Hormone-resistant Prostate Carcinoma Research Articles

Prognostic and Theragnostic Applications of Circulating Tumor DNA (CtDNA) in Metastatic Castrate- resistant Prostatic Carcinoma in Veterans: A Novel Promise in Precision Oncology

Abstract Introduction/Objective Utility of CtDNA in peripheral blood through liquid biopsies serves as a robust biomarker for precision oncology. Prostate cancer is most common cancer diagnosed in veterans, more commonly presenting at advanced stage with increased incidence of metastatic castrate-resistant prostatic carcinoma (MCRPC). Minimally invasive liquid biopsy is not limited by tumor site, type, tumor heterogeneity, and most importantly enables real time disease monitoring for best therapy decisions in MCRPC. The literature is sparse depicting the role of CtDNA in MCRPC in veteran patient population with distinct demographics/frequency of Tp53 mutations. We herein aim to study role of CtDNA in liquid biopsies for prognosis, treatment decisions and outcome in veterans with MCRPC. Methods QA documents from Foundation One (Cambridge MA, NGS) on liquid biopsies performed for the Corporal Michael J. Crescenz Veteran Affairs Medical Center (CMCVAMC) from May 2019 to April 15, 2020 were reviewed. All liquid biopsies were performed on MCRPC with evidence of tumor progression. Statistical data for adequacy, type of mutations either altering therapy, disease course or outcome was noted. Results A total of 23 liquid biopsies were performed. 21/23 (91.3%) biopsies were adequate, 19/21 (90.4%) showed signature mutations for resistance to therapy, predicting prognosis, or suggesting poor outcome with decreased overall survival. 4/21 (19%) showed androgen receptor amplification (ARV7 mutation) that helped in making treatment decisions. Increased frequency of Tp53 mutations were noted (12/21 (57.1%) compared to general population (30- 40%)) indicating worse prognosis/aggressive disease course with decreased survival. Conclusion Combined exposure of herbicide agent orange and smoking may be a fertile soil for observed differences in type and frequency of genomic alterations in veteran patient population with MCRPC. Comprehensive genomic profiling on CtDNA through minimally invasive liquid biopsy is feasible and can be successfully implemented in veterans with multiple co-morbidities. Although ARV7 mutation is much more common in general population, veterans with advanced hormone resistant prostatic carcinoma may benefit from aggressive approach in developing targeted therapy focused on DNA repair genes, especially Tp53.

946 - Cabazitaxel (CBZ) Shows Superior Antitumor Efficacy Over Docetaxel in a Hormone-Resistant Prostate Tumor Xenograft Model (HID28)

