News Article | December 15, 2016
LONDON, ON - The Retinoblastoma protein (pRB) has long been studied for its role in cell growth and the prevention of cancer. In a new study by Lawson Health Research Institute, scientists have discovered that pRB plays another, larger role with the potential to enhance therapies for cancer and other diseases such as HIV. Most of the DNA in the human genome is composed of repetitive sequences called 'junk DNA'. Many of these are leftover pieces of ancient infections. These sequences are thought to have no positive contribution to the human body and are normally kept silent. If they do replicate, they can be reinserted into the human genome where they damage genes and contribute to diseases such as cancer. Led by Dr. Fred Dick, the team of Lawson researchers is the first to discover that pRB works with another protein called EZH2 to silence repetitive sequences of DNA. EZH2 adds a tag to repetitive sequences, marking regions to be shut off or unexpressed by a cell. It appears that the retinoblastoma protein (pRB) acts as a vehicle that delivers EZH2 to those repetitive sequences. "This is a novel discovery that changes the way cancer geneticists have thought about pRB and EZH2. Most researchers never dreamt that these two proteins have thousands of locations in our DNA that they are regulating," said Dr. Dick, a scientist at Lawson and the London Regional Cancer Program at London Health Sciences Centre (LHSC). "This opens up endless avenues for therapeutics across a multitude of diseases, including anti-viral agents. It could give patients new choices in the treatment of their disease." A number of drugs are being tested to either activate pRB function or to block EZH2, focusing on the role these two proteins play in cell growth. pRB is understood to control cell growth while EZH2 can become overactive in some cancers and silence other genes that control cell growth. This new study predicts that drugs called EZH2 inhibitors may also be used to help the immune system target cancers. Blocking EZH2 will lead to expression of 'junk DNA', so cancer cells will appear to the immune system as if they are infected by a virus. The immune system can then target and kill these cells. "This discovery has significant implications for the use of immunotherapies and the importance of pRB testing in cancer diagnosis and prognosis," said Dr. Dick, also a professor in the Departments of Biochemistry and Oncology at the Schulich School of Medicine & Dentistry, Western University. "It suggests that cancers that are pRB deficient will respond better to immunotherapies since repeats will be expressed, and those that are pRB positive might respond well to a combination of EZH2 inhibitors and immunotherapies." The research also has implications for a number of other diseases. HIV is thought to hide in immune memory cells in a similar way to 'junk DNA'. Since these cells cannot be targeted by conventional treatments, patients remain HIV positive. EZH2 inhibitors could be used to reveal the virus' hiding place by forcing the virus to express. Active viral gene expression could then be targeted using drugs that are already on the market. "This study enhances our understanding of pRB's functions and its role as a tumor suppressor," said Dr. Dick. When the pRB-EZH2 complex was eradicated in a mouse model, there was no regulation of 'junk DNA' and the mice eventually developed cancer. Completely eliminating the silent repetitive sequences for long periods of time can lead to instability of the genome and formation of disease. "We have been researching pRB for years and have never seen such a significant effect. It's clear that the pRB-EZH2 complex is extremely important to both the genesis and the treatment of cancer." The study, "An RB-EZH2 Complex Mediates Silencing of Repetitive DNA Sequences", is published in the international journal, Molecular Cell. Its significance was also highlighted by Cancer Discovery. This is another example of how Lawson Health Research Institute is working to make Ontario healthier, wealthier and smarter. Lawson Health Research Institute. As the research institute of London Health Sciences Centre and St. Joseph's Health Care London, and working in partnership with Western University, Lawson Health Research Institute is committed to furthering scientific knowledge to advance health care around the world. http://www. For more information, please contact:
Percy D.B.,University of Western Ontario |
Ribot E.J.,University of Western Ontario |
Chen Y.,University of Western Ontario |
McFadden C.,University of Western Ontario |
And 4 more authors.
