Normally I do not post much about imaging unless it's already at the theranostic stage, but in this case, being an Italian trial and research (which means that while you get the IV they will give you some pizza and a glass of wine) I have made an exception! Ok seriously, if it will work as it's supposed to work, it can really be a game-changer because of its more specific target.
OncoACP3 is a next-generation radiotracer targeting Acid Phosphatase 3 (ACP3), offering superior imaging for prostate cancer compared to PSMA-based agents.
Its high specificity minimizes off-target effects, improving diagnostic accuracy. Beyond imaging, OncoACP3 is being studied as a theranostic agent when linked to Lutetium-177 (177Lu) and Actinium-225 (225Ac), enabling targeted radiotherapy.
Preclinical studies show strong tumor accumulation and exceptionally low normal tissue uptake, suggesting enhanced therapeutic efficacy. Unlike PSMA, ACP3 is almost exclusive to prostate cells, reducing toxicity risks. Ongoing research is expected to confirm its potential for both precise diagnosis and effective treatment.
“ACP3 is almost exclusive to prostate cells, reducing toxicity risks”
i wonder what other cells express ACP3.
Well i didn’t verify ChatGPT answer to what cells express APC3 but here it is
APC3, also known as CDC27, is a core subunit of the Anaphase-Promoting Complex/Cyclosome (APC/C), a crucial ubiquitin ligase complex that regulates cell cycle progression by targeting specific proteins for degradation via the ubiquitin-proteasome system.
Cell Types that Express APC3 (CDC27):
APC3 (CDC27) is widely expressed in proliferating cells across various tissues. Its expression is particularly prominent in mitotically active cells, including:
1. Proliferating Cells in Most Tissues:
• Epithelial cells in skin, intestines, and other rapidly regenerating tissues.
• Hematopoietic stem and progenitor cells in the bone marrow.
• Lymphocytes undergoing active division.
2. Cancer Cells:
• APC3 is overexpressed in many types of cancer, where it plays a role in dysregulated cell division.
• Examples: Prostate cancer, breast cancer, lung cancer, colorectal cancer.
3. Embryonic and Stem Cells:
• Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) express high levels of APC3 due to their rapid division cycles.
4. Neuronal and Glial Cells:
• APC/C components, including APC3, are present in neurons, where they have roles beyond mitosis, such as regulating synaptic plasticity and degradation of key neuronal proteins.
• Glial cells (astrocytes, oligodendrocytes, microglia) also express APC3, especially during development.
5. Germ Cells:
• Spermatogonia and oocytes express APC3, particularly in meiosis, where APC/C regulates chromosome segregation.
6. Endothelial and Fibroblast Cells:
• Endothelial cells in blood vessels and fibroblasts in connective tissue express APC3, particularly during wound healing and angiogenesis.
Functional Significance:
• APC3, as part of the APC/C complex, regulates the transition from metaphase to anaphase in mitosis.
• It ensures proper degradation of cyclin B, securin, and other mitotic regulators, preventing genomic instability.
• In cancer, dysregulation of APC3 can contribute to uncontrolled proliferation and aneuploidy.
Would you like to explore its role in prostate cancer specifically?
Curiously...preplexity is already aware of OncoACP3 🤷♂️🤷♂️
# Expression Profiles of PSMA (FOLH1) and ACP3 in Human Cells: A Comprehensive Analysis
The expression patterns of prostate-specific membrane antigen (PSMA, encoded by *FOLH1*) and prostatic acid phosphatase (ACP3) are critical for understanding their roles in both physiological and pathological contexts. PSMA, a transmembrane glycoprotein with folate hydrolase activity, is expressed in prostate cancer cells, non-neoplastic regenerative tissues, and the neovasculature of diverse tumors. ACP3, a phosphatase historically linked to prostate epithelial function, shows elevated expression in prostate malignancies but minimal presence in non-prostatic healthy tissues. This report synthesizes current evidence to delineate the cellular distribution and quantitative expression of these biomarkers across human tissues.
