Effects of a Fluorescent Myosin Light Chain Phosphatase Inhibitor on Prostate Cancer Cells

Myosin light chain phosphatase (MLCP) is an enzyme important to regulation of cell cycle and motility that is shown to be upregulated in aggressive prostate cancer cells and tissue. We developed a fluorescent small molecule inhibitor of MLCP using structure based design in recombinant protein phosphatase 1C. Several best fit compounds were synthesized and evaluated by their inhibition of MLCP/32P-MLC dephosphorylation, which resulted in the identification of novel MLCP inhibitors. Androgen dependent (AD) and castration resistant prostate cancer cell (CRPC) lines were treated with the lead inhibitor resulting in decreased growth rate, reduced DNA synthesis, and G2/M cell cycle arrest. Moreover, CRPC cell lines showed an increased sensitivity to drug treatment having GI50 values four times lower than the AD prostate cancer cell line. This was reinforced by reduced BrdU DNA incorporation into CRPC cells compared to AD cells. β-actin disruption was also seen at much lower drug concentrations in CR cells which caused a dose dependent reduction in cellular chemotaxis of PC-3 cells. Since there are currently few clinical therapeutics targeting CR prostate cancer, MLCP represents a new target for preclinical and clinical development of new potential therapeutics which inhibit this disease phenotype

MicroRNA-214 targets PTK6 to inhibit tumorigenic potential and increase drug sensitivity of prostate cancer cells.

Prostate cancer is the most commonly diagnosed cancer in men with African American men disproportionally suffering from the burden of this disease. Biomarkers that could discriminate indolent from aggressive and drug resistance disease are lacking. MicroRNAs are small non-coding RNAs that affect numerous physiological and pathological processes, including cancer development and have been suggested as biomarkers and therapeutic targets. In the present study, we investigated the role of miR-214 on prostate cancer cell survival/migration/invasion, cell cycle regulation, and apoptosis. miR-214 was differentially expressed between Caucasian and African American prostate cancer cells. Importantly, miR-214 overexpression in prostate cancer cells induced apoptosis, inhibiting cell proliferation and colony forming ability. miR-214 expression in prostate cancer cells also inhibited cell migration and 3D spheroid invasion. Mechanistically, miR-214 inhibited prostate cancer cell proliferation by targeting protein tyrosine kinase 6 (PTK6). Restoration of PTK6 expression attenuated the inhibitory effect of miR-214 on cell proliferation. Moreover, simultaneous inhibition of PTK6 by ibrutinib and miR-214 significantly reduced cell proliferation/survival. Our data indicates that miR-214 could act as a tumor suppressor in prostate cancer and could potentially be utilized as a biomarker and therapeutic target

CyberKnife with Tumor Tracking: An Effective Treatment for High-Risk Surgical Patients with Stage I Non-Small Cell Lung Cancer

Published data suggests that wedge resection for stage I non-small cell lung cancer (NSCLC) is associated with improved overall survival compared to stereotactic body radiation therapy. We report CyberKnife outcomes for high-risk surgical patients with biopsy-proven stage I NSCLC. PET/CT imaging was completed for staging. Three-to-five gold fiducial markers were implanted in or near tumors to serve as targeting references. Gross tumor volumes (GTVs) were contoured using lung windows; the margins were expanded by 5 mm to establish the planning treatment volume (PTV). Treatment plans were designed using a mean of 156 pencil beams. Doses delivered to the PTV ranged from 42 to 60 Gy in three fractions. The 30 Gy isodose contour extended at least 1 cm from the GTV to eradicate microscopic disease. Treatments were delivered using the CyberKnife system with tumor tracking. Examination and PET/CT imaging occurred at 3 month follow-up intervals. Forty patients (median age 76) with a median maximum tumor diameter of 2.6 cm (range, 1.4–5.0 cm) and a mean post-bronchodilator percent predicted forced expiratory volume in 1 s (FEV1) of 57% (range, 21–111%) were treated. A median dose of 48 Gy was delivered to the PTV over 3–13 days (median, 7 days). The 30 Gy isodose contour extended a mean 1.9 cm from the GTV. At a median 44 months (range, 12–72 months) follow-up, the 3 year Kaplan–Meier locoregional control and overall survival estimates compare favorably with contemporary wedge resection outcomes at 91 and 75%, respectively. CyberKnife is an effective treatment approach for stage I NSCLC that is similar to wedge resection, eradicating tumors with 1–2 cm margins in order to preserve lung function. Prospective randomized trials comparing CyberKnife with wedge resection are necessary to confirm equivalence

