The ghost of William B. Coley and his "toxins" live on in new research just funded by DOD. Another one to keep on your radar for future deveopments.
From the GEN artcle:
The U.S. Department of Defense has awarded a grant of over $1.7 million to Charles Spruck, PhD, and his team at Sanford Burnham Prebys to advance a novel therapeutic approach for metastatic prostate cancer. Known as viral mimicry, the technique causes the body to think that it has a viral infection, stimulating an immune response that can help the body fight cancer.
“In viral mimicry, the body thinks there’s an infection, which kicks the immune system into high gear,” said Spruck. “With the immune system activated, cancer cells are more responsive to treatment, and tumor growth slows. All of this can happen without triggering treatment resistance, which could be a huge benefit for treating prostate cancer.”
Second most diagnosed cancer in men
Prostate cancer is the second most diagnosed cancer in men worldwide and the fifth leading cause of cancer death among men. According to the World Health Organization, there were an estimated 1.4 million new cases of prostate cancer and more than 375,000 deaths from the disease in 2020 alone.
“Many cases of prostate cancer are treatable, so people don’t think of it as a major public health issue,” said Spruck. “But when prostate cancer becomes metastatic or resistant to therapy—such as hormone therapy—it can ultimately become a fatal disease. One of the benefits of this approach is that it works in a completely different way, so it’s not as susceptible to resistance.”
The new technique takes advantage of an evolutionary feature of our genomes called endogenous retroviruses (ERVs). These are small sequences in our genomes, left behind by viruses that infected our ancient ancestors. ERVs have been found in the genomes of early humans such as Neanderthals, but are thought to have first emerged in animals hundreds of millions of years ago. Unlike regular viruses, ERVs do not make anyone sick but remain in our genomes and help control gene expression.
“ERVs are inactive, so they don’t produce proteins the way regular genes do,” continued Spruck. “In this study, we discovered that we can reactivate these viruses selectively in cancer cells and essentially fool the body into thinking it needs to trigger an immune response against the tumor.”
Spruck’s team has already discovered a potential drug that can induce viral mimicry in prostate cancer cells. However, the drug is not potent or selective enough to enter the clinic. One of the goals of their project is to develop more potent compounds that can induce viral mimicry, which could lay the foundation for tomorrow’s prostate cancer treatments.
“Something exciting about this work is that it has the potential to move to the clinic extremely quickly,” points out Spruck. “We hope to have a drug ready for the clinic within three years.”
In addition to prostate cancer, the viral mimicry approach could be effective across a range of treatment-resistant cancers. The researchers are already exploring the approach in ER+ breast cancer in which up to 50% of patients experience a relapse due to treatment resistance.
“We initially discovered viral mimicry in breast cancer, and we suspected it could work in other cancers,” notes Spruck. “This project is helping us see how far we can take this unique approach, and I’m confident we’ll be able to apply it more broadly in the future as we continue to learn more about how it works.”
Link to the article is here:
“Ancient Virus” Therapy for Prostate Cancer Receives Department of Defense Grant, Genetic Engineering & Biotechnology News (GEN), April 27, 2023
Great find... The problem with the abscopal effect from SBRT is that it lasts about 90 days or so. Turned off by T cell exhaustion and Tregs... What is needed is a way to keep the immune system turned on to the cancer to eliminate it.
Is this part of the answer for a cure in oligometastatic prostate cancer - giving SBRT with IADT plus viral mimicry??
Time will give us our answer... but I think the Science is on track. They are looking for ways to turn off or decrease regulatory T cells...
Immune activation... decreasing T cell regulation... The immune system is the key to finishing off PCa in my opinion...
Potent Stimulation of the Androgen Receptor Instigates a Viral Mimicry Response in Prostate Cancer
Inhibiting the androgen receptor (AR), a ligand-activated transcription factor, with androgen deprivation therapy is a standard-of-care treatment for metastatic prostate cancer. Paradoxically, activation of AR can also inhibit the growth of prostate cancer in some patients and experimental systems, but the mechanisms underlying this phenomenon are poorly understood. This study exploited a potent synthetic androgen, methyltestosterone (MeT), to investigate AR agonist-induced growth inhibition. MeT strongly inhibited growth of prostate cancer cells expressing AR, but not AR-negative models. Genes and pathways regulated by MeT were highly analogous to those regulated by DHT, although MeT induced a quantitatively greater androgenic response in prostate cancer cells. MeT potently downregulated DNA methyltransferases, leading to global DNA hypomethylation. These epigenomic changes were associated with dysregulation of transposable element expression, including upregulation of endogenous retrovirus (ERV) transcripts after sustained MeT treatment. Increased ERV expression led to accumulation of double-stranded RNA and a “viral mimicry” response characterized by activation of IFN signaling, upregulation of MHC class I molecules, and enhanced recognition of murine prostate cancer cells by CD8+ T cells. Positive associations between AR activity and ERVs/antiviral pathways were evident in patient transcriptomic data, supporting the clinical relevance of our findings. Collectively, our study reveals that the potent androgen MeT can increase the immunogenicity of prostate cancer cells via a viral mimicry response, a finding that has potential implications for the development of strategies to sensitize this cancer type to immunotherapies.
