Nash Brain Tumour Fellowship Full Report

William Donald Nash Brain Tumour Research Fellowship
2010 - 2012 Research Project Final Report

Project title: Active-Site mTOR Inhibitors and Oncolytic Viruses against Malignant Gliomas
Project timing: July 2010 – July 2012
Research Fellow: Dr. Tommy Alain, McGill University, Montreal, Quebec

Project summary:

More effective treatments are needed for patients diagnosed with brain tumours. My project, as part of the William Donald Nash Fellowship, was to study two anti-cancer therapies with great potential against malignant gliomas. The first therapy is based on the inhibition of the kinase mTOR (mammalian target of rapamycin), a molecule highly activated in brain cancer. This molecule is also the selective target of the drugs rapamycin and newly developed active-site mTOR inhibitors (asTORi). The second therapy is a strategy in which highly selective viruses (oncolytic viruses) are used to specifically infect and kill cancer cells. Resistance to both of these therapies occurs in cancer, but combining the two approaches can result in a synergistic effect with increased therapeutic benefits. My goal was to understand the regulation of mTOR signalling, and to determine the synergistic factors between mTOR inhibition and oncolytic viruses for the treatment of brain tumours.

My studies uncovered a potentially valuable biomarker that can determine the therapeutic efficacy of mTOR inhibitors in the clinic, and provided the stepping-stones in understanding the mechanisms by which synergy occurs between mTOR inhibitors and oncolytic viruses to eliminate brain tumours.

Project findings:

The recently developed asTORi hold great promise for targeting dysregulated mTOR signalling in many cancers including brain tumours. However, due to the multifaceted nature of mTOR signalling, the identification of reliable biomarkers that can dictate efficacy is imperative for the clinical implementation of these drugs. In the course of my studies, I discovered that various cancer cells acquire resistance to asTORi by downregulating expression of the eukaryotic translation initiation factor (eIF4E) binding proteins (4E-BPs). This is important because mTOR inhibition should result in the suppression of eIF4E function through the activation of 4E-BPs. Therefore I set to determine whether lack of 4E-BPs, or dysregulation of eIF4E (frequently up-regulated in brain cancer), influence the therapeutic efficacy of mTOR inhibitors.

I found that genetic silencing of 4E-BPs or overexpression of eIF4E rendered neoplastic tumour growth largely insensitive to mTOR inhibition. Conversely, depletion of eIF4E augmented the anti-cancer effects of these drugs. This demonstrated that the anti-proliferative effect of asTORi in vitro and in vivo is significantly altered by perturbations in eIF4E/4E-BP levels, whereby an increase in the eIF4E/4E-BP ratio drastically decreases sensitivity of cancer cells to asTORi and vice versa. These data implicate that combining anti-sense therapy against eIF4E with targeted mTOR inhibition could have increased benefits against cancer, and particularly brain tumours, which often present with elevated eIF4E activity. In addition, the results propose that the eIF4E/4E-BP ratio could be considered as a predictive marker for therapeutic response to mTOR inhibitors in the clinical context. This study is part of a manuscript that has been submitted for publication and has provided direction for the project on oncolytic viruses.

My second project was to evaluate the synergistic combination of mTOR inhibition and oncolytic viruses. I previously reported that the specific inhibition of mTOR by rapamycin, limits innate immune responses of brain tumour cells, and allows for increased oncolytic viral infection resulting in increased therapeutic benefits. Using the novel asTORi, I found a better suppression of innate anti-viral responses in brain tumour cells, and that the treatment with asTORi enhanced oncolysis by Herpes Simplex Virus-1 (HSV-1).

Related to my concurrent study, I found that the elevated activity of eIF4E in brain tumour cell lines is a critical factor that mediates synergy between mTOR inhibition and oncolytic viruses. Overall, these findings reveal the important roles that mTOR/eIF4E play in type-I IFN signalling and the translation of viral mRNAs, and propose to combine asTORi with oncolytic viruses for the treatment of cancers with elevated eIF4E expression. This study is part of a manuscript under preparation and mouse models of brain cancers are currently being evaluated.

With ongoing clinical trials including phase III trials using oncolytic viruses for the treatment of cancers, as well as the asTORi presently undergoing extensive clinical developments, their synergistic combination may represent an exciting novel strategy to treat brain tumours. Further research into molecular targets and mechanisms involved are in progress, with the hope that this approach will eventually be explored in the clinical setting.

Impact of the Fellowship:

The William Donald Nash Fellowship had a great impact on my career. It allowed me to pursue my research in the area of brain tumours, which I hope to continue as an independent investigator. During the course of my Fellowship, I presented my work in several national and international conferences, I also participated in several other studies that resulted in a number of publications (listed below). These additional studies brought significant new knowledge on the translation dysregulation in cancer and offered a better understanding of how this process can be targeted against malignant diseases.

As part of my Fellowship, I set up a number of active collaborations with members of the Canadian Oncolytic Virus Consortium, particularly with the laboratories of Drs. John Bell, David Stojdl and Jean-Simon Diallo in Ottawa, and the laboratories of Drs. Brian Lichty and Karen Mossman at McMaster University. Our team grants received funding from the Terry Fox New Frontier Program in Cancer. Additionally, I initiated collaborations with Drs. Metrakos and George Zogopoulos at the Royal Victoria Hospital in Montreal on studies of neuroendocrine cancers. We successfully received funding by the Cancer Research Society for these projects.

I am very grateful for the funding I received from the William Donald Nash Fellowship of the Brain Tumour Foundation of Canada. I wish to deeply thank the Nash family for their support of my studies, and the Brain Tumour Foundation of Canada for their incredible work in promoting scientific research.

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