ABSTRACT Background Docetaxel (D) was the first cytotoxic treatment demonstrating a survival benefit in metastatic castration-resistant prostate cancer (mCRPC) patients. Recently, the novel taxane cabazitaxel and the CYP17 inhibitor abiraterone acetate have demonstrated a significant survival benefit in mCRPC patients progressing after receiving a D-containing regimen. Here we compare the antitumour efficacy of D, cabazitaxel and abiraterone acetate in the HID28 hormone-resistant human prostate carcinoma xenograft. Methods HID28 tumour-bearing nude mice received 20 mg/kg of D (IP, Q3W x 2), cabazitaxel at 15 and 20 mg/kg (IP, Q3W x 2) and abiraterone acetate at 50 mg/kg (PO, QD x 21). Median tumour growth inhibition (T/C%) was evaluated, as well as time-course androgen receptor expression (4, 8 and 24 h post-dosing) by western blot analysis. Results D inhibited tumour growth with a T/C% = 16.7% at day 35, 2 partial (PR) and 1 complete (CR) tumour regressions, and with relapse of all tumours (3/3) observed at day 42. Cabazitaxel demonstrated dose-dependent efficacy at day 35 with T/C% = 10.8% and 1.4% for 15 and 20 mg/kg doses, respectively. At a cabazitaxel dose of 15 mg/kg, 4/10 PR and 3/10 CR were observed, whereas 4/10 PR and 6/10 CR were observed at 20 mg/kg. At day 42, 6/6 tumour relapses were observed at 15 mg/kg, whereas only 3/6 relapses were observed at 20 mg/kg. No anti-tumour activity was demonstrated with abiraterone acetate as well as no significant decreases in testosterone levels compared with the vehicle group. Tolerability was good for all treatment groups, with a transitory maximum mean body weight loss of 12%, 6 days after treatments. Androgen receptor western blot expression analysis after 4, 8 and 24 h post-dosing demonstrated no significant difference between groups and over time. Conclusions Cabazitaxel demonstrated superior antitumour efficacy and a similar tolerability compared with D at equivalent dosing in the HID28 hormone-resistant tumour model. The model did not respond to abiraterone. These results support the clinical development of cabazitaxel in first-line treatment of mCRPC patients. This research was funded by Sanofi. Disclosure L. Bourre: Is a Xentech employee, D. Nicolle: Is a Xentech employee, M. Legrier: Is a Xentech employee, V. Yvonnet: Is a Xentech employee, J. Charpentier: Is a Xentech employee, M. Poupon: Has acted as an uncompensated consultant and has provided expert testimony. Is a Xentech employee, P. Vrignaud: Is a Sanofi employee (Research Investigator) and owns Sanofi stocks and shares, S. Oudard: Has acted as an advisor for, and received honoraria from Pfizer Oncology, Bayer Schering Pharma, Roche, GSK, Novartis and Sanofi, J-G. Judde: Is a Xentech employee.

Abstract LB-16: DACH1 inhibited prostate cancer cellular proliferation and interleukin-6 signaling

Abstract The Retinal Determination Gene Network (RDGN), consisting of dachshund (dac), eyes absent (eya), and sin oculis (so), is best known for its role in eye specification. Recently, coordinate abnormal expression of the DACH1/Eya/Six complex has been observed in human tumors supporting a tumor promoting role of Six and Eya family members, and a tumor-suppressor function of DACH. Oncogenes sustain host-cell interactions, promoting invasiveness, recruiting inflammatory mediators and developing angiogenic networks. Ras and Myc promote tumor angiogenesis through up-regulation of VEGF and the inflammatory mediator, interleukin-8(IL-8) and interleukin-6 (IL-6). Altered expressions of the IL-6 and IL-8 genes are seen in many cancers including prostate cancer. Hormone-resistant prostate carcinoma cell lines produce large amounts of IL-6 and IL-8 compared to hormone responsive prostate cancer cell lines. The expression of IL-8 and IL-6 are linked to poor prognosis and metastatic phenotype in prostate cancer. Recent finding demonstrated that IL-6 regulates the dynamic equilibrium between cancer stem cells and non-stem cancer cells in human breast and prostate cancer. Moreover, IL-6 alone can transform non-tumorigenic benign prostate epithelial cells and further progress to invasive phenotype. We had previously reported that the expression of DACH1 was reduced in human prostate cancer and DACH1 inhibited androgen signaling transduction. To explore the role of DACH1 in androgen resistant prostate cancer, PC3 cells stably expressing DACH1 were established. DACH1 inhibited cellular proliferation evaluated by MTT assay and growth curve. Microarray analyses demonstrated DACH1 inhibited mRNA expression of GRO, IL-6, IL-8 by 75%, 80% and 90%, respectively. However, there was no change of mRNA expression for IL-6 and IL-8 receptor. Ectopic expression of DACH1 in PC-3 cells significantly decreased tumor growth compared with vector control group (p<0.001), and DS domain was required. It has been reported that stable expression IL-6 in SV40T immortalized non-tumorigenic prostate epithelial cell line p69 induced EMT and acquired malignant phenotypes through autocrine loop IL6 and IGF-1R signaling. To further test the functional interaction of DACH1 with IL-6, a table cells expressing IL-6 alone or IL-6 with DACH1 were deployed. Ectopic expression of DACH1 attenuated activation of IGF-1R by IL-6 as evaluated by phosphorylation of IGF-1R. Subcutaneous implantation study showed an in vivo tumor growth initiated by IL-6 in p69 was inhibited by more than 60% with the expression of DACH1. Together, our studies suggest that DACH1 is a potential tumor suppressor of prostate through repression of IL-6 signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-16. doi:1538-7445.AM2012-LB-16