Investigative Radiology | Year: 2011
Objectives: The current lack of efficacy for any chemo-or molecular therapeutic in the treatment of brain metastases is thought to be due, in part, to the heterogeneous permeability of the blood-brain-barrier (BBB). Little is known about how heterogeneous permeability develops, or how it varies among individual metastases. Understanding the BBB's role in metastasis will be crucial to the development of new, more effective therapies. In this article, we developed the first magnetic resonance imaging-based strategy to detect and measure the volumes of BBB permeable and nonpermeable metastases and studied the development of altered BBB permeability in metastases in vivo, over time in a mouse model of breast cancer metastasis to the brain. Materials and Methods: Animals bearing human experimental brain metastases of breast cancer (231-BR cells) were imaged, using 3-dimensional balanced steady-state free precession to visualize total metastases, and contrast-enhanced T1-weighted spin echo with gadopentetic acid (Gd-DTPA) to visualize which of these displayed contrast enhancement, as Gd-DTPA leakage is indicative of altered BBB permeability. Results: Metastases detected 20 days after injection showed no Gd-DTPA enhancement. At day 25, 6.1% ± 6.3% (mean ± standard deviation) of metastases enhanced, and by day 30, 28.1% ± 14.2% enhanced (P < 0.05). Enhancing metastases (mid: 0.14 ± 0.18 mm, late: 0.24 ± 0.32 mm) had larger volumes than nonenhancing (mid: 0.04 ± 0.04 mm, late: 0.09 ± 0.09 mm, P < 0.05); however, there was no significant difference between the growth rates of the 2. Conclusions: A significant number of brain metastases were uniformly nonpermeable, which highlights the need for developing treatment strategies that can overcome the permeability of the BBB. The model developed herein can provide the basis for in vivo evaluation of both BBB permeable and nonpermeable metastases response to therapy. © 2011 by Lippincott Williams & Wilkins.
Bezjak A.,University of Toronto |
Rumble R.B.,Cancer Care Ontarios Program in Evidence based Care |
Rodrigues G.,London Regional Cancer Program |
Hope A.,University of Toronto |
Warde P.,Provincial Head
Clinical Oncology | Year: 2012
Intensity-modulated radiotherapy (IMRT) is an advancement in radiotherapy that uses intensity-modulated beams, which can provide multiple intensity levels for any single beam direction and any single source position, allowing shaped distributions and dose gradients with narrower margins than previously possible. IMRT is ideal for treating complex treatment volumes and avoiding close proximity organs at risk that may be dose limiting, allowing dose escalation (to improve tumour control) and/or reducing normal tissue complications (through organ at risk sparing). Given these potential advantages of IMRT and the availability of IMRT planning systems and linear accelerators, IMRT has been introduced in a number of disease sites. This systematic review examined the evidence for IMRT in the treatment of lung cancer in order to quantify the potential benefits and to make recommendations for radiation treatment programmes considering adopting IMRT. This review revealed two retrospective cohort studies reporting on cancer outcomes, which was considered insufficient on which to make evidence-based recommendations. However, due to the known dosimetric properties of IMRT and extrapolating from clinical outcomes from other disease sites, IMRT should be considered for lung cancer patients where the tumour is in close proximity to an organ at risk, where the target volume includes a large volume of an organ at risk, or in scenarios where dose escalation would be potentially beneficial while minimising normal tissue toxicity. Until randomised data are available, future research in IMRT for lung cancer should include a comprehensive prospective assessment of the relevant outcomes, including tumour control and normal tissue toxicity. © 2012.
Townson J.L.,University of New Mexico |
Lin Y.-S.,University of New Mexico |
Agola J.O.,University of New Mexico |
Carnes E.C.,Sandia National Laboratories |
And 5 more authors.
