Targeting mRNA-coding genes in prostate cancer using CRISPR/Cas9 technology with a special focus on androgen receptor signaling

[petercraig2]

Incredible and exciting updates on use of CRSPR/Cas9 technology to fight multiple aspects of Prostate Cancer and metastasis.

biosignaling.biomedcentral....

[petercraig2]

CRISPR/Cas9 summary of clinical research

Abstract

Background

Prostate cancer is among prevalent cancers in men. Numerous strategies have been proposed to intervene with the important prostate cancer-related signaling pathways. Among the most promising strategies is CRISPR/Cas9 strategy. This strategy has been used to modify expression of a number of genes in prostate cancer cells.

Aims

This review summarizes the most recent progresses in the application of CRISPR/Cas9 strategy in modification of prostate cancer-related phenotypes with an especial focus on pathways related to androgen receptor signaling.

Conclusion

CRISPR/Cas9 technology has successfully targeted several genes in the prostate cancer cells. Moreover, the efficiency of this technique in reducing tumor burden has been tested in animal models of prostate cancer. Most of targeted genes have been related with the androgen receptor signaling. Targeted modulation of these genes have affected growth of castration-resistant prostate cancer. PI3K/AKT/mTOR signaling and immune response-related genes have been other targets that have been successfully modulated by CRISPR/Cas9 technology in prostate cancer. Based on the rapid translation of this technology into the clinical application, it is anticipated that novel treatments based on this technique change the outcome of this malignancy in future.

Discussion

Prostate cancer, a prevalent and deadly disease with limited treatment options, requires innovative approaches to address its progression and overcome therapy resistance. Recent advancements in CRISPR technology have revolutionized research in this field, resulting in a significant progress in the detection and treatment of prostate cancer. Moreover, application of CRISPR-based techniques for gene regulation has offered opportunities to investigate gene function in cancer cells. In fact, it has demonstrated the role of interaction between classical tumor suppressors and epigenetic factors in the pathogenesis of this type of cancer [80].

The recent projects utilizing CRISPR technology in prostate cancer research have also provided new perceptions about the diagnostic and therapeutic strategies for this disease. Actually, the capacity of CRISPR/Cas system to target RNA has provided novel approaches to tumor diagnostics. However, most of applied research in this field has used mice models of cancer, thus making translation of the obtained data to clinical application challenging.

Most notably, mentioned experiments have shown that CRISPR/Cas9-mediated suppression of a number of genes can enhance therapeutic effects of conventional chemotherapeutic agents, suggesting novel combinatory regimens for treatment of prostate cancer. This technique has also facilitated identification of molecular events that contribute to each phase of prostate cancer development and progression. In fact, genome-wide CRISPR activation and inhibition screening has shown several drivers and inhibitors of metastasis cascades in prostate cancer [81]. Thus, several potential molecular targets for combating diverse aspects of carcinogenesis have been uncovered using this technique. In vivo application of CRISPR technology has unveiled the function of several commonly mutated genes in prostate cancer and their differential effects in the promotion of tumor growth and regulation of cell fate and dissemination.

As a novel therapeutic option, chimeric antigen receptor (CAR) T cell therapies were found to be safely tolerated in patients with prostate cancer. Moreover, this treatment led to TCR repertoire diversity and modulation of the tumor immune niche in a group of patients [82]. Meanwhile, CRISPR/Cas9 technique offered an effective way for enhancement of the proliferation ability and perseverance of CAR-T cells in the body. This tool was used in CAR-T cells to produce a memory phenotype, decrease exhaustion, and find novel targets to enhance the anti-tumor ability [83].

The main obstacle to bringing CRISPR technology into the clinic is the delivery of CRISPR/Cas to prostate tumors. An optimal targeted delivery system should have a safe vehicle protecting RNA from nuclease degradation in the circulation; and a targeting moiety/ligand that specifically recognizes the receptor and efficiently direct cargo into a specific tissue or cell [70]. In fact, this strategy requires a highly specific targeting ligand that has high affinity to a cellular receptor [84]. Thus, recognition of specific receptors on prostate cancer cells which are not expressed on normal cells can enhance the efficiency of this system. Among different delivery systems, the aptamer-liposome-CRISPR/Cas9 chimera has been proved to have a significant cell-type binding specificity, an extraordinary gene silencing impact in vitro, and a noticeable effect on in vivo regression of prostate tumors [70].

CRISPR therapy has experienced a truly extraordinary achievement, since it has been translated into the clinical application in just 11 years [85]. A number of clinical trials of CRISPR therapy are currently recruiting patients with hematological malignancies (NCT05885464) or solid tumors (NCT05795595). Thus, it is expected that this technology revolutionizes current therapy of cancer in near future. At this time, identification of appropriate targets for this system is a priority. In the context of prostate cancer research and therapy, this target should have an indispensable role in the carcinogenesis being dysregulated in a wide array of patients with different pathological features.

[MelodyCat in reply to petercraig2]

Thanks for the post. This is indeed interesting. I hope it extends past AR signaling since the worst forms are less sensitive to androgens and some not at all. We need to extend our thinking past just androgen blocking since one theory believes we start with some AR- populations. mRNA strategies are also interesting but, as many know, prostate cancer is a cold tumor so it will only be really effective if you block its defenses. Personally, I have high hopes for cell penetrating peptide therapies since they are highly selective to cancer cells due to polarity and are genetically indifferent (cancer is very heterogeneous.)

[TJGuy in reply to MelodyCat]

Don't forget cancer cells have a different PH level surrounding them, solutions that require two conditions PH level and PSMA or other be true to active the therapy can make it more specific. Cas 9 was an early discovery as to how to perform CRISPR , while work continues to improve this, other more accurate CRISPR technology has surpassed it and is being discovered daily. Truly a gold rush going on in this work.

[MelodyCat in reply to TJGuy]

Have you found anything with therapeutic value targeting pH levels since that is a byproduct of lactate metabolism rather than a regulator? I am also concerned with therapies that rely on PSMA since I believe neuroendocrine varieties don’t express it. I should have included CRISPR and even AI as hopeful developments in the field. I am sure I speak for all when saying we will accept robust therapies no matter where they come from.

[petercraig2]

Seems to have truly remarkable possibilities. I'd like to see out Cancer Research Centers get behind CRISPR in a big way.

I just read that in UK there is now an approved CRISPR therapeutic for Cycle Cell Anemia

[TJGuy in reply to petercraig2]

Yes just approved in UK. But FDA approved it in the US getting close to a year ago. CRISPR Therapeutics developed it along with a partnership with another larger drug company. The roll out has been slow in setting up treatment centers around the world and the treatment expense is around $2 million for each individual so there has been limited sales. Insurance companies have to approve payment coverage before this treatment can be more widespread.The stock of the company has lost probably 60% of it value since FDA approval and is considered a takeover candidate.