Abstract A21: DACH1 blocks prostate cancer cell growth and interleukin-6 signaling

Abstract In Drosophila, eye development is coordinately regulated by the retinal determination gene network (RDGN), mainly consisting of dachshund (dac), eyes absent (eya), and sin oculis (so). The mammalian homologues are Dach, Eya, and Six, respectively. RDGN, although best known for its role in eye specification, is essential for the development of many organs including retinal, kidney, brain, and limb in both flies and mammals. Recently, coordinate abnormal expression of the DACH1/Eya/Six complex has been observed in human tumors supporting a tumor promoting role of Six and Eya family members, and a tumor-suppressor function of DACH. Oncogenes sustain host-cell interactions, promoting invasiveness, recruiting inflammatory mediators and developing angiogenic networks. Ras and Myc promote tumor angiogenesis through up-regulation of VEGF and the inflammatory mediator, interleukin-8(IL-8) and interleukin-6 (IL-6). Our previous studies demonstrate DACH1 inhibits migration of MCF10A cells transformed with distinct oncogenes (Ha-Ras, c-Raf, c-Myc, and ErbB2) as well as the highly metastatic MDA-MB-231 human breast cancer cell line. An unbiased proteomic approach to identify candidate proteins regulated by DACH1 expression, using antibody array analysis, demonstrated DACH1 expression correlated with reduced secretion of IL-8 and the related chemokines IL-1, IL-6, GRO, and MIP1 (α, β, γ) from Ras or c-Myc transformed MCF-10A cells and repressed IL-8 promoter activity. Altered expressions of the IL-6 and IL-8 genes are seen in many cancers including prostate cancer. Hormone-resistant prostate carcinoma cell lines produce large amounts of IL-6 and IL-8 compared to hormone responsive prostate cancer cell lines. The expression of IL-8 and IL-6 are linked to poor prognosis and metastatic phenotype in prostate cancer. Recent finding demonstrated that IL-6 regulates the dynamic equilibrium between cancer stem cells and non-stem cancer cells in human breast and prostate cancer. IL-6 alone can transform non-tumorigenic benign prostate epithelial cells and further progress to invasive phenotype. To explore the role of DACH1 in androgen resistant prostate cancer, PC3 cells stably expressing DACH1 were established. DACH1 inhibited proliferation evaluated by MTT assay and growth curve. Microarray analyses demonstrated DACH1 inhibited mRNA expression of GRO, IL-6, IL-8 by 75%, 80% and 90%, respectively. However, there was no change of mRNA expression for IL-6 and IL-8 receptor. It has been reported that stable expression IL-6 in SV40T immortalized non-tumorigenic prostate epithelial cell line p69 induced EMT and acquired malignant phenotypes through autocrine loop IL6 and IGF-1R signaling. To further test the functional interaction of DACH1 with IL-6, a table cells expressing IL-6 alone or IL-6 with DACH1 were deployed. Ectopic expression of DACH1 attenuated activation of IGF-1 R by IL-6 as evaluated by phosphorylation of IGF-1R. Subcutaneous implantation study showed a 60% inhibition of in vivo tumor growth by DACH1. Together, our studies suggest that loss expression of DACH1 is an important cause of prostate tumorigenesis and restoration of DACH1 expression provides a potential therapeutic application. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A21.