Journal of the American Chemical Society | Year: 2013
The combination of nanoparticle (NP) size, charge, and surface chemistry (e.g., extent of modification with polyethylene glycol (PEG)) is accepted as a key determinant of NP/cellular interactions. However, the influence of spatial arrangement and accessibility of the charged molecules on the NP surface vis-à-vis the average surface charge (zeta (ζ) potential) is incompletely understood. Here we demonstrate that two types of mesoporous silica nanoparticles (MSNP) that are matched in terms of primary and hydrodynamic particle size, shape, pore structure, colloidal stability, and ζ potential, but differ in surface chemistry, viz. the spatial arrangement and relative exposure of surface amines, have profoundly different interactions with cells and tissues when evaluated in vitro and in vivo. While both particles are ∼50 nm in diameter, PEGylated, and positively charged (ζ = +40 mV), PEG-PEI (MSNPs modified with exposed polyamines), but not PEG-NMe 3+ (MSNP modified with distributed, obstructed amines) rapidly bind serum proteins, diverse cells types in vitro, and endothelial and white blood cells in vivo (ex ovo chick embryo model). This finding helps elucidate the relative role of surface exposure of charged molecules vs ζ potential in otherwise physicochemically matched MSNP and highlights protein corona neutrality as an important design consideration when synthesizing cationic NPs for biological applications. © 2013 American Chemical Society.
Vincent M.,London Regional Cancer Program
Current Drug Targets | Year: 2010
Platinum-based doublet chemotherapy is now established as a standard of care in the adjuvant treatment of resected stage II and stage IIIA nonsmall cell lung cancer, and seems reasonable also in resected stage IB when the primary tumor measures ≥4 cm. Several issues remain unresolved, however, including individualized selection of both the optimal platinum (cisplatin vs carboplatin), and the optimal nonplatinum drug; and identification of patients who will not need chemotherapy ("surgically cured"), as well as patients who cannot benefit because of inherently drug resistant disease. Furthermore, while efficacy remains a priority, it is also necessary to improve the management of toxicity, both because it may compromise dose intensity and because it carries a risk of morbidity and even mortality. Other issues, such as the role of postoperative radiotherapy, the choice between neoadjuvant and adjuvant approaches, the role of targeted agents, and the possibility of harm and how it can be mediated, also merit serious attention. Finally the durability of benefit, the question of late toxicity, and the importance of smoking cessation are also open questions. I will discuss a potential role for pemetrexed in the adjuvant treatment of early stage nonsmall cell lung cancer with some of these issues in mind. © 2010 Bentham Science Publishers Ltd.
Ashworth A.,London Regional Cancer Program |
Rodrigues G.,London Regional Cancer Program |
Boldt G.,London Regional Cancer Program |
Palma D.,London Regional Cancer Program
Lung Cancer | Year: 2013
Objectives: Long-term survival has been observed in patients with oligometastatic non-small cell lung cancer (NSCLC) treated with locally ablative therapies to all sites of metastatic disease. We performed a systematic review of the evidence for the oligometastatic state in NSCLC. Materials and Methods: A systematic review of MEDLINE, EMBASE and conference abstracts was undertaken to identify survival outcomes and prognostic factors for NSCLC patients with 1-5 metastases treated with surgical metastatectomy, Stereotactic Ablative Radiotherapy (SABR), or Stereotactic Radiosurgery (SRS), according to PRISMA guidelines. Results: Forty-nine studies reporting on 2176 patients met eligibility criteria. The majority of patients (82%) had a controlled primary tumor and 60% of studies included patients with brain metastases only. Overall survival (OS) outcomes were heterogeneous: 1. year OS: 15-100%, 2 year OS: 18-90% and 5 year OS: 8.3-86%. The median OS range was 5.9-52 months (overall median 14.8 months; for patients with controlled primary, 19 months). The median time to any progression was 4.5-23.7 months (overall median 12 months). Highly significant prognostic factors on multivariable analyses were: definitive treatment of the primary tumor, N-stage and disease-free interval of at least 6-12 months. Conclusions: Survival outcomes for patients with oligometastatic NSCLC are highly variable, and half of patients progress within approximately 12 months; however, long-term survivors do exist. Definitive treatment of the primary lung tumor and low-burden thoracic tumors are strongly associated with improved long-term survival. The only randomized data to guide management of oligometastatic NSCLC pertains to patients with brain metastases. For other oligometastatic NSCLC patients, randomized trials are needed, and we propose that these prognostic factors be utilized to guide clinical decision making and design of clinical trials. © 2013 Elsevier Ireland Ltd.
