Pharma Strategy Blog

Yesterday, I covered some of the key pathways and kinases associated with cell energy metabolism, LKB1 and AMPK.  These, together with Insulin-like Growth Factor-I (IGF-I) and the insulin receptor (IR), appear to play important roles in the broader regulation of energy and homeostasis.  Experimental evidence suggests that an overexpression of IGF-I is implicated in pancreatic tumours, for example. Increased IGF-II and decreased IGF binding protein (IGFBP)-3 serum concentrations have also been linked to a number of other cancers (see journal link below).

If we look at the IGF-IR pathway, we can see more clearly how they all interlink and how mTOR, LKB1 and AMPK may all be a critical part of the process:

Source: Tao et al., (2007)

Research conducted over the past two decades has shown the importance of the type 1 insulin-like growth factor receptor (IGF-1R) in tumorigenesis, metastasis, and resistance to existing forms of cancer therapy. We also now know that feedback and cross-talk between IGF1R and IR can exist, driving hyperglycemia and free insulin production, as shown in a previous post regarding IGF-1R inhibition with figitumumab.  

Clearly, there are drugs commercially available that reduce hyperglycemia in diabetes, so the next logical step would be to see what happens if they were to be used in cancer patients or people with a very high risk for developing cancer.

Background:

The journal Cancer Prevention Research has just published an interesting series of research papers around metformin, a generically available oral biguanide for the treatment of Type II diabetes, in cancer prevention.  An excellent overview to the topic was covered in a comprehensive review of metformin for oncology applications by Michael Pollak, which is well worth reading.

In short, metformin was originally derived from a plant extract from the French lilac and activates AMPK in the liver.  This means that it plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose.  In diabetes, metformin therefore improves hyperglycemia primarily through its suppression of hepatic glucose production, ie gluconeogenesis. 

If we accept the research that shows high levels of free IGFI (from the higher IGF-I/IGFBP-3 molar ratio) are important in cancer growth, then it makes logical sense to see what effects taking metformin might have on cancer prevention and risk reduction in animal models and humans.

Effect of metformin on lung cancer

Memmot et al., published a paper entitled, "Metformin Prevents Tobacco Carcinogen– Induced Lung Tumorigenesis" in Cancer Prevention and Research. The idea was that activation of the mammalian target of rapamycin (mTOR) pathway is an important and early event in tobacco carcinogen–induced lung tumorigenesis, thus therapies that target mTOR might be effective in the prevention or treatment of lung cancer.  Since metformin activates AMPK, which in turn inhibits mTOR, they decided to investigate the possibilities in a mouse model.  The mice were given a known cancer causing carcinogen, nitrosame ketone (NNK) and a group were treated with metformin and compared to controls (no treatment).

What they found was startling:

"Oral administration of 1 or 5 mg/mL metformin decreased lung tumor burden in mice by 38% and 53%, respectively."

What happened to the control mice who did not receive metformin? 100% of them developed tumorigenesis.  To put these findings into perspective:

"The steady-state levels of metformin in mice given 5 mg/mL are similar to those in diabetic patients using metformin, suggesting the possibility that clinical prevention of lung cancer could be achieved with standard oral dosing."

Unsurprisingly even greater results were observed with direct intravenous metformin:

"intraperitoneal administration of metformin was more effective than oral administration and decreased tumor burden by 72%."

Overall, the researchers found that inhibition of the mTOR pathway in tumours was associated with decreases in levels of circulating IGF-I and insulin, which may well explain the dramatic results they saw with metformin.

Effect of metformin on colorectal cancer

Animal models are all very well, but what about human data? Japanese researchers have now reported the first study of metformin in people without diabetes, albeit on a small scale. Hosono et al., published an article, "Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial" after their earlier work in rodents. Rectal aberrant crypt foci (ACF) are an endoscopic surrogate marker of colorectal cancer, essentially an early precursor to malignant disease.

This work looked at prospectively randomized people without diabetes (n=26) with ACF to either treatment with metformin (250 mg/d, n=12) or no treatment (control, n=14).  The initial results are promising:

"At 1 month, the metformin group had a significant decrease in the mean number of ACF per patient (8.78 ± 6.45 before treatment versus 5.11 ± 4.99 at 1 month, P = 0.007), whereas the mean ACF number did not change significantly in the control group (7.23 ± 6.65 versus 7.56 ± 6.75, P = 0.609)."

In other words, this is the first reported trial showing that metformin can inhibit colorectal carcinogenesis in man. It also provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal ACF formation and may be a potentially useful agent for early cancer chemoprevention.

Conclusions

In an accompanying editorial, Engelman and Cantley provided some useful commentary on the underlying pathways and highlighted the promise of metformin for cancer prevention and therapy in the lung and other sites.

Of course, no pharma company is going to sponsor large scale epidemiology trials as metformin is now available generically, but given the prominence given to chemoprevention by Harold Varmus in his NCI acceptance speech earlier this year, perhaps we will see some progress from both the NCI and the NIH in this field. It's really a public health issue that needs a broader perspective than individual companies can offer alone.

We all intuitively know that preventing or catching cancer as early as possible will likely yield better long term outcomes for patients than treating end-stage metastatic disease with highly expensive therapies.

Additional References:

Douglas JB, Silverman DT, Pollak MN, Tao Y, Soliman AS, & Stolzenberg-Solomon RZ (2010). Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 Molar Ratio and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology PMID: 20699371

Tao Y, Pinzi V, Bourhis J, & Deutsch E (2007). Mechanisms of disease: signaling of the insulin-like growth factor 1 receptor pathway–therapeutic perspectives in cancer. Nature clinical practice. Oncology, 4 (10), 591-602 PMID: 17898809

Chitnis MM, Yuen JS, Protheroe AS, Pollak M, & Macaulay VM (2008). The type 1 insulin-like growth factor receptor pathway. Clinical cancer research : an official journal of the American Association for Cancer Research, 14 (20), 6364-70 PMID: 18927274

Douglas JB, Silverman DT, Pollak MN, Tao Y, Soliman AS, & Stolzenberg-Solomon RZ (2010). Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 Molar Ratio and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology PMID: 20699371