The Bigger and Bolder Weekend
We have some very exciting news to share about The Weekend to End Breast Cancer benefiting the Jewish General Hospital. Our epic journey is becoming even bigger and bolder after listening to you. Some of you have been asking why just breast cancer? The answer has been simple. Breast cancer impacts 1 in 9 women in their lifetime and that number is just too high. But new research is starting to find links between breast and gynecological cancers. In Canada, in 2007 there were over 8,000 new cases of women’s cancers including cervical, endometrial, and ovarian. Funding for these cancers is now also critical to our fight. So why not expand the power of The Weekend to include all women’s cancers? With the dollars you raise during The Weekend, these numbers can be lowered, and one day eliminated.
It’s important to be clear on this point, though. Your donor dollars will continue to exclusively fund breast cancer research, treatment, and care and your Weekend will be the same amazing event it has always been. Only now, new registrants will be able to choose the destination of their donor funds: breast cancer or other women’s cancers.
How Your Fundraised Dollars are Making an Impact
Thanks to the tremendous efforts of the “Weekend” participants, the Jewish General Hospital (JGH) has been able to accomplish the following:
- Dr. Laura Musselman, a breast surgeon from Toronto, who is also completing a PhD in sociology is the latest winner of the Weekend to End Breast Cancer Distinguished Scientist Award. Dr. Marc Tischkowitz, a medical oncologist and PhD in cancer genetics from the United Kingdom and the award's first recipient has now had his work underwritten by the Quebec government.
- Development of novel radio-tracers for PET analysis of mouse breast cancer models, to provide critical information on tumour biology. JGH is in the testing phase of molecules that were designed and synthesized in the WEBC laboratories. They are currently being tested on tumour cell lines to test their potential to provide critical information on tumour biology. This will have a significant impact on tumour control and response to treatment.
- JGH researchers are currently collecting blood samples from breast cancer patients with cancer with special tubes that were tested against blood samples from healthy volunteers in an effort to identify blood "biomarkers" that will identify which patients are most likely to respond to a particular therapy. This will allow doctors to avoid giving an ineffective and potentially toxic treatment.
- Development of new targeted drugs to treat breast cancer by chemically combining two different types of anticancer drugs into one continues. Combinations of Taxol or Doxorubicin with Herceptin are now being tested in the laboratory on breast cancer cells which express her2-neu (targeted by Herceptin). Their killing ability, in respect to agents that are not chemically combined, is being compared.
- Ongoing support for students, research scientists and post-doctoral fellows who are the most promising breast cancer researchers of the future.
- Micro-genetic analysis of cancer tissues involves the combining of two recently introduced technologies in the fight against cancer. Laser capture microdissection allows for the genetic analysis of a very small number of extremely homogeneous cancer cells dissected from tumors. Ultra-deep pyrosequencing is a much more sensitive DNA sequencing technology that for the first time can pick up subtle and unknown gene alterations in cancer tissues. By combining these two technologies for the first time we are hoping to open up new areas of understanding in the genetics of cancer.
- In 2007 we were part of an international team which identified the PALB2 gene as a potential breast cancer gene. We have subsequently identified a common PALB2 gene alteration in a number of French Canadian families with a history of breast cancer and we have now set up a service offering to test the PALB2 gene in eligible families throughout the world. We are also working on the function of PALB2 in cell models to try to understand why PALB2 gene changes cause breast cancer.
- About half of all families with a strong history of breast cancer have an alteration in the two most thoroughly investigated genes called BRCA1 and BRCA2. There are at least eight other genes that can predispose to breast cancer which we do not routinely test for in the clinic as we know less about them. This project aims to systematically look for changes in these genes in Quebec breast cancer families to determine what contribution they make to hereditary breast cancer.
Weekend to End Breast Cancer Cell Imaging Facility
Thanks to the funds raised in the Weekend to End Breast Cancer, the Segal Cancer Centre (SCC) established the WEBC Cell Imaging Facility and purchased a Confocal Spinning Disk Microscope. This ultra-sophisticated microscope will have a major impact on the research performed at the SCC. A spinning disk system allows high-resolution, multidimensional and live-cell fluorescent imaging. With this type of microscope, it becomes possible to track a tumor cell or a group of tumor cells in real time. The system can be used to identify a number of new drug targets for chemotherapies and sensitization to other cancer therapies.