Palma D.,VU University Amsterdam |
Lagerwaard F.,VU University Amsterdam |
Rodrigues G.,London Regional Cancer Program |
Haasbeek C.,VU University Amsterdam |
Senan S.,VU University Amsterdam
International Journal of Radiation Oncology Biology Physics | Year: 2012
Objectives: Patients with severe chronic obstructive pulmonary disease (COPD) have a high risk of lung cancer and of postsurgical complications. We studied outcomes after stereotactic body radiotherapy (SBRT) in patients with severe COPD, as defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, and performed a systematic review of the literature on outcomes after SBRT or surgery in these patients. Methods: A single-institution cohort of 176 patients with COPD GOLD III-IV and Stage I non-small-cell lung cancer (NSCLC) treated with SBRT was evaluated. A systematic review identified studies reporting outcomes after SBRT or surgery for Stage I NSCLC in patients with GOLD III-IV or a predicted postoperative forced expiratory volume in 1 second (FEV1) of ≤40%. Results: In the single-institution cohort, median follow-up was 21 months and median overall survival (OS) was 32 months. Actuarial 3-year local control was 89%, and 1- and 3-year OS were 79% and 47%, respectively. COPD severity correlated with OS (p = 0.01). The systematic review identified four other studies (two surgical, two SBRT, n = 196 patients). SBRT studies were published more recently and included older patients than surgical studies. Mean 30-day mortality was 0% post-SBRT and 10% after surgery. Local or locoregional control was high (≥89%) after both treatments. Post-SBRT, actuarial OS was 79-95% at 1 year and 43-70% at 3 years. Postsurgical actuarial OS was 45-86% at 1 year and 31-66% at 3 years. Conclusions: SBRT and surgery differ in risk of 30-day mortality in patients with severe COPD. Despite the negative selection of SBRT patients, survival at 1 and 3 years is comparable between the two treatments. © 2012 Elsevier Inc.
Dranitsaris G.,Caduceus Information Systems Inc. |
Vincent M.D.,London Regional Cancer Program |
Yu J.,Bayer AG |
Huang L.,Bayer AG |
And 2 more authors.
Annals of Oncology | Year: 2012
Background: This study describes a repeated measures prediction index to identify patients at high risk of ≥ grade 2 hand-foot skin reaction (HFSR) before each week of sorafenib therapy. Methods: Data from 451 patients who received a sorafenib (400 mg bid) as part of a clinical trial were reviewed (Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: 125-134). Generalized estimating equations were used to develop the final risk model. A risk-scoring algorithm (range 0-58) was then derived from the final model coefficients. External validation was then carried out on a new sample of 1145 patients who received sorafenib under an expanded access program. Results: Pretreatment white blood cell count, female gender, good performance status, presence of lung and liver metastases and number of affected organs were predictors for ≥ grade 2 HFSR. A nonlinear association between HFSR risk and treatment duration was also identified where risk was maximized at week 5 followed by a gradual decline. Before each week of therapy, patients with risk scores >40 would be considered at high risk for developing ≥ grade 2 HFSR. Conclusions: The application and planned continued refinement of this prediction tool will be an important source of patient-specific risk information for the development of moderate to severe HFSR. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
Senan S.,VU University Amsterdam |
Palma D.A.,London Regional Cancer Program |
Lagerwaard F.J.,VU University Amsterdam
Journal of Thoracic Disease | Year: 2011
