. Lee H. Lee N. 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The and of The 2012; PubMed Scopus Google Scholar are also issues related to this type of strategy in cancer as the of malignant driven targets that, will determine a prominent of and also research and clinical In light of the discussed aspects, we are proposing a novel type of combined therapy by the effects of miRNA inhibition or with the action of small molecule inhibitors to obtain a superior inhibitory effect upon cancer possible therapeutic for different signaling within cancer cells, on combinatorial strategies miRNAs and small The proposed idea consists of administration of miRNA inhibitors or to small molecule inhibitors to an for the specific activity of the second In this way, the non-coding sequence will target the central knot targeted by the small molecule but will also the levels of transcripts involved in the same pathway and other signaling in drug due to the of targeted The role of miRNA is to the field for the effect of the small molecule inhibitor, weakening the cancer cells at multiple this administration, the second agent targeted the same central oncogenic molecule will the line of treatment in terms of cancer The sequence of where miRNA is as a first is chosen in favor of the other administration or second line of the ability of miRNAs to target multiple oncogenic targets at will be used to the malignant cell, its ability to through compensatory and the efficiency of the small molecule this type of combined the like with therapeutic effects and also drug could be strongly crucial is also represented by the administrated where the amount of drugs for both type of agents will be significantly with the of toxicity events. 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Calin G.A. molecule targeting miRNAs for cancer Drug Deliv. Rev. 2015; 81: PubMed Scopus Google Scholar One strategy is the idea of with the proposed strategy by using small molecule inhibitors able to modulate miRNAs levels and central oncogenic within the targeted However, within this kind of the of the levels of miRNA becomes more difficult due to the action of the small molecule Moreover, the of the proposed strategy is the ability to significantly smaller doses of exogenous miRNAs for the of cancer cells not of a small molecule in doses to a level of the targeted In one of we that is downregulated in colon cancer patients and cells, with a inhibition ability upon in turn, inhibits the levels of a epithelial with the of cells as downregulated in the same is able to the of in colon cancer by of expression and upregulation of as in D. Magdo L. Jurj A. Raduly L. Cojocneanu-Petric R. Moldovan A. Moldovan C. Florea A. Pasca S. Pop L.A. et al.The silent healer: miR-205-5p up-regulation inhibits epithelial to mesenchymal transition in colon cancer cells by indirectly up-regulating E-cadherin expression.Cell Death Dis. 2018; 9: 66Crossref PubMed Scopus (60) Google Scholar as a the a central molecule for that the of for the of cancer cells and also for the of the mesenchymal A. H. A. A.K. role of in and of Mol. 2015; PubMed Scopus Google Scholar as in cancer with with disease and D. Y. of and in with clinical and 9: PubMed Scopus Google Scholar Therapeutic upregulation of could be followed by administration of a small molecule inhibitor for its ability to tumor S. J. in PubMed Scopus Google gene with and ability to modulate and cancer the transition of human Biol. Cell. PubMed Scopus Google Scholar, Y. H. S. S. J. both transition and cell in human epithelial cells by Res. PubMed Scopus (60) Google Scholar, L. Y. J.L. 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