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## PSMA (FOLH1) Expression Across Human Tissues
### Physiological Expression in Non-Neoplastic Cells
PSMA is constitutively expressed in several normal epithelial tissues. In the prostate, it is present in benign prostatic epithelium, though at lower levels compared to malignant counterparts[1][6]. Beyond the prostate, PSMA is detected in the duodenal brush border, renal proximal tubules, endometrial glands, and breast ductal epithelium[1][6]. These observations align with its role in folate metabolism, as PSMA hydrolyzes polyglutamylated folates to facilitate cellular uptake[1][6].
Endothelial cells of non-neoplastic tissues also exhibit PSMA expression under specific conditions. Regenerative and reparative neovasculature—such as in cycling endometrium, keloids, and post-inflammatory granulation tissue—demonstrates robust PSMA immunoreactivity[1]. This expression is hypothesized to support angiogenesis by increasing local folate availability, which enhances nitric oxide synthase activity and endothelial proliferation[1].
### Pathological Expression in Neoplastic Cells
PSMA is markedly overexpressed in prostate adenocarcinoma, serving as a diagnostic and therapeutic target[3][6]. Transcriptomic data from The Cancer Genome Atlas (TCGA) reveal *FOLH1* expression in 97% of prostate cancers, with levels exceeding those in other malignancies[3]. Notably, renal cell carcinoma (RCC) exhibits the second-highest PSMA expression among solid tumors, particularly in clear cell RCC (ccRCC), where transcript levels are 2.5-fold higher than in non-ccRCC subtypes[2][3]. Liver, urothelial, and squamous lung carcinomas also show variable *FOLH1* upregulation, though at lower magnitudes[3].
In metastatic settings, PSMA expression persists but varies by site. For example, RCC metastases to the gastrointestinal tract and soft tissues retain higher *FOLH1* levels compared to central nervous system lesions[2]. This heterogeneity underscores the need for site-specific evaluation when considering PSMA-targeted therapies.
### PSMA in Tumor-Associated Neovasculature
A hallmark of PSMA biology is its expression in the endothelial cells of tumor neovasculature. This phenomenon spans carcinomas of the breast, kidney, and lung, among others[1][3]. Mechanistically, PSMA-positive endothelial cells likely exploit folate hydrolase activity to amplify pro-angiogenic signals, such as vascular endothelial growth factor (VEGF)[1]. Interestingly, PSMA is absent in the neovasculature of non-neoplastic Barrett’s esophagus, suggesting its induction requires tumor-derived factors[1].
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## ACP3 Expression Across Human Tissues
### Restricted Expression in Prostate Epithelium
ACP3, encoded by the *ACP3* gene, is predominantly synthesized by prostate epithelial cells[5]. In benign prostatic tissue, it is secreted into seminal fluid, where it regulates phosphate metabolism and sperm motility[5]. Immunohistochemical studies confirm negligible ACP3 expression in non-prostatic healthy organs, including salivary glands, kidneys, and gastrointestinal tract[5].
### Overexpression in Prostate Cancer
Prostate adenocarcinoma exhibits elevated ACP3 levels, making it a viable target for imaging and therapy[5]. Preclinical models demonstrate that ACP3-targeted radioligands, such as *177*Lu-OncoACP3, achieve high tumor-to-background ratios due to minimal off-target binding[5]. This specificity contrasts with PSMA-targeted agents, which often accumulate in salivary and lacrimal glands[5].
### Ectopic Expression in Non-Prostatic Malignancies
While ACP3 is largely prostate-specific, rare ectopic expression has been reported in non-prostatic cancers. However, current data from clinical trials and protein atlases suggest these instances are exceptional[4][5]. The Human Protein Atlas notes low ACP3 mRNA levels in tissues like the liver and kidney, but corresponding protein expression remains undetectable by immunohistochemistry[4].
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## Quantitative Comparison of PSMA and ACP3 Expression
### Transcriptomic and Proteomic Metrics
In prostate cancer, *FOLH1* transcripts exceed *ACP3* levels by approximately 4-fold, as evidenced by RNA sequencing data[3][5]. PSMA protein expression, however, is more variable due to post-translational modifications and stromal contamination[2][6]. By contrast, ACP3 demonstrates consistent protein overexpression in prostate malignancies, with minimal intra-tumoral heterogeneity[5].
