Development Of Clinical Prostate Cancer Research Articles

Preclinical biodistribution and dosimetry and human biodistribution comparing 18F-rhPSMA-7 and single isomer 18F-rhPSMA-7.3

BackgroundRadiohybrid prostate-specific membrane antigen (rhPSMA) ligands such as 18F-rhPSMA-7 are a new class of theranostic agents in clinical development for prostate cancer. We compared preclinical dosimetry and human biodistribution of 18F-rhPSMA-7 with that of single diastereoisomer form, 18F-rhPSMA-7.3.MethodsPreclinical dosimetry was performed with SCID-mice sacrificed at multiple timepoints (10–300 min) post-injection of 25.6 ± 3.6 MBq 18F-rhPSMA-7 or 28.5 ± 4.8 MBq 18F-rhPSMA-7.3 (n = 3–6 mice per timepoint). Heart, lung, liver, spleen, pancreas, fat, stomach, small intestine, large intestine, kidney, muscle, bone, bladder, testicles, tail, and brain tissue were harvested, and urine and blood samples collected. Percentage of injected dose per gram was calculated. Absorbed doses were estimated with OLINDA/EXM 1.0.18F-rhPSMA-7 (n = 47) and 18F-rhPSMA-7.3 (n = 33) PET/CT exams were used to estimate human biodistribution. Mean (range) injected activities were 324 (236–424) MBq versus 345 (235–420) MBq, and acquisition times were 84 (42–166) versus 76 (59–122) minutes for 18F-rhPSMA-7 versus 18F-rhPSMA-7.3, respectively. SUVmean was determined for background (gluteal muscle), normal organs (salivary glands, blood pool, lung, liver, spleen, pancreas, duodenum, kidney, bladder, bone) and up to three representative tumour lesions. Qualitative analyses assessed image quality, non-specific blood pool activity, and background uptake in bone/marrow using 3/4-point scales.ResultsPreclinical dosimetry revealed that at 3.5 h and 1 h bladder voiding intervals, the extrapolated total effective doses were 26.6 and 12.2 µSv/MBq for 18F-rhPSMA-7 and 21.7 and 12.8 µSv/MBq for 18F-rhPSMA-7.3 respectively.Human biodistribution of both agents was typical of other PSMA-ligands and broadly similar to each other; SUVmean were 16.9 versus 16.2 (parotid gland), 19.6 versus 19.9 (submandibular gland), 2.0 versus 1.9 (blood pool, p < 0.005), 0.7 versus 0.7 (lungs), 7.0 versus 7.3 (liver), 9.1 versus 8.4 (spleen), 32.4 versus 35.7 (kidney), 2.5 versus 2.8 (pancreas), 10.9 versus 11.0 (duodenum), 1.1 versus 1.3 (bone) and 4.6 versus 2.0 (bladder; p < 0.001) for 18F-rhPSMA-7 versus 18F-rhPSMA-7.3, respectively. Tumour SUVmean was higher for 18F-rhPSMA-7.3 (32.5 ± 42.7, n = 63 lesions) than for 18F-rhPSMA-7 (20.0 ± 20.2, n = 89 lesions).ConclusionsRadiation dosimetry is favourable for both agents. Radiation exposure, assuming a 1 h voiding interval, is less than 5 mSv after injection of 370 MBq. 18F-rhPSMA-7.3 showed significantly lower bladder uptake, and a higher uptake trend in tumours compared with 18F-rhPSMA-7.

Homologous repair deficiencies and current insights in clinical evaluation of PARP inhibitors in prostate cancer

SummaryHomologous repair deficiency is a clinically relevant molecular aberration in prostate cancer. The goal of this short review is to summarize the study landscape of treatments targeting these aberrations through discussion of the most relevant clinical trials. Due to its shortness, this review does not claim to be exhaustive and a major focus is being laid on PARP inhibitors in clinical development for prostate cancer.

Galeterone and its analogs inhibit Mnk-eIF4E axis, synergize with gemcitabine, impede pancreatic cancer cell migration, invasion and proliferation and inhibit tumor growth in mice.

