Subject categories include. Doi: PubMed indexing, Sentinel lymphadenectomy in breast cancer. Scopus indexing, Sentinel lymphadenectomy in breast cancer. Medline indexing, Sentinel lymphadenectomy in breast cancer. ESCI indexing, Sentinel lymphadenectomy in breast cancer. SCI indexing, Sentinel lymphadenectomy in breast cancer. PubMed indexing, Archive of "Prostate Cancer". Scopus indexing, Archive of "Prostate Cancer". Medline indexing, Archive of "Prostate Cancer". These authors concluded that survivin-specific T-cell reactivity strongly correlates with tumor response and patient survival [ ], indicating that vaccination with survivin-derived peptides is a promising treatment strategy.
No dose-dependent effects were observed. EMD was well tolerated; local injection-site reactions constituted the most frequent AE [ ]. The authors concluded that vaccination with EMD elicited T-cell responses against survivin peptides in the majority of patients [ ], demonstrating the immunologic efficacy of EMD Using the previously reported survivin peptide cocktail [ , ], the authors formulated the survivin peptide cocktail in a novel and strongly immunogenic vaccine platform called DepoVax TM to form DPX-Survivac [ ].
A Phase I clinical trial to test the safety and immune potency of DPX-Survivac in combination with immune-modulator metronomic cyclophosphamide in ovarian cancer patients was conducted [ ].
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All of the patients receiving the therapy produced antigen-specific immune responses; higher dose vaccine and cyclophosphamide treatment generated significantly higher magnitude responses [ ]. Treatment was repeated biweekly for a period of up to 6 months. Patients still benefiting from treatment would continue temozolomide biweekly and vaccination injections every 4 weeks until disease progression.
Based on these results, the authors concluded that vaccine-induced immunity towards survivin and IDO-derived peptides can be achieved in combination with temozolomide in patients mainly suffering from grade M1c melanoma including patients with brain metastases. However, at the same time, these authors also indicated that significant clinical activity could not be proven in this small cohort study and a larger setup is needed for a more proper assessment [ ]. High frequencies of spontaneous T-cell precursors specific to the survivin peptide cocktail were also detected in the blood of various cancer patients [ ], demonstrating the absence of tolerance against these peptides.
When tumors were eradicated, generated memory T-cell responses protected against re-challenge, allowing long-term protection against relapses [ ]. These authors highlighted that this survivin long peptide cocktail-based survivin vaccine appears to be a promising cancer vaccine strategy and warrants further clinical development [ ]. The expression pattern and the multiple important functions of survivin through diverse mechanisms of action [ 1 ] Tables 1 and 2 supports the targeting of survivin for cancer therapy.
As reviewed above, we may find that each of the five survivin-therapeutic strategies has its advantages and disadvantages. We would like to discuss the 5 strategies below. In order to discover survivin-partner protein interaction-disruptive inhibitors and survivin homodimerization-disruptive inhibitors, we have many modern technologies to create computational docking models for in silico selection of such inhibitors. This would allow us to find good drugs economically.
The inhibitors discovered in this way could be highly specific with few off-target effects. Such inhibitors have a better possibility of becoming useful research tools that can be used to enrich our knowledge of survivin biology, even if we eventually discover that the inhibitors do not possess sufficient antitumor efficacy for cancer mono-therapy. Nevertheless, the potential low toxicity features of such survivin inhibitors have a great potential for combination treatment with other therapeutic drugs that have distinct or overlapped mechanisms of action.
An important question that we asked ourselves is whether we would be able to find small molecules that have both high antitumor efficacy and high specificity to disrupt survivin homodimerization or interactions with other partner proteins. It remains to be seen whether this can be achieved. We acknowledge that some degree of luck always plays a role in achieving such success. However, the success of past efforts on Bcl-2 inhibitors encourages further studies. Importantly, such drugs can be moved relatively quickly into the clinic, once discovered.
When it comes to the task of finding survivin gene transcription inhibitors, it is our view that it would be nearly impossible to find a small molecule that exclusively inhibits survivin transcription, although we do know now that selectively inhibiting survivin is possible. In this regard, YM and FL are the typical examples; both of them inhibit survivin as well as other oncogenic proteins. Of course, whether a promising candidate can successfully become a drug for cancer treatment would depend on many factors. This includes, but is not limited to, drug stability, PK profiles, in vivo availability, toxicity profiles and so on.
It is our view that two important factors would affect the success of finding high efficacy inhibitors through this approach. The other factor would be the use of the right compound libraries, which have the right structural diversity and a sufficient number of compounds for HTS. If these factors are present, then the chance of finding good hits will significantly increase.
Of course, the type of reporter used would be another factor; both luciferase reporter and EGFP reporters were used. While EGFP could provide a convenient method for detection, luciferase could provide much more sensitivity and a wider dynamic range for compound identification. Again, luck always plays some role in drug discovery and development.
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These disappointing results may be due to many different factors. As discussed earlier, one possibility may arise from the special modification of the oligonucleotides, which causes a decrease in efficacy and increase in toxicity in clinical trials due to its difficulty to be cleared from the body, for example.
The failure may also be resulted in part from the only partial inhibition of survivin mRNA by survivin antisense oligonucleotide, which may exhibit insufficient efficacy. Nevertheless, based on the siRNA reviewed earlier and the study status of miRNA presented in Table 1 , we believe that nanotechnology delivery-mediated siRNA therapeutics may give us hope for this type of survivin inhibitory drugs to be developed in the coming decade. We reviewed the major findings of survivin immunotherapy in detail by focusing on those that have been moved into clinical trials. Survivin immunotherapy will continue to be a busy area of research in the coming years.
This is mainly due to its potential nontoxic nature, as well as its unique cancer treatment approach of stimulating the immune system and inducing CTL production to kill cancer cells. Based on the current outcome, while survivin immunotherapy alone may not be sufficient to effectively manage cancer, this approach provides a great opportunity for combination treatment not only with standard therapies, but also potentially with targeted precision medicine as well. Survivin remains a promising target and biomarker for drug discovery and cancer therapeutics.
Such survivin-specific inhibitors are expected to have low toxicity in vivo models and in human. Nevertheless, while it remains to be seen whether the inhibitors that specifically disrupt survivin protein-protein interactions could exhibit sufficient antitumor efficacy when used alone, the success of the Bcl-2 inhibitor [ ] and siRNA [ ] drugs for human disease treatment gives us encouragement, despite the fact that clinical trials of survivin antisense oligonucleotides obtained disappointing results, which may stem from irrelevant reason s as discussed early.
In the case of survivin immunotherapy, it has been demonstrated that survivin peptide-mediated immunotherapy exhibited low toxicity in clinical trials and can increase survivin peptide-specific CTLs for patients to kill cancer cells. Based on the outcomes from the updated studies, it appears that survivin immunotherapy alone might be insufficient for effective cancer management.
However, there is a great potential for survivin immunotherapy in combination either with standard therapy or possibly with targeted precision medicine. Survivin at a glance.
Recent Advances and Challenges in microRNABased Cancer Therapeutics | Bentham Science
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