CyberKnife with Tumor Tracking: An Effective Treatment for High-Risk Surgical Patients with Single Peripheral Lung Metastases

Standard treatment for operable patients with single peripheral lung metastases is metastasectomy. We report mature CyberKnife outcomes for high-risk surgical patients with biopsy proven single peripheral lung metastases. Twenty-four patients (median age 73 years) with a mean maximum tumor diameter of 2.5 cm (range, 0.8–4.5 cm) were treated over a 6-year period extending from September 2004 to September 2010 and followed for a minimum of 1 year or until death. A mean dose of 52 Gy (range, 45–60 Gy) was delivered to the prescription isodose line in three fractions over a 3–11 day period (mean, 7 days). At a median follow-up of 20 months, the 2-year Kaplan–Meier local control and overall survival rates were 87 and 50%, respectively. CyberKnife with fiducial tracking is an effective treatment for high-risk surgical patients with single small peripheral lung metastases. Trials comparing CyberKnife with metastasectomy for operable patients are necessary to confirm equivalence

Rationale for Stereotactic Body Radiation Therapy in Treating Patients with Oligometastatic Hormone-Naïve Prostate Cancer

Despite advances in treatment for metastatic prostate cancer, patients eventually progress to castrate-resistant disease and ultimately succumb to their cancer. Androgen deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer and has been shown to improve median time to progression and median survival time. Research suggests that castrate-resistant clones may be present early in the disease process prior to the initiation of ADT. These clones are not susceptible to ADT and may even flourish when androgen-responsive clones are depleted. Stereotactic body radiation therapy (SBRT) is a safe and efficacious method of treating clinically localized prostate cancer and metastases. In patients with a limited number of metastatic sites, SBRT may have a role in eliminating castrate-resistant clones and possibly delaying progression to castrate-resistant disease

Predictors of multidomain decline in health‐related quality of life after stereotactic body radiation therapy (SBRT) for prostate cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136687/1/cncr30519_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136687/2/cncr30519.pd

Improved Irritative Voiding Symptoms 3 Years after Stereotactic Body Radiation Therapy for Prostate Cancer

Background: Irritative voiding symptoms are common in elderly men and following prostate radiotherapy. The impact of hypofractionated treatment on irritative voiding symptoms has not been determined. This study sought to evaluate urgency, frequency and nocturia following SBRT for prostate cancer. Methods: Patients treated with SBRT monotherapy for localized prostate cancer from August 2007 to July 2011 at Georgetown University Hospital were included in this study. Treatment was delivered using the CyberKnife® with doses of 35 Gy-36.25 Gy in 5 fractions. Patient-reported urinary symptoms were assessed using the International Prostate Symptom Score (IPSS) before treatment and at 1, 3, 6, 9, 12 months post-treatment and every 6 months thereafter.Results: 204 patients at a median age of 69 years received SBRT with a median follow-up of 4.8 years. Prior to treatment, 50.0% of patients reported moderate to severe lower urinary track symptoms and 17.7% felt that urinary frequency was a moderate to big problem. The mean prostate volume was 39 cc and 8% had prior procedures for benign prostatic hyperplasia (BPH). A mean baseline IPSS-irritative score of 4.8 significantly increased to 6.5 at 1 month (p 8) at baseline, the mean IPSS-I decreased from a baseline score of 6.8 to 4.9 at three years post-SBRT. This decrease was both statistically (p < 0.0001) and clinically significant (MID = 1.45). Only 14.6% of patients felt that urinary frequency was a moderate to big problem at three years post-SBRT (p = 0.23).Conclusions: Treatment of prostate cance