Funded Projects

James Fund donors are funding some of the most promising research in the field of childhood cancer.  We greatly appreciate your support are proud to report that the $547,000 you donated last year was matched, dollar for dollar, by the Stem Cell Network of Canada!

The seed grants James Fund donors funded years ago have contributed much data to the world’s knowledge about neuroblastoma and other groups are joining in to help develop those promising findings.  Thank you to all our funding partners, both large granting agencies and neuroblastoma family groups, for your confidence in our work.

In 2011, The James Fund funded the following projects:

  1. The Stem Cell Network funded David Kaplan for approximately $500,000 over the next three years for neuroblastoma drug discovery, matched with $500,000 by the James Fund and $100,000 from Solving Kid’s Cancer. Sam’s Day and Shania’s Sunflower of Hope are also partners for this project.
  2. The Canadian Cancer Society funded Meredith Irwin for about $400,000 over the next three years to look for new drugs for neuroblastoma.
  3. The Terry Fox Cancer Institute and Ontario Institute for Cancer Research funded David Kaplan for $200,000 for neuroblastoma drug discovery. The James Fund was a partner on these greats.
  4. Solving Kid’s Cancer funded David Kaplan for $100,000, matched by the James Fund, for a drug discovery collaboration with Boehringer Ingelheim to bring one of their adult cancer drugs to the clinic for kid’s cancer.
  5. Solving Kid’s Cancer funded Sylvain Baruchel for $120,000 for a rapamycin clinical trial, matched by the James Fund.
  6. The James Fund, in the amount of $223,400, funded, seven trainees in four SickKids neuroblastoma research laboratories, with the fellowships called James Fund Fellowships in Neuroblastoma Research.
  7. The James Fund funded $145,892 in equipment crucial to neuroblastoma research efforts in 5 SickKids laboratories.
  8. Natalie Grinshtein (trainee in the Kaplan laboratory) received a fellowship from the Canadian Institute for Health Research of $40,000 per year for three years for neuroblastoma research. Lilah’s Fund and the James Fund are partners in funding Natalie’s salary and research project.

Within Canada, James Fund researchers work closely with groups at U. British Columbia, U. Calgary, U. of Winnipeg, McMaster University, and Children’s Hospital of Eastern Ontario in Ottawa.

 

JAMES FUND FELLOWSHIPS FOR NEUROBLASTOMA RESEARCH – 2011/12

The James Fund is committed to providing opportunities for brilliant young researchers to further their careers in the field of neuroblastoma research.  This year we are very proud to fund seven fellowship
awards.

1.  LOEN HANSFORD (DAVID KAPLAN LAB)

We believe that neuroblastoma (NB) cells that spread to the bone marrow disguise themselves in this foreign environment by modifying their cell surfaces so that they look like blood cells, the cells that would normally reside in that niche. In the past year we identified NB tumour-initiating cells (TICs) that looked like blood cells when in the bone marrow of patients and that responded to drugs commonly used to treat blood cancers like leukaemia and lymphoma both in the laboratory and in animal models. Unfortunately while the manuscript was in review, we discovered that the cells we had isolated from the bone marrow of patients was the result of a cultural artifact, that is, they were normal blood cells that had been made to become immortal by becoming infected with the Epstein-Barr Virus (EBV). The artifact caused by the infection of bone marrow-derived NB cells was responsible for the features of these cells that made them look like blood cells. Following this discovery, we have discarded our old NB TIC lines and have worked hard to try to isolate new bone marrow-derived TICs that are free of EBV-infection and which look like blood cells despite the fact that they originated from a neural tumour. We have recently isolated two new TIC lines from the bone marrow of NB patients that are free from EBV-infection (and thus the associated artifact) and appear to express proteins that would be present on blood cells in addition to proteins that are unique to NB cells. We are currently characterizing our new TIC lines to show that these cells evade treatment by disguising themselves as blood cells, are asking how these cells change their disguise as they move throughout the body, and asking whether this knowledge will help design better therapeutic strategies for patients with metastatic NB.

2.     KELLY FATHERS (DAVID KAPLAN LAB)

Neuroblastoma (NB) is the most frequent cancer diagnosed in the first year of life and despite intensive therapy, accounts for 15% of all pediatric cancer related deaths. NB is highly variable, as some tumours  pontaneously regress, whereas others, particularly in children over one year of age, spread throughout the body (metastasize) and are associated with poor outcome. Metastasis is a key reason for the lack of success in cancer therapy and a major cause of mortality in human cancer. Metastatic cancer cells are genetically different from those found within the primary tumour, making them difficult to kill using conventional therapy. The goal of this project is to identify specific genes and proteins within metastatic NB cells that represent potential therapeutic targets. Using NB cancer cells and mouse models, I will study the spread of NB to bone, liver and brain, which are common metastatic sites in children suffering from NB. Genetic differences between cancer cells found in the metastatic sites will be studied and their importance for the spread of NB will be assessed. This project will provide information that could be valuable for the design and implementation of targeted therapeutic drugs for NB and its metastases.