Survival rate for pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is poor, with about 80% of patients presenting with the metastatic disease. Gemcitabine, the standard chemotherapeutic agent for locally advanced and metastatic PDAC has limited efficacy, attributed to innate/acquired resistance and activation of pro-survival pathways. The Mnk1/2-eIF4E and NF-κB signaling pathways are implicated in PDAC disease progression/metastasis and also associated with gemcitabine-induced resistance in PDAC. Galeterone (gal), a multi-target, agent in phase III clinical development for prostate cancer has also shown effects on the aforementioned pathways. We show for the first time, that gal/analogs (VNPT55, VNPP414 and VNPP433-3β) profoundly inhibited cell viability of gemcitabine-naive/resistance PDAC cell lines and strongly synergized with gemcitabine in gemcitabine-resistant PDAC cells. In addition, to inducing G1 cell cycle arrest, gal/analogs induced caspase 3-mediated cell-death of PDAC cells. Gal/analogs caused profound downregulation of Mnk1/2, peIF4E and NF-κB (p-p65), metastatic inducing factors (N-cadherin, MMP-1/-2/-9, Slug, Snail and CXCR4) and putative stem cell factors, (β-Catenin, Nanog, BMI-1 and Oct-4). Gal/analog also depleted EZH2 and upregulated E-Cadherin. These effects resulted in significant inhibition of PDAC cell migration, invasion and proliferation. Importantly, we also observed strong MiaPaca-2 tumor xenograft growth inhibition (61% to 92%). Collectively, these promising findings strongly support further development of gal/analogs as novel therapeutics for PDAC.

Extracting the Benefit of Nexrutine® for Cancer Prevention.

The current standard of care for prostate cancer includes hormone therapy, radiation therapy and radical prostatectomy, each with its own set of undesirable side effects. In this regard there is an unmet need to develop strategies that can prevent or delay the development of clinical prostate cancer. One potential area involves the use of natural compounds involving botanicals. Along these lines we have found that Nexrutine®, a dietary supplement derived from Phellodendron amurense bark extract, has prostate cancer prevention activity. The "extract" nature of this botanical, which constitutes a blend of several active protoberberine alkaloids, allows it to target several pathways deregulated in prostate cancer simultaneously. In this review, we will emphasize the prospective translational benefit of Nexrutine® as a chemopreventive agent for prostate cancer management. The potential of Nexrutine® was first identified and has subsequently been most exhaustively studied with reference to prostate cancer. Therefore the focus of this review is on the use of Nexrutine® in prostate cancer. In addition we have summarized the emerging evidence regarding the use of Nexrutine® in other tumor models to demonstrate the potential benefits of Nexrutine®.

Drugs in Clinical Development for Prostate Cancer

Drugs in Clinical Development for Prostate Cancer

Cellular immunotherapies for prostate cancer

Prostate cancer is currently the most commonly diagnosed malignancy, and the second leading cause of cancer-related death, in men in the United States. Most deaths from prostate cancer are due to metastatic disease that no longer responds to androgen deprivation. There have been several advances within the last decade leading to the approval of new agents for treating patients with castration-resistant prostate cancer. However, these agents can have significant side effects, and the average survival benefit from chemotherapy has been modest. Results from several clinical trials have suggested that immune-based therapies may have clinical benefits in patients with prostate cancer with significantly fewer adverse events. These new therapies, however, pose new potential benefits and risks. We review here two cellular immunotherapies furthest in clinical development for prostate cancer, and discuss the potential challenges to the treating oncologist with the possible advent of these new therapies.