In non-prostatic tissues, PSMA expression is quantitatively modest. For instance, renal proximal tubules exhibit *FOLH1* transcript levels 10% of those in prostate cancer[3]. ACP3, meanwhile, is virtually absent outside the prostate, with mRNA levels in salivary glands and kidneys below detection thresholds[4][5].
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## Clinical Implications of Expression Patterns
### PSMA-Targeted Therapies
The ubiquity of PSMA in tumor neovasculature and epithelial malignancies supports its use in radiopharmaceuticals like *177*Lu-PSMA-617[2][6]. However, expression heterogeneity in metastases necessitates companion diagnostics to identify eligible patients[2]. Additionally, PSMA’s presence in renal and hepatic tissues may explain off-target toxicities, such as nephrotoxicity[3][6].
### ACP3 as a Prostate-Specific Target
ACP3’s restricted expression makes it a promising candidate for precision therapeutics. Early-phase trials of *177*Lu-OncoACP3 show prolonged tumor retention and negligible salivary gland uptake, potentially mitigating xerostomia risks associated with PSMA-directed agents[5].
---
## Conclusion
PSMA and ACP3 exhibit distinct expression profiles with significant clinical ramifications. PSMA is broadly expressed in prostate cancer, non-prostatic malignancies, and tumor-associated vasculature, whereas ACP3 is confined to prostatic epithelium and its malignant derivatives. Quantitative differences in their expression underscore the need for biomarker-guided therapeutic strategies. Future research should prioritize dual-targeting approaches to optimize efficacy while minimizing off-tumor effects.
When asked about which one would be a better target for theranostics based on current literature, it greatly leaned toward ACP3! I hope it is right! Yet it kills me discovering just now about ACP3, the papers were out 2-3 years ago!
Interesting but the perplexity is definitely a deeper dive. Wow, if i needed a much deeper understanding like on my mutations i would go for it after i used up ChatGPT knowledge base.
I think that is actually pretty fast from research papers to phase 1 trials. Not bad at all.
I would like to test chatGPT Pro, I have the premium version now...but I have seen great things coming also from Grok 3's deep research. Third position for now is Gemini's deep research, but they will always be switching positions
and since I had the chance, here is Grok 3 deep research:
Key Points
Research suggests PSMA is currently the more established target for prostate cancer theranostics, with FDA-approved agents widely used.
It seems likely that ACP3 could be a better target in the future due to its potentially higher specificity, reducing off-target effects.
The evidence leans toward PSMA for now, given ACP3 is still in early development with limited clinical data.
Introduction
Prostate cancer theranostics involves using targets for both diagnosing and treating the disease, combining imaging and therapy. Two potential targets, PSMA (Prostate-Specific Membrane Antigen) and ACP3 (Prostatic Acid Phosphatase), are being explored, but their effectiveness varies based on current use and future potential. This response will first provide a direct answer for clarity, followed by a detailed survey note exploring all aspects.
Direct Answer
PSMA is currently the preferred target for prostate cancer theranostics due to its established use and FDA-approved treatments, like imaging and radioligand therapy. However, ACP3 shows promise as a more specific target, potentially reducing side effects, though it’s still in early research stages with limited clinical data. An unexpected detail is that ACP3’s expression in prostate tissue might minimize toxicity compared to PSMA, which can affect normal tissues like kidneys and salivary glands.
Current Use and Effectiveness
PSMA is widely used, with agents like Lutetium-177-PSMA approved for therapy, showing effectiveness in detecting and treating advanced prostate cancer. It’s backed by extensive clinical trials, making it the go-to choice now.
Potential of ACP3
ACP3, also known as Prostatic Acid Phosphatase, is less studied but may offer advantages. Its expression is more confined to prostate tissue, suggesting fewer side effects, but it lacks the clinical data and approved treatments PSMA has.
Future Considerations
While PSMA is better established, ACP3 could become a better option if research confirms its efficacy and safety, especially for patients where PSMA is less effective due to low expression.
