Undifferentiated Prostate Cancer Research Articles

Unexpected tumor response to palliative pelvic radiotherapy in mismatch repair-deficient advanced prostate cancer: a case report

BackgroundMismatch-repair-deficiency resulting in microsatellite instability (MSI) may confer increased radiosensitivity in locally advanced/metastatic tumors and thus radiotherapy (RT) potentially might have a changing role in treating this subset of patients, alone or in combination with checkpoint inhibitors.Case presentationWe report a 76 year-old Italian male patient presenting with locally advanced undifferentiated prostate cancer (LAPC), infiltrating bladder and rectum. Molecular analysis revealed high-MSI with an altered expression of MSH2 and MSH6 at immunohistochemistry. Two months after 6 chemotherapy cycles with Docetaxel associated to an LHRH analogue, a computed tomography scan showed stable disease. After palliative RT (30 Gy/10 fractions) directed to the tumor mass with a 3D-conformal setup, a follow-up computed tomography scan at 8 weeks revealed an impressive response that remained stable at computed tomography after 9 months, with sustained biochemical response. To our knowledge, this is the first case of such a sustained response to low dose RT alone in high-MSI LAPC.ConclusionsRoutine evaluation of MSI in patients with locally problematic advanced tumors might change treatment strategy and treatment aim in this setting, from a purely palliative approach to a quasi-curative paradigm.

68Ga-PSMA-11 PET/CT in a patient with non-PSA-secreting undifferentiated prostate cancer before and after treatment with cabozantinib

68Ga-PSMA-11 PET/CT in a patient with non-PSA-secreting undifferentiated prostate cancer before and after treatment with cabozantinib

Radical prostatectomy in T4 prostate cancer after inductive androgen deprivation: results of a single-institution series with long-term follow-up.

To determine the outcomes of complete surgical resection of T4 prostate cancer after inductive androgen-deprivation therapy (ADT), as inductive ADT and subsequent radical prostatectomy (RP) is not recommended by any guideline yet. A monocentric RP database was queried for patients initially diagnosed with T4 prostate cancer, considered primarily as inoperable because of a fixed mass defined by rectal examination in combination with high PSA level and/or large foci of biopsy confirmed undifferentiated prostate cancer. Treatment consisted of primary ADT until PSA nadir with consecutive RP. Patients underwent retropubic RP (RRP) or robot-assisted laparoscopic RP (RALP) after inductive ADT until achievement of the PSA nadir, which is in general reached after 6-7months. The intraoperative course and complications were analysed. Finally, Kaplan-Meier estimates were calculated for overall survival (OS) and prostate cancer-specific survival (PCSS). We retrospectively identified 116 patients treated between 2000 and 2014. At diagnosis, the median (range) PSA level was 37.6 (2.44-284) ng/mL. The preoperative median (range) PSA after inductive ADT was 0.73 (0.01-34) ng/mL. Thereafter, patients underwent RRP or, since 2006, RALP. The median (95% confidence interval) OS was 156 (118.9-193.1) months. The PCSS at 150months was 82%. Surgical therapy of primarily inoperable prostate cancer is feasible and safe after inductive ADT. The OS of this cohort seems comparable with results described for patients with primary operable high-risk prostate cancer.

Defining a Population of Stem-like Human Prostate Cancer Cells That Can Generate and Propagate Castration-Resistant Prostate Cancer.

We have shown that the phenotypically undifferentiated (PSA(-/lo)) prostate cancer cell population harbors long-term self-renewing cancer stem cells (CSC) that resist castration, and a subset of the cells within the PSA(-/lo) population bearing the ALDH(hi)CD44(+)α2β1(+) phenotype (Triple Marker(+)/TM(+)) is capable of robustly initiating xenograft tumors in castrated mice. The goal of the current project is to further characterize the biologic properties of TM(+) prostate cancer cell population, particularly in the context of initiating and propagating castration-resistant prostate cancer (CRPC). The in vivo CSC activities were measured by limiting-dilution serial tumor transplantation assays in both androgen-dependent and androgen-independent prostate cancer xenograft models. In vitro clonal, clonogenic, and sphere-formation assays were conducted in cells purified from xenograft and patient tumors. qPCR, Western blot, lentiviral-mediated gene knockdown, and human microRNA arrays were performed for mechanistic studies. By focusing on the LAPC9 model, we show that the TM(+) cells are CSCs with both tumor-initiating and tumor-propagating abilities for CRPC. Moreover, primary patient samples have TM(+) cells, which possess CSC activities in "castrated" culture conditions. Mechanistically, we find that (i) the phenotypic markers are causally involved in CRPC development; (ii) the TM(+) cells preferentially express castration resistance and stem cell-associated molecules that regulate their CSC characteristics; and (iii) the TM(+) cells possess distinct microRNA expression profiles and miR-499-5p functions as an oncomir. Our results define the TM(+) prostate cancer cells as a population of preexistent stem-like cancer cells that can both mediate and propagate CRPC and highlight the TM(+) cell population as a therapeutic target. Clin Cancer Res; 22(17); 4505-16. ©2016 AACR.