Rapid Suppression of Plasma Testosterone Levels and Tumor Growth in the Dunning Rat Model Treated with Degarelix, a New Gonadotropin-Releasing Hormone Antagonist

Degarelix (FE 200486) is a member of a new class of water-soluble (>50 mg/ml) gonadotropin-releasing hormone (GnRH) antagonists in clinical development for prostate cancer. Upon subcutaneous administration, degarelix forms a gel that results in a sustained release of the compound into the circulation, immediately blocking GnRH receptors in the pituitary and inducing a fast and sustained suppression of gonadotrophin secretion in rats and primates. One of the few animal models of prostate adenocarcinoma is the Dunning R-3327H rat carcinoma transplanted into Copenhagen rats. The growth of the Dunning tumor can be inhibited by various treatments reported to be effective in the clinic, such as GnRH superagonists, antiandrogens, 5-alphareductase inhibitors, tyrosine kinase inhibitors, and surgical castration. We report in this study that degarelix produces a fast and sustained suppression of the pituitary gonadal axis in rats and a similar inhibition of tumor growth compared with surgical castration in the Dunning R-3327H rat carcinoma model. First, degarelix as been compared with d-Trp(6)-luteinizing hormone-releasing hormone and surgical castration on a short-term study (2 months); and second, degarelix has been compared with leuprolide and surgical castration on a long-term study (12 months). In both studies, degarelix demonstrated a sustained inhibition of tumor growth at least comparable with surgical castration. These data provide a convincing profile of degarelix as a potential candidate for the clinical management of sex steroid-dependent pathologies, such as prostate cancer, where long-term reversible chemical castration is required.

Clinical, haemodynamic, anthropometric, metabolic and insulin profile of men with high‐stage and high‐grade clinical prostate cancer

Aims: Previous studies have shown that non‐insulin‐dependent diabetes mellitus (NIDDM), hypertension, atherosclerotic disease manifestations, tallness, obesity, dyslipidaemia, hyperuricaemia, hyperinsulinaemia and high alanine aminotransferase (ALAT) levels are risk factors for development of benign prostatic hyperplasia (BPH). This indicates that BPH is a component of the metabolic syndrome. In a subsequent study, we found that there was an association between the BPH growth rate and the development of clinical prostate cancer. These findings generated a hypothesis that clinical prostate cancer also was a component of the metabolic syndrome. In the present study, this hypothesis was tested on 299 patients with recently diagnosed clinical prostate cancer. If this hypothesis is true, patients with clinical prostate cancer of high stage and grade would have a larger prostate gland volume, a faster BPH growth rate and a more pronounced clinical, haemodynamic, anthropometric, metabolic and insulin profile than patients with clinical prostate cancer of low stage and grade have. Methods: Two hundred and ninety‐nine patients in whom clinical prostate cancer was diagnosed were consecutively included. The prevalence of NIDDM, treated hypertension and atherosclerotic manifestations was provided by the respective patient's medical history. Body length, body weight, waist measurement, hip measurement and blood pressure were determined. Body mass index (BMI) and waist/hip ratio (WHR) were calculated. Blood samples were drawn to determine triglycerides, total cholesterol, high‐density lipoprotein (HDL)‐cholesterol, low‐density lipoprotein (LDL)‐cholesterol, uric acid, ALAT and the fasting plasma insulin level. The prostate gland volume was measured using transrectal ultrasound. The annual BPH growth rate was calculated. The prostate cancer diagnosis was established. Results: Patients with clinical prostate cancer, prostate‐specific antigen (PSA) < 50 ng/ml, stage T3, had a bigger prostate gland volume (p < 0.001), a faster BPH growth rate (p < 0.001), were more obese, as measured by body weight (p = 0.062), BMI (p = 0.003), waist measurement (p = 0.011) and hip measurement (p = 0.051) and showed a higher systolic blood pressure (p < 0.070) than patients with T2 clinical prostate cancer. When patients with clinical prostate cancer, PSA >50 ng/ml, were included at the comparison, T3 tumour patients showed a higher prevalence of treated hypertension (p = 0.026) than patients with T2 tumours. Patients with clinical prostate cancer, PSA <50 ng/ml, G3, had a greater prostate gland volume (p = 0.004), a faster BPH growth rate (p = 0.005) and were more obese as determined by waist measurement (p = 0.044) and WHR (p = 0.073). Moreover, subjects with a G3 tumour were more dyslipidaemic, as shown by a higher triglyceride level (p = 0.019) and a lower HDL‐cholesterol level (p = 0.005), and were more hyperuricaemic (p = 0.023), showed a higher plasma insulin level (p = 0.019) and a higher ALAT level (p = 0.061) than those with a G1 tumour. When patients with clinical prostate cancer, PSA >50 ng/ml, were included at the comparison, G3 patients had a greater prostate gland volume (p = 0.002) and a faster BPH growth rate (p = 0.003) than patients with G1 tumours. Conclusions: The results of the present study suggest that the prostate gland volume, the BPH growth rate, hypertension, obesity, dyslipidaemia, hyperuricaemia, hyperinsulinaemia and high ALAT levels are risk factors for the development of clinical prostate cancer. Thus, our results support the hypothesis that clinical prostate cancer is a component of the metabolic syndrome. Patients with clinical prostate cancer may have the same metabolic abnormality of a defective insulin‐stimulated glucose uptake and secondary hyperinsulinaemia as patients with the metabolic syndrome. Our data also support the hypothesis that hyperinsulinaemia is a promoter of clinical prostate cancer.