Procyanidin Induces Apoptosis and Necrosis of Prostate Cancer Cell Line PC‐3 in a Mitochondrion‐Dependent Manner

Our objective was to study the effects of procyanidin on the cell death of human hormone-resistant prostate carcinoma cell line PC-3 and its mechanism. PC-3 cells were treated with procyanidin of different concentrations. The cell apoptosis rates were detected by annexin V-FITC and propidium iodide double staining followed by flow cytometry (FCM) analysis. Mitochondrial membrane potential (Deltapsim) was analyzed by FCM with rhodamine 123 staining. After 24 hours of treatment with 300 microg/mL procyanidin, the apoptosis rate of PC-3 cells was 44.86%, and Deltapsim was significantly decreased by 87.30%. With the extending of procyanidin treatment, the apoptosis rate decreased whereas the necrosis rate increased. Procyanidin could induce apoptosis and necrosis in PC-3 cells, which might be related to down-regulation of Deltapsim.

Local TNF-α and Systemic IFN-α-2b for the Treatment of Locally Advanced Hormone-Resistant Prostatic Carcinoma

Local TNF-α and Systemic IFN-α-2b for the Treatment of Locally Advanced Hormone-Resistant Prostatic Carcinoma

Phase II trial investigating the effects of zoledronate and dexamethasone in hormone resistant prostate cancer

15629 Background: Response rates to second line therapy in hormone resistant prostate cancer have been shown to be relatively low. Current options of management include dexamethasone, zoledronate or more recently, cytotoxic chemotherapy. Many trials have studied their effects as monotherapy. The aim of this study is to assess the efficacy and safety of the combination of zoledronate and dexamethasone in these patients. Methods: 20 patients were identified in 2004–2005. All had histologically confirmed prostatic adenocarcinoma and biochemically confirmed hormone resistance. All patients had bone metastases as confirmed on radionuclide imaging. Treatment consisted of 6 cycles of zoledronate at a dose of 4 mg, given at 4 weekly intervals, in combination with dexamethasone 2–4 mg once a day. Calcium/vitamin D supplementation was given throughout the zoledronate treatment. Data was collected prospectively on serum PSA, quality of life and pain score. Results: Of the 20 patients in the study, 11 completed the full 24 weeks of treatment. Reasons for not completing the study included disease progression, treatment toxicity, fracture and death. The overall response rate, as defined by an initial fall of serum PSA of more than 50%, was 35% (7 out of 20 patients). In those who responded, the sustained fall in PSA, during the trial period, lasted on average 3.0 months. Conclusion: This study has demonstrated clinically significant effects on tumour response for the combination of zoledronate and dexamethasone in hormone resistant prostate carcinoma. With the emergence of newer chemotherapeutic agents, this combination could be used as an effective, but less toxic alternative. No significant financial relationships to disclose.

<a name="home"></a>Effects of gamma-radiation on cell growth, cycle arrest, death, and superoxide dismutase expression by DU 145 human prostate cancer cells

Gamma-irradiation (gamma-IR) is extensively used in the treatment of hormone-resistant prostate carcinoma. The objective of the present study was to investigate the effects of 60Co gamma-IR on the growth, cell cycle arrest and cell death of the human prostate cancer cell line DU 145. The viability of DU 145 cells was measured by the Trypan blue exclusion assay and the 3(4,5-dimethylthiazol-2-yl)-2,5,diphenyltetrazolium bromide test. Bromodeoxyuridine incorporation was used for the determination of cell proliferation. Cell cycle arrest and cell death were analyzed by flow cytometry. Superoxide dismutase (SOD), specifically CuZnSOD and MnSOD protein expression, after 10 Gy gamma-IR, was determined by Western immunoblotting analysis. Gamma-IR treatment had a significant (P < 0.001) antiproliferative and cytotoxic effect on DU 145 cells. Both effects were time and dose dependent. Also, the dose of gamma-IR which inhibited DNA synthesis and cell proliferation by 50% was 9.7 Gy. Furthermore, gamma-IR induced cell cycle arrest in the G2/M phase and the percentage of cells in the G2/M phase was increased from 15% (control) to 49% (IR cells), with a nonsignificant induction of apoptosis. Treatment with 10 Gy gamma-IR for 24, 48, and 72 h stimulated CuZnSOD and MnSOD protein expression in a time-dependent manner, approximately by 3- to 3.5-fold. These data suggest that CuZnSOD and MnSOD enzymes may play an important role in the gamma-IR-induced changes in DU 145 cell growth, cell cycle arrest and cell death.