Abstract 96: Effect of LSD-1 inhibition on docetaxel resistance in prostate cancer cells

Abstract Lysine Specific Demethylase-1 (LSD-1) overexpression correlates with undifferentiated prostate cancer and predicts poor survival. Demethylation of lysine residues on histone protein by LSD-1 also mediates Epithelial-Mesenchymal Transition (EMT) and resistance to chemotherapy by genome-wide reprogramming of large heterochromatin domains (Large Organized Chromatin K (lysine) modifications or “LOCKs”) to a state of reduced H3 Lys9 dimethylation (H3K9Me2), a repressive mark. This leads to a more stem cell like state of chromatin and enables transcription of genes that confer survival advantage in a given cellular environment. Activation of c-Myc signaling is downstream from several different oncogenic survival pathways and has been shown to mediate EMT and docetaxel resistance in prostate cancer cells. In this study, we investigate the effect of LSD-1 inhibition on sensitivity to docetaxel in docetaxel resistant prostate cancer cells, PC-3D12 (donated to us by Dr. William Watson and Dr. Amanda O’Neill, University College Dublin, Ireland), using HCI2509, a reversible LSD-1 inhibitor. We also investigate LSD-1 and c-Myc expression in PC-3D12 cells in comparison to the docetaxel sensitive parent cell line PC-3, and the effect of LSD-1 inhibition on H3K9Me2 and c-Myc signaling in these cells. We performed cell viability assays on PC-3 and PC-3D12 cells with increasing concentrations of HCI2509 alone and docetaxel alone. We then pretreated PC-3D12 cells with a sub-toxic dose of HCI2509 for 48 hours and performed cell viability assays with increasing concentrations of docetaxel in continued presence of the constant sub-toxic dose of HCI2509. Next, western blot analysis was performed for LSD-1, c-Myc, H3K9me2 and GAPDH using whole cell lysates from PC-3D12 and PC-3 cells treated with vehicle and increasing doses of HCI2509 for 48 hours. PC-3D12 cells were more resistant to treatment with docetaxel than PC-3 cells with an approximately 10-fold difference in sensitivity. HCI2509 pretreated PC-3D12 cells had an approximately 10-fold improvement in chemosensitivity to docetaxel, to a range similar to the chemosensitive PC-3 cells. Western Blot analyses of whole cell lysates of untreated PC-3 and untreated PC-3D12 cells showed higher LSD-1 protein and c-Myc protein levels in PC-3D12 cells compared to PC-3 cells. Treatment with HCI2509 resulted in a dose dependent decrease in c-Myc levels and an increase in H3K9me2 mark in PC-3D12 cells. We conclude that LSD-1 overexpression correlates with chemoresistance in prostate cancer. LSD-1 inhibition rescues chemosensitivity to docetaxel with inhibition of c-Myc signaling in docetaxel resistant prostate cancer cell line and can be developed as a potential treatment strategy in docetaxel resistant prostate cancer. Citation Format: Sumati Gupta, Alexis Weston, Jared Bearrs, Raffaella Soldi, Sunil Sharma. Effect of LSD-1 inhibition on docetaxel resistance in prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 96. doi:10.1158/1538-7445.AM2015-96

