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Therapeutic options for managing Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of aggressive malignancies, are limited and disappointing. Therefore, despite suboptimal clinical effects, gemcitabine (GEM) remains the first-line chemotherapeutic drug in the clinic for PDAC treatment. The therapeutic limitations of GEM are primarily due to poor bioavailability and the development of chemoresistance resulting from the addiction of mutant-K-RAS/AKT/ERK signaling-mediated desmoplastic barriers with a hypoxic microenvironment. Several new therapeutic approaches, including nanoparticle-assisted drug delivery, are being investigated by us and others. This study used pH-responsive nanoparticles encapsulated ERK inhibitor (SCH772984) and surface functionalized with tumor-penetrating peptide, iRGD, to target PDAC tumors. We used a small molecule, SCH772984, to target ERK1 and ERK2 in PDAC and other cancer cells. This nanocarrier efficiently released ERKi in hypoxic and low-pH environments. We also found that the free-GEM, which is functionally weak when combined with nanoencapsulated ERKi, led to significant synergistic treatment outcomes in vitro and in vivo. In particular, the combination approaches significantly enhanced the GEM effect in PDAC growth inhibition and prolonged survival of the animals in a genetically engineered KPC (LSL-KrasG12D/+/LSL-Trp53R172H/+/Pdx-1-Cre) pancreatic cancer mouse model, which is not observed in a single therapy. Mechanistically, we anticipate that the GEM efficacy was increased as ERKi blocks desmoplasia by impairing the production of desmoplastic regulatory factors in PDAC cells and KPC mouse tumors. Therefore, 2nd generation ERKi (SCH 772984)-iRGD-pHNPs are vital for the cellular response to GEM and denote a promising therapeutic target in PDAC with mutant K-RAS. [ABSTRACT FROM AUTHOR]

The article explores the potential benefits and challenges of using a glycosylation inhibitor called Tunicamycin (TM) in cancer therapy. TM has been shown to inhibit abnormal carbohydrate attachment to proteins in cancer cells, leading to the inhibition of tumor growth and promotion of cell death. However, TM lacks specificity in targeting cancer cells, which can limit its effectiveness and cause toxicity in normal tissues. The article also discusses the use of nano-based drug delivery systems to enhance the targeted therapy of TM and reduce its toxicity. The potential benefits of TM therapy are discussed in the context of breast, colon, and pancreatic cancers. Additionally, the article highlights the potential use of TM in targeted and immunotherapy for advanced colon cancer, lung cancer, and pancreatic ductal adenocarcinoma (PDAC). TM has shown promise in inhibiting cell growth, enhancing apoptosis, sensitizing cells to chemotherapy, and targeting specific proteins involved in cancer progression. However, further research is needed to fully understand the mechanisms and effectiveness of TM in these cancers. The article also addresses the challenges associated with the toxicity of TM and explores the use of nanoparticles for drug delivery to reduce toxicity and improve efficacy. More research and clinical trials are necessary to determine the safety and effectiveness of TM in targeted therapy. [Extracted from the article]

BACKGROUND. A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3[beta]-hydroxysteroid dehydrogenase 1 (3[beta]HSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3[beta]HSD1 to multiple steroidal metabolites, including 3-keto-5[alpha]- abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5[alpha]-abiraterone synthesis in patients. METHODS. First, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5[alpha]-abiraterone levels and HSD3B1 genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics. RESULTS. Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto- 5[alpha]-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002). CONCLUSION. Increased generation of 3-keto-5[alpha]-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition. FUNDING. Prostate Cancer Foundation Challenge Award, National Cancer Institute., Introduction Prostate cancer progression is highly dependent on androgen receptor (AR) stimulation by testosterone and its more potent 5[alpha]-reduced metabolite, 5[alpha]-dihydrotestosterone (DHT) (1, 2). The long-standing standard-of-care treatment for metastatic [...]

The prostate cancer drug abiraterone can be metabolized into several substances with different effects, and optimization of this process could be helpful for fine-tuning the treatment of prostate cancer. Manipulating antitumour activity of abiraterone The anti-androgen prostate cancer drug abiraterone is metabolized in the body to [DELTA]4-abiraterone (D4A), a more potent steroid than abiraterone with structural similarities to endogenous steroidal 5[alpha]-reductase substrates, such as testosterone. These authors show that D4A is converted in the body to at least six previously unrecognized metabolites with a range of different metabolic effects. In a clinical trial of abiraterone alone, followed by abiraterone plus the 5[alpha]-reductase inhibitor dutasteride, production of a downstream tumour-promoting metabolite was blocked and D4A concentrations rose. These findings suggest a previously unappreciated method of clinically fine-tuning abiraterone metabolism to optimize cancer therapy. Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis.sup.1,2. Abiraterone is metabolized in patients to [DELTA].sup.4-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5[alpha]-reductase substrates, such as testosterone.sup.3. Here, we show that D4A is converted to at least three 5[alpha]-reduced and three 5[beta]-reduced metabolites in human serum. The initial 5[alpha]-reduced metabolite, 3-keto-5[alpha]-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5[alpha]-reductase inhibitor), 3-keto-5[alpha]-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5[beta]-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5[alpha]-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy., Author(s): Zhenfei Li [sup.1] , Mohammad Alyamani [sup.1] , Jianneng Li [sup.1] , Kevin Rogacki [sup.2] , Mohamed Abazeed [sup.2] , Sunil K. Upadhyay [sup.3] , Steven P. Balk [sup.4] [...]

Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5a-dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer (1-3). Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly requires enzymatic reactions by 3[beta]-hydroxysteroid dehydrogenase (3[beta]HSD), steroid-5[alpha]-reductase (SRD5A) and 17[beta]-hydroxysteroid dehydrogenase (17[beta]HSD) isoenzymes (4,5). Abiraterone, a steroidal 17a-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival (6,7). We hypothesized that abiraterone is converted by an enzyme to the more active [[DELTA].sup.4]-abiraterone (D4A), which blocks multiple steroidogenic enzymes and antagonizes the androgen receptor, providing an additional explanation for abiraterone's clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3[beta]HSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive androgen receptor antagonism by D4A is comparable to the potent antagonist enzalutamide. D4A also has more potent anti-tumour activity against xenograft tumours than abiraterone. Our findings suggest an additional explanation--conversion to a more active agent--for abiraterone's survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment., The central role and critical requirement for androgen metabolism and androgen receptor (AR) in castration-resistant prostate cancer (CRPC) are demonstrated by the clinical benefit and overall survival benefit conferred by [...]