SERIAL TISSUE POLYPEPTIDE SPECIFIC ANTIGEN DETERMINATIONS IN THE FOLLOWUP OF HORMONE TREATED CARCINOMA OF THE PROSTATE

We determined the impact of serum cytokeratin-18-related tissue polypeptide specific antigen (TPS) in monitoring hormone treated carcinoma of the prostate. From 1991 to 1996, serial TPS and prostate specific antigen (PSA) determinations (3,882) in 443 hormone treated prostate carcinoma patients were correlated with the clinical course for a mean of 22 months. Elevated TPS levels were significantly associated with disease progression in hormone treated stage M1 carcinoma of the prostate (p = 0.001), even in high grade, PSA negative tumors. Post-therapy TPS declines following second line therapy in hormone refractory prostate cancer patients (92) correlated significantly with subjective response (p = 0.001, PSA p = 0.02) and progression-free survival time (r(s) = -0.76, PSA r(s) = -0.32). A TPS decrease of more than 50% coincided with palliation in 90% of patients (PSA 64%) and predicted the best chance of a longer progression of free survival (p < 0.00005, PSA p = 0.036). Vice versa, rising TPS levels (more than 20%) coincided with subjective response in only 1 of 37 patients (PSA 9 of 33). TPS may be a useful adjunct to PSA in monitoring hormone refractory, metastasized prostate cancer.

Secretion of prostate-specific antigen-suppressing activity by two human prostate carcinoma cell lines

The well-differentiated human prostatic carcinoma cell line LNCaP has often been used as a model to study the modulation of prostate-specific antigen (PSA) expression. In this study, we examined the effect of conditioned medium from two androgen-unresponsive, PSA-negative human prostatic carcinoma cell lines, PC-3 and DU-145, on PSA expression by the LNCaP cells. Our results show, for the first time, that the undifferentiated PC-3 and DU-145 cells secrete a factor that lowers PSA mRNA and protein levels in LNCaP cells. Further characterization of the PSA-suppressing activity indicated that it was trypsin as well as acid sensitive, heat-stable, and ammonium sulfate precipitable. The activity was present in the 30–100-kd fraction of PC-3 and DU-145 conditioned media. This PSA-suppression factor could act in an autocrine manner to render undifferentiated prostatic carcinoma cells PSA negative. It may also be responsible for the lack of increase in serum PSA levels observed in a subset of patients with hormone-resistant prostatic carcinoma.

Hormone resistant prostatic adenocarcinoma. An evaluation of prognostic factors in pre- and post-treatment specimens.

Pre- and post-treatment specimens from 47 patients with hormone resistant prostatic carcinoma were compared with each other regarding histological grade and immunoreactivity for p53 protein, neuron specific enolase and c-erbB-2 protein. Significantly more specimens expressed a high malignancy grade when the tumour had become hormone resistant than at the time of initial diagnosis (Gleason P: < 0.0001, WHO P:0.0003). p53 protein immunoreactivity increased significantly with disease progression (P:0.006), while tissue PSA immunoreactivity was reduced in post-treatment specimens (P:0.011). p53 protein expression did not correlate with histological grade or PSA expression and seems to be an independent parameter which participates late in the neoplastic transformation. Thirty-two percent of the tumours were neuron specific enolase positive, but this parameter did not correlate with development of hormone resistance. c-erbB-2 protein reactivity was not recognised.