New Translational Physics and Radio-Biology Laboratory equipped with WEBC funds
The type of research to be investigated in the new laboratory, equipped thanks to Weekend to End Breast Cancer funding, involves novel molecular targeted agents to combine with radiotherapy to potentiate the cytotoxic effect of ionizing radiation while sparing normal tissue.
1. Research continues into gamma-carboxylated periostin. This potential novel molecular target/marker for breast cancer is a protein expressed in most breast cancer tumours in human patients. We are working on understanding the role it plays in metastasis and possibly modulate its activity.
2. A Segal Cancer Centre First: Researchers have established 3D mammary gland cultures that mimic the ducts of normal mammary glands. The next step is to examine how Breast Tumour Kinase, an oncogene that is only expressed in breast tumours and not normal human mammary tissue, disrupts the normal architecture of these cultures.
3. Early research indicates that modification of Stat1 protein by phosphorylation in breast tumour cells is likely to be of prognostic value of the efficacy of the chemotherapeutic drug Lapatinib in the treatment of breast cancer.
4. By computer-based simulations and bio-assays using a panel of various breast cancer cellular models, 30 traditional Chinese medicinal herbs have been investigated. This lead to the discovery of several novel chemical compounds that are currently being optimized for tamoxifen-resistant breast cancer.
5. The recruitment and initial assessment of patients in a study on psychological distress, anxiety, and depression in breast cancer survivors, which takes place at the time of the radiotherapy treatment, has been completed. We are now in the process of reassessing the level of distress of the study participants at three months post-treatment.
Projects Funded by The Weekend to End Breast Cancer
In front, left to right : Drs. JianHui Wu,
Krikor Bijian (WEBC postdoctoral fellowship), Raquel Aloyz, and Koren Mann;
Back, left to right : Drs. Jacques Galipeau, Bruce Gottlieb, Esther Schirrmacher, and Stéphane Richard
Investigators: Raquel Aloyz and Marc Tischkowitz
Title: Investigating how mutations in the PALB2 gene cause breast cancer
This new gene, recently discovered by Segal Cancer Centre scientists (with WEBC funding), is associated with hereditary breast cancer. It has been added to the list of other breast cancer-related genes, such as BRCA1 and 2. This project aims to examine this new gene in greater detail.
Investigator: William D. Foulkes
Title: MicroRNA, transcriptome, and Paclitaxel response in triple negative breast cancer
This project aims to understand the behaviour of a particular sub-group of breast cancers that appear to be resistant to most treatments. These are the so-called “triple negative” tumours. Through better understanding, we will improve therapy.
Investigators: Guillaume Galbaud Du Fort, Karl Looper and Zeev Rosberger
Title: Psychological distress, anxiety, and depression in breast cancer survivors
This study, conducted by psychologists and psychiatrists, tries to understand anxiety and depression that persist even in cured patients. This is a critical aspect of surviving the disease.
Investigators: Jacques Galipeau and Mark Basik
Title: Gamma-carboxylated periostin:
a potential novel molecular target/marker for breast cancer
This project is working on a newly identified protein in breast cancer that may be useful in diagnosis and classification, but could also be the target of novel therapies.
Investigator: Antonis E. Koromilas
Title: Stat1 as a target for therapeutic intervention in breast tumorigenesis
This project builds on preliminary scientific work which suggests that this protein may be a target against which new treatments for breast cancer might be developed.
Investigator: Koren K. Mann
Title: Combination therapies to overcome mTOR inhibitor-indiced survival signals
This exciting project has tremendous potential for new breast cancer therapies against tumours that are particular in their expression of the protein mTOR. Yet another sub-group of patients will probably benefit from the more customized approach of this research.
Investigators: Richard Margolese and Mark Basik
Title: Pilot study of axillary reverse mapping in breast cancer
It may be possible to completely avoid the risks of lymphedema after surgery. This project will examine the possibility of limiting even further the axillary lymph node dissections that are needed.
Investigator: Stéphane Richard
Title: Targeting the breast tumour kinase (BRK) in breast cancer therapy
A new potential target in breast cancer, opens the opportunity for yet another entirely novel therapy. This project moves the work closer to the clinic.