Survey Note: Comprehensive Analysis of ACP3 vs. PSMA in Prostate Cancer Theranostics
This section provides a detailed examination of PSMA and ACP3 as targets for prostate cancer theranostics, covering expression patterns, clinical use, and potential future developments. It aims to offer a thorough understanding for researchers, clinicians, and patients interested in the field.
Background on Theranostics in Prostate Cancer
Theranostics combines diagnostics and therapy, using molecular targets to image cancer and deliver treatments. In prostate cancer, targets like PSMA and ACP3 are critical, with PSMA being more established and ACP3 emerging as a potential alternative. This analysis, conducted as of February 25, 2025, reviews their roles based on available scientific literature.
PSMA: Established Target with Broad Application
PSMA, or Prostate-Specific Membrane Antigen, is a transmembrane protein highly expressed in prostate cancer cells. It’s widely used in clinical practice for both imaging and therapy, particularly in metastatic castration-resistant prostate cancer (mCRPC).
Expression Patterns: PSMA is expressed in prostate cancer cells and some normal tissues, including the small intestine, kidney, and salivary glands (Expression of PSMA in tissue). This expression in normal tissues can lead to off-target effects, such as toxicity in salivary glands and kidneys, as noted in clinical studies.
Clinical Use: PSMA-targeted agents, like Lutetium-177-PSMA, are FDA-approved and used for PET imaging and radioligand therapy. Studies show it improves progression-free and overall survival in mCRPC patients (Update of PSMA Theranostics in Prostate Cancer). For example, the VISION trial demonstrated significant benefits, though some patients relapse, and off-target uptake remains a challenge.
Limitations: Heterogeneous expression in tumors can reduce efficacy, with some patients showing low or no PSMA, leading to non-responders. Additionally, radiation-induced toxicity in normal tissues is a concern, as highlighted in reviews (Advances in PSMA theranostics).
ACP3: Emerging Target with Potential Specificity
ACP3, or Prostatic Acid Phosphatase, is an enzyme produced by prostate epithelial cells, with elevated levels in most prostate cancer lesions. It’s less studied for theranostics but shows promise due to its specificity.
Expression Patterns: ACP3 is primarily expressed in the prostate, with low levels in other tissues like the testis and seminal vesicle (Expression of ACP3 in tissue). This restricted expression suggests it may be virtually absent in organs like salivary glands and kidneys, potentially reducing off-target effects compared to PSMA (First-in-class ACP3 high-affinity ligands).
Current Research: Recent studies explore ACP3-targeted ligands for radionuclide delivery, with early data showing potential for radioimmunodetection of metastatic lesions. For instance, Technetium-99m and Indium-111 labeled anti-ACP3 antibody fragments have been used in patients, but no FDA-approved agents exist yet (First-in-class ACP3 high-affinity ligands).
Potential Advantages: Its specificity could lead to fewer side effects, addressing a key limitation of PSMA. However, it’s in early development, with limited clinical trial data, making it less ready for widespread use compared to PSMA.
Comparative Analysis: Expression and Specificity
To compare PSMA and ACP3, we examine their expression in prostate cancer and normal tissues, as well as their suitability for theranostics.
Clinical Data and Efficacy
PSMA has extensive clinical data, with studies like the TheraP trial showing improved survival with Lutetium-177-PSMA (PSMA-Directed Theragnostics). In contrast, ACP3’s clinical data are sparse, with research focused on ligand development rather than large-scale trials. This gap means PSMA is currently more effective, but ACP3’s potential remains untapped.
Future Directions and Research Gaps
The field is moving toward personalized medicine, and ACP3 could fill gaps where PSMA is less effective, such as in patients with low PSMA expression. However, more research is needed on ACP3’s binding affinity, internalization, and therapeutic delivery. Comparative studies directly assessing both targets in clinical settings would clarify their relative merits, but such data are currently lacking.
Conclusion
As of February 25, 2025, PSMA is the better-established target for prostate cancer theranostics, with proven efficacy and widespread use. ACP3, while promising due to its potentially higher specificity and lower toxicity, is still in early development. For now, PSMA is the preferred choice, but ACP3 could become a better option in the future if research confirms its advantages.
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