Suramin in combination with mitomycin C in hormone-resistant prostate cancer. A phase II clinical study

Hormone-resistant prostate cancer can respond to mitomycin C or to suramin. This trial was undertaken to investigate the value of mitomycin C given with low dose suramin. Thirty-two patients with hormone-refractory prostate cancer were given suramin 350 mg/m2 daily for 5 days, followed by 350 mg/m2 weekly starting on day 14. Mitomycin C 12 mg/m2 was given every 5 weeks starting on day 14. Toxicity included maculo-papular skin rash in 8 patients, haematological toxicity in 16 (anaemia 13, leucopenia 11 and thrombocytopenia 9, bleeding 8), infection in 4 and fatigue in 11. Ten patients developed neurotoxicity, (temporary sensory peripheral neuropathy in 8, upper limb motor neuropathy in 1, and restless legs syndrome in 1) and 9 developed proteinuria. Other toxicities were mild nausea and vomiting, oedema, transient elevation of liver enzymes, stomatitis, upper gastrointestinal symptoms, and alopecia. During induction treatment the median trough suramin level was 140 micrograms/ml (range 100-273) and during maintenance treatment the median suramin level was 93 micrograms/ml. The median overall trough level was 93 micrograms/ml. There were one complete and 6 partial responses. Fifteen patients had disease stabilization. The median time to treatment failure was 103 days, and the median survival 209 days. The combination of suramin and mitomycin C has therapeutic activity, but causes significant toxicity in patients with hormone-resistant prostatic carcinoma.

Mitomycin C treatment of advanced, hormone-resistant prostatic carcinoma: a phase II study

From February 1984 to February 1987, 29 patients with advanced, hormone-resistant prostatic carcinoma were treated with mitomycin-C at a dose of 20 mg/m2 every 6 weeks (15 mg/m2 in patients greater than 75 years old and in those who had undergone previous radiotherapy). In the 27 evaluable patients, there were no complete remissions (CR), 2 partial remissions (PR), 14 stabilizations (STAB), and 11 cases of progressive disease (PRO). Ten stabilized patients showed significant pain reduction. Toxicity was minimal. The actuarial median survival was 10.8 months. In this study, mitomycin C was not active in terms of CR + PR; however, a beneficial symptomatic effect was frequently observed.

Toxicities of human recombinant interferon-alpha 2 in patients with advanced prostate carcinoma.

Nine patients with hormone-resistant prostate carcinoma were treated with subcutaneous injection of recombinant human interferon-alpha 2 (rHuIFN-alpha 2), 5-10 X 10(6) U/m2, three times a week. One patient had a mixed clinical response with reduction of bone pain. The study was closed due to intolerable grade III and IV toxicities including weight loss (8/9), fatigue/malaise (7/9), central nervous system toxicity (4/9), leukopenia (3/9), and uncontrollable nausea and vomiting (2/9). These toxicities resulted in deterioration of performance status. It is concluded that rHuIFN-alpha 2, at least at the dose and schedule studied, should not be used for the treatment of patients with hormone-resistant prostate carcinoma.

The Use of Ethane-1-Hydroxy-1,1-Diphosphonate (EHDP) in the Management of Hormone-Resistant Prostatic Carcinoma

The Use of Ethane-1-Hydroxy-1,1-Diphosphonate (EHDP) in the Management of Hormone-Resistant Prostatic Carcinoma

Chemotherapy of advanced prostatic cancer with adriamycin, BCNU, and cyclophosphamide.

A phase II trial of Adriamycin, BCNU, and cyclophosphamide was performed in 29 patients with advanced prostatic carcinoma (Southeastern Cancer Study Group protocol SEG 76 PR 0102P). Therapy consisted of BCNU 100 mg/m2, plus cyclophosphamide, 300 mg/m2 i.v., on day 1, followed by Adriamycin, 30 mg/m2 i.v., on day 2. Therapy was repeated every four weeks. In 27 evaluable patients refractory to prior estrogen therapy, one patient had a complete response, six patients had partial responses, and two patients had objective improvement (complete plus partial response rate 26%, and overall response rate 33%). Responders had a median time to progression of disease of 5.5 months, compared with a median time to progression of 4.0 months for those patients with stable disease. The median survival of responders was 9.3 months, compared with 6.7 months for stable disease and 3.9 months for patients with progression. Patients with higher pretreatment performance status did not have higher response rates. No life-threatening toxicity was observed. Only five patients had nadir platelet counts below 50,000/mm3, and only six patients had nadir granulocyte counts below 750/mm3. This regimen palliates the effects of hormone-resistant metastatic prostatic carcinoma.