Randomized, controlled chemoprevention trials in populations at very high risk for prostate cancer: Elevated prostate-specific antigen and high-grade prostatic intraepithelial neoplasia

This is a report of research efforts underway at the Arizona Cancer Center. These efforts build upon Larry Clark’s unanticipated clinical prevention trial results: those results indicated that 200 μg/day of selenium in selenized yeast decreased prostate cancer risk by almost 60%. The trials underway address various phases of the possible preventive activity of selenium. The first of these, for men who are suspected to have prostate cancer but who have had a biopsy revealing no evidence of cancer, will test the ability of selenium to prevent the development of clinical prostate cancer. The second is for men with high-grade prostatic intraepithelial neoplasia; the trial will test whether selenium will prevent the development of prostatic cancer in this high-risk group. The third trial is for men who have been diagnosed with prostate cancer and are scheduled for prostatectomy: the trial is designed to test whether evidence of selenium-linked changes can be identified in the tissue removed at prostatectomy. The fourth trial is for men who have been diagnosed with prostate cancer but who have chosen neither surgery nor irradiation; this trial will evaluate whether treatment with selenium will inhibit the progress of prostate cancer. Together, these trials will provide important information as to the prostate cancer chemopreventive potential of selenium.

Decreased Growth of Human Prostate LNCaP Tumors in SCID Mice Fed a Low-Fat, Soy Protein Diet With Isoflavones

Epidemiological studies suggest that high intake of dietary fat is a risk factor for the development of clinical prostate cancer. Soy protein has also been proposed to play a role in the prevention of prostate cancer, and one of the isoflavones in soy protein, genistein, inhibits the growth of human prostate cancer cell lines in vitro. This study was de-signed to evaluate whether altering dietary fat, soy protein, and isoflavone content affects the growth rate of a human androgen-sensitive prostate cancer cell line (LNCaP) grown in severe-combined immunodeficient (SCID) mice. SCID mice were randomized into four dietary groups: high-fat (42.0 kcal%) = casein, high-fat (42.0 kcal%) = soy protein = isoflavone extract, low-fat (12.0 kcal%) = casein, and low-fat (12.0 kcal%) = soy protein = isoflavone extract. After two weeks on these diets, the mice were injected subcutaneously with 1 = 10 5 LNCaP tumor cells and placed in separate cages (1 mouse/cage) to strictly control caloric intake. Isocaloric diets were given 3 days/wk, and tumor sizes were measured once per week. The tumor growth rates were slightly reduced in the group that received the low-fat = soy protein = isoflavone ex-tract diet compared with the other groups combined (p = 0.05). In addition, the final tumor weights were reduced by 15% in the group that received the low-fat = soy protein = isoflavone extract diet compared with the other groups combined (p = 0.05). In this xenograft model for prostate cancer, there were statistically significant effects on tumor growth rate and final tumor weight attributable to a low-fat = soy protein = isoflavone extract diet.

Androgen-receptor gene structure and function in prostate cancer.