3.   SUSHIL KUMAR (SYLVAIN BARUCHEL LAB)

The Antitumor Efficacy of Combination of Antiangiogenic Drugs with Low Dose Metronomic Chemotherapy and Hypoxia Activated Prodrugs in Pediatric Preclinical Tumor Models

Though the survival rate in childhood cancers is comparatively higher than adult cancers, unacceptable mortality is still prevalent in advanced cases of some childhood cancers. Hence we are investigating alternate strategy i.e. antiangiogenic therapy, in mouse models of pediatric solid tumors. The hypothesis is that antiangiogenic therapy blocks angiogenesis, the process of blood vessel formation in the tumor tissue, thereby starve tumor cells. Single agent antiangiogenic therapies have limited efficacy, therefore need to be combined with other agents.

The first type of combination therapy, which we are investigating, is the combination of antiangiogenic drugs with Low Dose Metronomic (LDM) Chemotherapy. LDM therapy is the administration of conventional anticancer agents in lower doses for a prolonged period of time, is itself an antiangiogenic therapy. Combining LDM therapy with antiangiogenic drugs enhances the efficacy of either drugs. Here we are comparing the efficacy of the combination of LDM topotecan and antiangiogenic drug pazopanib, with the efficacies of either single agents in the mouse models of neuroblastoma and pediatric sarcoma. Until now, the combination has demonstrated significantly higher antitumor efficacy, in terms of tumor growth reduction and survival enhancement in the mouse models of neuroblastoma, osteosarcoma and rhabdomyosarcoma. We are further investigating the mechanism of action and optimum duration of our antiangiogenic therapies by studying the effect of resultant hypoxia (condition characterized by low oxygen) on the expression of angiogenic and apoptotic genes.

The second type of therapy under investigation is the combination of antiangiogenic agent with Hypoxia Activated Prodrug (HAP) in mouse models of neuroblastoma and osteosarcoma.  HAPs preferentially distribute and activate in the hypoxic zones of tumor (low in oxygen) and destroy cancer cells .

4.   PAULA MARRANO (PAUL THORNER LAB)

Identification of genetic changes in the ‘nodular ganglioneuroblastoma’ subtype of neuroblastoma. 

There is a subtype of neuroblastoma called nodular ganglioneuroblastoma (NGNB) which represents less than 10% of neuroblastoma cases but is the subtype with the worst prognosis, the reasons for which are poorly understood.  NGNB consists of two types of cells in patient’s tumors, one responsible for the poor prognosis, and another that is not harmful (called the benign portion) which in the tumor becomes two much less harmful cell types, called ganglion cells and Schwann cells.  Our objective is to identify genetic markers unique to the malignant component that could be used clinically to predict prognosis in patients and provide areas of the human genome to focus on in further research, to help explain the poor outcome in NGNB.  To do this we have been using a relatively new technique, which has not been used before in NGNB, to compare the genetic material of the harmful neuroblastoma and of the benign component in NGNB. By this approach we were able to identify changes in the overall DNA of the two components.  We then used a different technique which allows us to check these changes in each cell in the tumor.  We found that ganglion cells in the benign component possess the same genetic changes as the neuroblastoma cells, whereas the Schwann cells do not. This suggests that the ganglion cells in the benign component are derived from the harmful neuroblastoma component rather than representing a separate benign and less harmful tumor cell, and that the Schwann cells are probably growing as a reaction to the tumour or could be making the harmful neuroblastoma cells differentiate into harmless ganglion cells.  This is the first demonstration of the relationships between these cell types in NGNB and goes against what was believed previously.

We now need to determine if the genetic changes we have found in NGNB can be used for diagnosis and prognosis in patients.  This will be investigated in the coming year first by examining other subtypes of  euroblastoma for these changes.  Some of these genetic changes are not known to be involved in other subtypes of neuroblastoma and may provide unique markers for NGNB and clues for its dismal biologic behaviour.  We also hope our approach will uncover clues why some cells in NGNB differentiate into less harmful cell types and not others, if all are derived from the same tumor cell. Our findings could have relevance for the more common subtypes of neuroblastoma and may aid in categorizing patient risk and treatment, and also susceptibility to this disease.