Stereotactic ablative radiotherapy (SABR) is a technique that has rapidly entered routine care for early-stage peripheral non-small cell lung cancer in many countries in the last decade. The adoption of SABR was partly stimulated by advances in the so-called 'image guided' radiotherapy delivery. In the last 2 years, a growing body of publications has reported on clinical outcomes, acute and late radiological changes after SABR, and sub-acute and late toxicity. The local control rates in many publications have exceeded 90% when tumors of up to 5 cm have been treated, with corresponding regional nodal failure rates of approximately 10%. However, these results are not universal: lower control rates reported by some authors serve to emphasize the importance of quality assurance in all steps of SABR treatment planning and delivery. High-grade toxicity is uncommon when so-called 'risk-adapted' fractionation schemes are applied; an approach which involves the use of lower daily doses and more fractions when critical normal organs are in the proximity of the tumor volume. This review will address the new data available on a number of controversial topics such as the treatment of patients without a tissue diagnosis of malignancy, data on SABR outcomes in patients with severe chronic obstructive airways disease, use of a classification system for late radiological changes post-SABR, late treatment-related toxicity, and the evidence to support a need for expert multi-disciplinary teams in the follow-up of such patients. © 2011 Journal of Thoracic Disease.
Fakir H.,London Regional Cancer Program |
Gaede S.,London Regional Cancer Program |
Mulligan M.,London Regional Cancer Program |
Chen J.Z.,London Regional Cancer Program
Medical Physics | Year: 2012
Purpose: To design a versatile, nonhomogeneous insert for the dose verification phantom ArcCHECK™ (Sun Nuclear Corp., FL) and to demonstrate its usefulness for the verification of dose distributions in inhomogeneous media. As an example, we demonstrate it can be used clinically for routine quality assurance of two volumetric modulated arc therapy (VMAT) systems for lung stereotactic body radiation therapy (SBRT): SmartArc ® (Pinnacle3, Philips Radiation Oncology Systems, Fitchburg, WI) and RapidArc® (Eclipse™, Varian Medical Systems, Palo Alto, CA). Methods: The cylindrical detector array ArcCHECK™ has a retractable homogeneous acrylic insert. In this work, we designed and manufactured a customized heterogeneous insert with densities that simulate soft tissue, lung, bone, and air. The insert offers several possible heterogeneity configurations and multiple locations for point dose measurements. SmartArc® and RapidArc® plans for lung SBRT were generated and copied to ArcCHECK™ for each inhomogeneity configuration. Dose delivery was done on a Varian 2100 ix linac. The evaluation of dose distributions was based on gamma analysis of the diode measurements and point doses measurements at different positions near the inhomogeneities. Results: The insert was successfully manufactured and tested with different measurements of VMAT plans. Dose distributions measured with the homogeneous insert showed gamma passing rates similar to our clinical results (∼99) for both treatment-planning systems. Using nonhomogeneous inserts decreased the passing rates by up to 3.6 in the examples studied. Overall, SmartArc® plans showed better gamma passing rates for nonhomogeneous measurements. The discrepancy between calculated and measured point doses was increased up to 6.5 for the nonhomogeneous insert depending on the inhomogeneity configuration and measurement location. SmartArc ® and RapidArc® plans had similar plan quality but RapidArc® plans had significantly higher monitor units (up to 70). Conclusions: A versatile, nonhomogeneous insert was developed for ArcCHECK™ for an easy and quick evaluation of dose calculations with nonhomogeneous media and for comparison of different treatment planning systems. The device was tested for SmartArc® and RapidArc ® plans for lung SBRT, showing the uncertainties of dose calculations with inhomogeneities. The new insert combines the convenience of the ArcCHECK™ and the possibility of assessing dose distributions in inhomogeneous media. © 2012 American Association of Physicists in Medicine.