Clinical Targeting of IGF-1 / Insulin / Signaling via the PI3K / AKT / mTOR Pathway to Treat Breast and Prostate Cancer
| Period from: | 2008-10-01 to 2010-09-30 |
| Principal Investigators: | Dr. Michael Pollak |
| Co-Investigators: | Nahum Sonenberg; Michel Tremblay |
| Institution: | McGill University |
| Department: | Medicine and Oncology |
| Program: | Research Project |
| Abstract: |
Metformin, an inexpensive generic drug which is used as a first line treatment for Type 2 diabetes, has also been associated with a decrease in cancer incidence in diabetics. The objective of this program is to investigate strategies to target the insulin growth factor 1 (IGF-1) / insulin signaling pathway, and to launch a clinical study to investigate the effectiveness of Metformin treatment against breast and prostate cancers.
We have shown that Metformin acts as a growth inhibitor rather than an insulin sensitizer for breast cancer cells. Our research indicates that the inhibition of cancer growth may result from direct (AMP kinase pathway activation) and indirect (reduction of insulin levels) mechanisms. Although early stage clinical development of IGF-1 receptor antagonists is underway commercially, our study will target clinical development of an approved drug, Metformin, as a potential therapy (monotherapy or in combinations) for cancer prevention and treatment for the following reasons:
- IGF-1R inhibition alone may not be enough to maximally inhibit tumour growth. Modulation of insulin receptor signaling may be necessary since a recent study indicates that IGR-1R blockade might lead to reactive increase in insulin sensitivity
- The "obesity epidemic" implies that there are large numbers of hyper-insulinemic cancer patients that would benefit from an invention of Metformin to reduce insulin levels
- As a proven safe and effective generic drug, Metformin may provide a novel and cost-effective treatment against cancer.
Specifically we shall:
- Conduct a Phase II clinical trial to monitor pharmacodynamic and pharmacokinetic endpoints and confirm Metformin safety in breast and prostate cancer patients
- Partner with the National Cancer Institute of Cancer's Clinical Trials Group to use high-throughput tissue microarrays (TMAs) as a means of understanding the clinical impact of relevant molecular biomarkers; and
- Use mouse models to validate which cancer phenotypes are responsive to the anti-proliferative activity of Metformin, and validate pharmacodynamic and predictive Metformin response markers.
In addition, this translational program will enable the future clinical evaluation of novel Metformin combination therapies with IGF-1R antagonists and protein kinase phosphatase 1B (PTP-1B) inhibitors.
A major outcome of this study will be to prepare for public and/or private sector partnerships to conduct a large-scale clinical trial to test the efficacy of Metformin in cancer patients most likely to respond to treatment.
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| Funding Information: | |
| 2008-2009 | $355,000 |
| 2009-2010 | $505,000 |
| 2010-2011 | $150,000 |
| 2011-2012 | |
| 2012-2013 | |
| 2013-2014 | |
| TOTAL | $1,010,000 |
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