5.   MONIKA PODKOWA (MEREDITH IRWIN LAB)

Neuroblastoma (NB) is a childhood cancer that targets cells in the developing nervous system.  It is the 3rd most common cancer in children, but is the leading cause of childhood cancer mortality.  The majority of children have metastatic disease at diagnosis, where the cancer cells have already spread from a primary tumor to a secondary site, and their survival rate is approximately 35%. Very little is known about the specific genes and signaling pathways implicated in the development and spread of the disease.  My post-doctoral research is thus focused on understanding neuroblastoma cell signaling and ultimately will lead to the development of innovative therapies to target neuroblastoma.

Preventing metastasis, the spread of cancer cells from a primary tumor to a secondary site, represents an important therapeutic approach to cancer treatment. Cancer cells become metastatic because they acquire the ability to migrate and to invade other tissues.  Our research focuses on understanding the cellular mechanisms underlying neuroblastoma cell migration and will aid in the development of novel therapeutic targets.  We have identified genes and proteins required for the movement of neuroblastoma cells and are currently studying ways to inhibit these “metastasis pathways”. Normal cells die after they detach from the primary xtracellular matrix (ECM) (the tissue to which they are attached), a process termed ‘anoikis’.  Cancer cells have a unique ability to survive after detachment from their primary site while traveling through the bloodstream. Anoikis resistance is considered to be a critical step to allow tumors to metastasize or spread, and may therefore be an attractive target for therapies. We are working to identify novel chemical compounds and drugs that sensitize neuroblastoma cells to anoikis, as well as important genes and signaling pathways that regulate neuroblastoma anoikis resistance.

The James Fund Fellowship will be a critical support to allow us to pursue the identification of genes and proteins regulating the spread of metastatic disease of neuroblastoma patients.  The ultimate goal of our studies is to translate the knowledge we generate into innovative clinical therapeutic trials that will benefit patients with metastatic neuroblastoma.

6.  JENNIFER WOLTER (MEREDITH IRWIN LAB)

Despite intensive therapy, survival rates for metastatic neuroblastoma remain poor. As such, it is important to investigate new therapies that could potentially be used for treatment in the future.  While fascinating work is  currently underway in labs studying new molecular pathways with potential use in treatment, development of these compounds into viable treatment options takes years.  In our lab, we have identified existing medications that may have utility in treatment of neuroblastoma.  One of these is a cardiac glycoside related to digoxin originally used in the treatment of heart failure.  Due to the high cardiac toxicity of digoxin-like compounds, analogues were developed to decrease the toxicity while maintaining the cancer killing properties.  Another promising medication is the beta-blocker propranolol, typically used in heart disease and more recently in treatment of vascular birth defects.  I will be investigating the ability of these medications to induce neuroblastoma cell death as well as the mechanism by which they destroy neuroblastoma cells. I will then initiate mouse testing to better understand the effects of these drugs.

My work is to discover if these drugs that are currently used clinically in children (for indications other than cancer) can induce neuroblastoma cell death. This would suggest a novel therapeutic approach in the treatment of relapsed neuroblastoma.

7.  LIBO ZHANG (SYLVAIN BARUCHEL LAB)

Neuroblastoma is one of the most common pediatric tumors. Despite the advancement in therapy, high mortality is still prevalent in these two aggressive tumors. Since most current anti-tumor drugs have serious toxicities and side effects, we are investigating novel therapeutic agents which specifically targets tumor instead of normal tissues. Aiming for those unique cancer targets, we are testing different classes of novel agents in childhood tumor models. Imetelstat is a drug which inhibits the activity of telomerase which is mostly expressed in cancer cells. Therefore, Imetelstat may target specifically against tumor cells and leave most normal cells unaffected. Another novel compound, BI-6727, is an inhibitor of Polo-like kinase 1, a target that functions predominantly in cell division. Our studies show marked antitumor activity with both agents in preclinical  neuroblastoma tumor models. All these new agents have been tested in both cell culture and mouse tumor models to determine if those agents can really slow the tumor growth and block tumor cell dissemination, a hallmark of neuroblastoma. The mechanism of how those anti-tumor agents take effect and which markers can be identified to monitor the drug response will also be studied. In addition, those novels agents will be combined with known anti-tumor drugs to demonstrate if those combined therapies could result in more significant and sustained anti-tumor effect in the mouse models. In this way, my hope is to discover better therapies for future clinical trials, and eventually improve the current treatments for these deadly childhood tumors.