Medline - Thanks for the reply. There has been a lot of basic research on endogenous retroviruses over the years, but most of it has been related to AIDS. Here is one specific to PCa that is now 13 years old. Thier concluding suggestion for additional research using the drug being researched, Abacavir, in combo with docetaxel was apparently never done. (That might have been the result of some toxic reaction to similar drug combinations in AIDS patients?) In the case of PCa, it is just another in-vitro study that never got advanced to CT. Maybe with the DOD behind the current one, the outcome will be more positive for us.
The Reverse Transcription Inhibitor Abacavir Shows Anticancer Activity in Prostate Cancer Cell Lines, PLoS One. 2010; 5(12): e14221. Published online 2010 Dec 3
Transposable Elements (TEs) comprise nearly 45% of the entire genome and are part of sophisticated regulatory network systems that control developmental processes in normal and pathological conditions. The retroviral/retrotransposon gene machinery consists mainly of Long Interspersed Nuclear Elements (LINEs-1) and Human Endogenous Retroviruses (HERVs) that code for their own endogenous reverse transcriptase (RT). Interestingly, RT is typically expressed at high levels in cancer cells. Recent studies report that RT inhibition by non-nucleoside reverse transcriptase inhibitors (NNRTIs) induces growth arrest and cell differentiation in vitro and antagonizes growth of human tumors in animal model. In the present study we analyze the anticancer activity of Abacavir (ABC), a nucleoside reverse transcription inhibitor (NRTI), on PC3 and LNCaP prostate cancer cell lines.
Principal Findings
ABC significantly reduces cell growth, migration and invasion processes, considerably slows S phase progression, induces senescence and cell death in prostate cancer cells. Consistent with these observations, microarray analysis on PC3 cells shows that ABC induces specific and dose-dependent changes in gene expression, involving multiple cellular pathways. Notably, by quantitative Real-Time PCR we found that LINE-1 ORF1 and ORF2 mRNA levels were significantly up-regulated by ABC treatment.
Conclusions
Our results demonstrate the potential of ABC as anticancer agent able to induce antiproliferative activity and trigger senescence in prostate cancer cells. Noteworthy, we show that ABC elicits up-regulation of LINE-1 expression, suggesting the involvement of these elements in the observed cellular modifications.
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A search of Clinical Trails indicates Abacavir has beeen tested alomost exclusively in AIDS - while the following conculsion passage in the full report linked above suggested it should be tested for PCa efficacy in combo with docetaxel. That has apparently never taken place.
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In conclusion, we propose ABC as an anticancer agent able to selectively affect multiple cellular functions and trigger senescence in PC3 and LNCaP cells. We also suggest that ABC-induced senescence may be related to the up-regulation of LINE-1 transcripts in prostate cancer cells. Our findings strongly support the emerging concept of endogenous RT as an attractive target in cancer therapy, providing an innovative strategy to circumvent the difficulties related to the genetic heterogeneity of cancer phenotypes. It would be interesting to evaluate in preclinical studies the efficacy of ABC in combination with docetaxel, a chemotherapeutic agent used in hormone-refractory metastatic prostate cancer. Since Abacavir is clinically approved for human use in AIDS therapy, drug repositioning in prostate and, possibly, in other cancer forms resistant to current therapies, could accelerate the traditional drug development. (emphasis added)
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After surveying basic research for multiple cancers over the last 16 years, I have seen hundreds of such promising research findings that were never acted on. In many cases they involved plant compounds or off-patent repurposed agents that had no profit potential for taking on the expenses of further trials. In other cases, one just suspects the researchers moved on to more fertile (i.e., profitable) areas. It used to be rather frustrating to me as a patient and advocate for others, but now I see it as just the way our capitalists system works within the regulatory confines that are there to supposedly protect us from harmful drugs and treatments. (I'll reserve comment on how well I think that is working.)
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Androgen Receptor Activity (ARA) for BAT
ADT vacation versus Continuous
Dose titration for CRPC 
