AACR: Insulin Signaling and Cancer Development, Progression

April 17, 2015

Ahead of the 2015 AACR Annual Meeting we discuss how insulin resistance relates to current cancer therapies.

Ahead of the 2015 American Association for Cancer Research (AACR) Annual Meeting we are speaking with Michael Pollak, MD, a medical oncologist at the Jewish General Hospital in Montreal and the director of the division of cancer prevention of the department of oncology at McGill University in Montreal. Dr. Pollak conducts research on insulin signaling as it relates to cancer development and progression, a topic he will be discussing at the upcoming AACR meeting;  specifically, how insulin resistance relates to current cancer therapies.

 -Interviewed by Anna Azvolinsky 

Cancer Network: Dr. Pollak, could you describe briefly how insulating signaling is relevant to cancer and whether there are specific tumor types that seem to rely on insulin-receptor signaling for growth?

Dr. Pollak: It turns out that many cancers express the insulin receptor and some of those actually appear to benefit from insulin stimulation in the sense that the insulin causes them to proliferate more quickly. This is not something that is specific to a certain anatomical tumor type but rather it is something that occurs in a certain percentage of probably all tumor types. So for example, a sizable proportion of prostate, colon, and breast cancers are all responsive to insulin.

Cancer Network: As far as the connection of metabolic syndrome and type II diabetes, how does this tie into cancer and cancer prognosis?

Dr. Pollak: Metabolic syndrome is something that is characterized by high insulin levels. It is found in many, many people. Metabolic syndrome has become much more common as the obesity epidemic is increasing, and people who have metabolic syndrome seem to have somewhat increased risks of certain cancers and somewhat worse prognosis of cancer. And the hypothesis that many people are interested in is the notion that the high levels of insulin in the blood of these patients contributes to the worsening of the cancer burden.

Cancer Network: What are the potential issues for those patients who are diabetic and take insulin therapy and are diagnosed with cancer? Does this influence the types of therapies these patients can receive?

Dr. Pollak: Well, it is quite clear that if the drug metformin, which is commonly used for type II diabetes, is sufficient to control blood sugar-it is probably the preferred treatment for a diabetic who also has cancer. There has been lots of controversy about whether metformin actually can favorably affect cancer outcomes, and that question is now being studied in clinical trials. The interesting part about metformin is that it lowers blood sugar, but it also lowers insulin levels, and therefore it would be the preferred way to treat the diabetes if it is sufficiently potent. it is not our strongest way to control diabetes, but if it is applicable for diabetic control for certain patients who also have cancer, I would consider it the first-line diabetic treatment.

Cancer Network: There have been studies that show metformin, can improve cancer outcomes in diabetic patients. Do we know if this is applicable to the broader cancer patient population?

Dr. Pollak: Well, I would actually correct that statement a bit: there is a lot of interest in the possibility that metformin may improve cancer outcomes, but we really don't know that for sure and there are clinical trials ongoing to look at that. As a matter of fact, it is being studied intensively, there are more than 100 clinical trials that are ongoing. One of these trials is in press, and it's the first randomized trial that actually looks at the effect of metformin on cancer outcome, in this case pancreatic cancer. This was a well-conducted, placebo-controlled trial, but unfortunately it showed no benefit. The evidence that metformin may favorably affect cancer outcomes comes mainly from laboratory models and retrospective population studies that really should be regarded as hypothesis-generating rather than absolute proof-of-concept studies. So that really the idea that metformin is actually going to favorably affect outcomes in either diabetics or non-diabetics remains an active research topic and everyone in the field is looking forward to the results of the many clinical trials.

Cancer Network: And lastly as far as the metabolic effects of cancer therapies. For example, the PI3 kinase inhibitors are downstream of insulin receptor signaling, what are the effects of these on metabolism?

Dr. Pollak: Well, this is a very important point and a very interesting point. PI3 kinase pathway is one that helps to stimulate cancer growth, and so the pharmaceutical industry has made major investments to come up with PI3 kinase inhibitors and many of these are in clinical trials and some are making the transition into clinical practice. But any drug that is intended to block PI3 kinase in the tumor also has in principle, the chance of blocking PI3 kinase in other tissues including normal tissues, including classic insulin target tissues such as the liver, muscle, and fat. So if you treat a patient with a PI3 kinase inhibitor with the intent of blocking the pathway in the tumor, in general, you will also block the pathway in normal tissues which will result in a kind of insulin resistance, because the PI3 kinase pathway mediates the effects of insulin and therefore insulin will not act well and patients will have metabolic toxicities such as hyperglycemia or hyperinsulinemia.

Those metabolic toxicities that are theoretically predicted, have been seen in clinical trials. As a matter of fact, some investigators believe that those toxicities are actually a pharmacodynamics readout that the target has been successfully engaged, at least in those classic insulin target tissues. So not to overemphasize the fact, but it does show that there is an intimate relationship between cancer and metabolism and whole organism insulin metabolism, and this leads to a number of interesting research question which many people are now addressing. Another example where insulin levels are being raised everyday in clinical practice is with androgen deprivation therapy for prostate cancer. This of course benefits the patient in the short term, but it also does raise insulin levels, and there is some evidence that in the longer term raised insulin levels may contribute to the development of castration resistance. So overall, the take-home message is that insulin and insulin resistance are variables that differ between patients, that can be impacted by current treatments, and that we should pay attention to when looking for factors that influence our patients outcomes.

Cancer Network: Thank you so much for speaking with us today, Dr. Pollak. 

Dr. Pollak: A pleasure.