Investigators: Nora Wong and Carmen Loiselle
Title: Mapping the decisional trajectory in breast cancer risk
management among BRCA1 and BRCA2 mutation carriers
How do people with higher risk of breast cancer, due to BRCA mutation, use information to guide their approach to the risk? This project combines the expertise of a senior and accomplished research nurse, together with an experienced genetic counsellor.
Investigator: JianHui Wu
Title: Mining of traditional medicinal herbs for
multi-component therapeutics against breast cancer
Dr. Wu, using a sophisticated series of computer-based algorithms, and his extensive knowledge of chemistry, examines the potential for active anti-cancer molecules in extracts of Chinese herbs.
Investigator: Mark Basik
Title: Targeting carcinoma-associated fibroblasts in breast cancer
Normal cells that surround the cancer appear to interact with the cancer cells. This project aims to determine whether this interaction can be used to control the growth of the tumour.
Investigators: Bruce Gottlieb, Mark Trifiro, Mark Basik, Tarek Bismar, and Baback Ghaizadeh
Title: Program for micro-genetic analysis of cancer tissues
This project is exploring an entirely novel approach to genetics. It is examining the significance of small differences in the gene sequence between individuals, and between cancers from different individuals.
Investigators: Esther Schirrmacher, Raquel Aloyz, and Uri Saragovi
Title: Targeted therapy for breast cancer
These three highly innovative researchers are developing a novel approach that specifically targets cancer cells and avoids normal cells. They develop small protein fragments that can identify the cancer, and attach to them lethal radio-isotopes that kill the cells to which they become attached.
Investigators: Marc Tischkowitz, Jean-Yves Masson,
George Chong, William Foulkes, and Tarek Bismar
Title: Ten genes for hereditary breast cancer estimating the contribution
of breast cancer genes in Quebec hereditary breast cancer families
Dr. Tischkowitz and his colleagues are examining the impact of mutations in a selected number of genes on breast cancer development in the Quebec population. This has implications for diagnosis and for treatment.
Arsenic Enhances mTORi Cytotoxicity
Enhancing mTORi efficacy by decreasing AKT feedback loop with arsenic trioxide.
Koren K. Mann, Cynthia Guilbert, Alessandra MS Padovani, and Wilson H. Miller Jr.
Segal Cancer Centre, Lady Davis Institute for Medical Research,
McGill University, Montreal, QC H3T 1E2
Several novel rapamycin-derivatives have entered into clinical trials as inhibitors of the mammalian target of rapamycin (mTOR). These inhibitors (mTORi) have exciting clinical activity in renal cell carcinoma, breast cancer, and some hematologic malignancies. However, there is growing evidence that the potential benefits of mTOR inhibition are limited by a feedback mechanism that results in AKT activation. While mTORi can block important growth promoting events downstream from TORC1, an increased activation of AKT may inhibit apoptotic signals. It has been postulated that the increased AKT activity resulting from mTOR inhibition is a result of increased IGF signaling or alternatively, via the second mTOR complex, TORC2, which may not be inhibited by the mTORi tested to date.
We have previously shown that arsenic trioxide (ATO) inhibits AKT activity and in some cases, decreases AKT protein expression. Therefore, we propose that combining ATO and mTORi may circumvent the AKT feedback loop and increase the anti-tumor effects of these drugs. Using a panel of breast cancer cell lines, we find that ATO, at clinically achievable doses, can enhance the inhibitory activity of the mTORi temsirolimus in some, but not all, cell lines. MCF-7, MDA-MB-468, and SKBR3, but not T47D cells, exhibit a decrease in cell number that correlates with an increase in the percentage of cells arrested in the G0/G1 phase of the cell cycle. In all these cell lines, temsirolimus treatment resulted in AKT activation, which was decreased by concomitant ATO treatment only in MCF-7, MDA-MB-468, and SKBR3 cell lines.
Recent studies show that mTORi treatment also results in activated ERK signaling, a finding we confirmed in our cell lines. ATO co-treatment decreased ERK activation, as well as total ERK protein expression, in MCF7 and SKBR3. Therefore, we propose that adding ATO to mTORi treatment may overcome the negative feedback loop by decreasing MAPK and activated AKT in addition, to the downstream targets of mTOR/TORC1.