A case of particular diffusion of prostate cancer

Neoplastic diffusion can occur due to dissemination, continuity, through lymphatic or haematic vessels, or, more rarely originate from surgical instruments. We report a particular case of prostate cancer spread. A 64-year-old man was diagnosed with undifferentiated prostate cancer through prostate biopsy. The patient was treated with a total androgenic block allowing a decrease in PSA blood level. The patient, wishing to regain his sexual activity compromised by hormonal therapy, interrupted the treatment spontaneously and unchecked. 19 months later he contacted us again: we had to hospitalize him due to a 12-hour anuresis. A urgent right transcutaneous nephrostomy was carried out, yielding an improvement in the patient's condition. A descending pyelography carried out by means of nephrostomy revealed a completely reduced urethral lumen. During the following surgery for transcutaneous urinary derivation we observed the two ureters entangled in whitish tissue, spreading bilaterally up to the renal pelvis. The histological examination of tissue samples showed the presence of neoplastic metastasis of prostatic origin. We assume that this neoplastic diffusion has occurred due to permeability through the lymphatic vessels of the urethral wall, producing a subsequent neoplasm growth: this has been limited by the urethral connective sheath, thus preventing its wide diffusion to the surrounding tissues, but fostering its spreading upwards along the ureter pathway.

A case of particular diffusion of prostate cancer

Neoplastic diffusion can occur due to dissemination, continuity, through lymphatic or haematic vessels, or, more rarely originate from surgical instruments. We report a particular case of prostate cancer spread. A 64-year-old man was diagnosed with undifferentiated prostate cancer through prostate biopsy. The patient was treated with a total androgenic block allowing a decrease in PSA blood level. The patient, wishing to regain his sexual activity compromised by hormonal therapy, interrupted the treatment spontaneously and unchecked. 19 months later he contacted us again: we had to hospitalize him due to a 12-hour anuresis. A urgent right transcutaneous nephrostomy was carried out, yielding an improvement in the patient's condition. A descending pyelography carried out by means of nephrostomy revealed a completely reduced urethral lumen. During the following surgery for transcutaneous urinary derivation we observed the two ureters entangled in whitish tissue, spreading bilaterally up to the renal pelvis. The histological examination of tissue samples showed the presence of neoplastic metastasis of prostatic origin. We assume that this neoplastic diffusion has occurred due to permeability through the lymphatic vessels of the urethral wall, producing a subsequent neoplasm growth: this has been limited by the urethral connective sheath, thus preventing its wide diffusion to the surrounding tissues, but fostering its spreading upwards along the ureter pathway.

Identification of differentially expressed genes during cyclic adenosine monophosphate–induced neuroendocrine differentiation in the human prostatic adenocarcinoma cell line LNCaP

The LNCaP cell line is a versatile and useful model suitable for the study of human prostate cancer in vitro. It has been determined that the elevation of LNCaP intracellular cyclic adenosine monophosphate (cAMP) levels through the addition of membrane-permeable cAMP analogs, phosphodiesterase inhibitors, adenylate cyclase activators, or components of the cAMP signal-transduction pathway can induce reversible neuroendocrine (NE) differentiation. Elucidation of those genes that are differentially expressed between undifferentiated prostate cancer cells and prostate cancer cells that have been induced to differentiate may present new insights into the molecular mechanisms governing NE differentiation, early detection of prostate cancer, and potential targets for gene therapy. In this study, differential display polymerase chain reaction (PCR) was used to identify 226 differentially expressed PCR products. Twelve of the differential display PCR products were confirmed by Northern blot analysis and were cloned. DNA sequencing and database comparisons were performed. To our knowledge, this is the first report of the use of differential gene expression techniques to analyze gene expression during cAMP-induced NE differentiation in LNCaP cells. Confirmation of NE differentiation reversibility also was accomplished.

Site‐specific growth of the prostate xenograft line UCRU‐PR‐2

A xenografted small-cell, undifferentiated prostate (SCUCP) cancer line, UCRU-Pr-2, was implanted at different sites within nude mice to examine the effect of local environmental factors on tumor growth and behavior. All tumors that grew were small-cell carcinomas. Fragments implanted within muscle and under the kidney capsule were locally invasive; however, tumors that grew subcutaneously or intraperitoneally showed no invasion. UCRU-Pr-2 did not grow in the spleen or the liver. No induced metastases were observed in the lung after intravenous injection. The sites of implantation did not allow the outgrowth of subpopulations as detected by the parameters used: light and electron microscopy, expression of tumor markers, levels of hormone production, and DNA flow cytometry. Electron microscopy, which showed both glandular and neuroendocrine differentiation within the same cell, does not support a dual-cell origin of SCUCP.