Androgen-receptor (AR) gene mutations have been found in clinical prostate cancer, both prior to hormonal therapy and in hormone-refractory disease that persists despite androgen-ablative therapy. Thus, mutations that are present in late-stage disease might arise prior to therapy rather than as a result of therapy. A common feature of mutations in untreated prostate cancer and in hormone-refractory prostate cancer is that the AR retains activity as a ligand-dependent transcription factor. Some AR mutations in prostate cancer show broadened ligand specificity, such that the transcription-factor activity of the AR can be stimulated not just by dihydrotestosterone (DHT) but also by estradiol and other androgen metabolites that have a low affinity for the AR. The activation of mutant AR by estrogen and weak androgens could confer on prostate cancer cells an ability to survive testicular androgen ablation by allowing activation of the AR by adrenal androgens or exogenous estrogen. Such mutations might confer an advantage even prior to androgen ablation, since prostate cancer has lower levels of 5 alpha-reductase and, therefore, of DHT, than normal. Thus, AR mutations that occur prior to therapy may characterize a more aggressive disease. A large percentage of tumors appear to have no AR gene mutation. In tumors without an AR gene mutation, AR function might be affected via other mechanisms (e.g., AR gene amplification, which could increase the amount of AR activity at a given DHT level). Importantly, the apparent absence of AR gene mutations in the majority of earlystage tumors indicates that the role of androgen in the development of clinical prostate cancer is mediated predominantly by a normal AR gene. There are actually multiple alleles of the normal AR gene; these allelic variants differ in glutamine and glycine repeat length in the transactivation domain of the protein, and they may differ in signal-transducing activity. The glutamine and glycine repeat length may thereby modulate the effect of androgen on tumor-cell proliferation that occurs during clonal expansion.

APC Gene Mutations in Human Prostate Cancer

Prostate cancer is the most common cancer in aged men. Although ras and p53 gene mutations have been detected in some prostate cancers, the major genetic alterations involved in its carcinogenesis are not well understood. Mutation of the APC gene is responsible for colorectal tumors in which ras and p53 mutations are also often involved. Using PCR-SSCP analysis and sequencing, we examined 31 human primary prostate cancers (three cases at stage A, 10 at stage B, five at stage C and 13 at stage D) and four cases of lymph node metastasis from the stage D cases, for mutations in the APC gene. A mutation was detected in only one of the 35 samples (3%). This mutation, present in a primary stage B cancer, had a T to C transition in exon 15 at the first position of codon 956, resulting in substitution of histidine for tyrosine. This study clarified that APC gene mutations are not largely involved in the development of clinical prostate cancer.

Suramin, hydrocortisone, and retinoic acid modify inhibitory effects of 1,25-dihydroxyvitamin D 3 on prostatic epithelial cells

The proliferation of prostatic epithelial cells is regulated by the complex interplay of numerous growth-stimulatory and growth-inhibitory factors. 1,25-dihydroxyvitamin D 3 [1,25(OH) 2D 3] has recently been identified as a potent inhibitor of the growth of prostatic epithelial cells. Epidemiologic studies indicate that vitamin D deficiency may be a risk factor for the development of clinical prostate cancer, possibly due to increased growth and reduced differentiation of prostatic cells in an environment with decreased 1,25(OH) 2D 3. The application of vitamin D or analogs in chemotherapy against prostate and other cancers is being explored by several investigators. In order to use vitamin D most efficaciously in a clinical setting, it may be beneficial to learn more about the interaction of 1,25(OH) 2D 3 with other factors that regulate prostatic epithelial cellular growth. In this study, we examined the effect of the proliferative status of cultured cells on their ability to respond to 1,25(OH) 2D 3, and found that minimally proliferative cells were equally as responsive to 1,25(OH)2D3 as actively dividing cells. We noted no apparent interaction of 1,25(OH) 2D 3 with epidermal growth factor, insulin-like growth factor, cholera toxin, or transforming growth factor-β, but we did find synergistic inhibitory effects of 1,25(OH) 2D 3 with suramin and retinoic acid. Perhaps most noteworthy was the dramatic increase in potency of 1,25(OH) 2D 3 that occurred upon deletion of hydrocortisone from the culture medium. Our in vitro studies indicate that combination therapy of vitamin D analogs with suramin, vitamin A analogs, or anti-glucocorticoids might be considered for prostate cancer.