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PI3K Inhibitors and Keto Diet Better Than Drug Alone

Ketogenic diet

Many mesothelioma experts believe the route to better disease management — and possibly a cure — lies with drugs that target genes and cell pathways that promote cancer growth.

New research published July 4 in the journal Nature supports a novel approach for making PI3K inhibitors, medications that inhibit cancer growth, more effective.

Trials on these drugs have been mixed, and now cancer experts may know why. PI3K inhibitors seem to work poorly in the presence of high glucose (sugar) and insulin levels.

The new study in cells and mice shows reducing glucose and insulin with a ketogenic diet, popularly known as the keto diet, improves the effectiveness of PI3K inhibitors against cancer.

“While these data do not exclude insulin-independent effects of combining PI3K inhibition with anti-glycemic therapy, they demonstrate that utilizing this approach has the potential to significantly increase the therapeutic efficacy of these compounds,” the authors wrote.

PI3K inhibitors are approved for some clinical use, but not yet for mesothelioma. However, they are being studied extensively, including in mesothelioma clinical trials.

PI3K Drugs Should Work Well, Yet Often Don’t

According to cancer experts, inhibiting the PI3K enzyme should greatly reduce tumor growth in many cancer types.

Unfortunately, this hasn’t been a consistent finding in clinical trials.

According to lead author Dr. Benjamin D. Hopkins and senior author Dr. Lewis C. Cantley, both of Weill Cornell Medicine in New York City, drugs targeting PI3K may not be effective if blood sugar and insulin levels are elevated during treatment.

The new research provides support this can happen, at least in mice and cells.

Observations of elevated blood and insulin levels in cancer patients suggest this may hold true for people, too.

Patients on PI3K inhibitors develop high blood sugar levels. The body compensates by producing insulin to bring sugar down. For some patients, the body may not adapt well enough and glucose remains dangerously high.

In these cases, the drugs have to be discontinued. And even in patients who do produce enough insulin to normalize blood sugar levels, this response could be interfering with how well PI3K inhibitors work.

Proof of Concept: Diet and Glucose-Lowering Medications

To study this possibility, the authors used mice to show blood sugar and insulin levels do go up in response to these medications.

Next, the researchers used cancer cell models to test whether increases in insulin can prevent PI3K inhibitors from blocking cancer cell growth.

Several cancer cell types were treated with the drugs, with or without insulin. In the presence of insulin, the drugs didn’t work as well. Many cancer cell types continued to grow when insulin was added.

The authors also applied this approach to the animal model. They found the presence of excess insulin restarts the PI3K pathway in mice, too. This reduced the drugs’ ability to block tumor growth.

Continuing their work in mice, the researchers looked at whether keeping blood sugar levels low with a keto diet or glucose-lowering medications would improve the ability of PI3K inhibitors to treat cancer.

When a keto diet or glucose-lowering drugs were added to the mix, the mice had fewer and smaller tumors.

Researchers concluded keeping glucose and insulin low made the drugs much more effective against several cancer types in animal models. They demonstrated the keto diet was the most effective way for improving the PI3K inhibitors’ ability to reduce signals that spur tumor growth in mice.

Overactive Pathway Common in Mesothelioma

Although PI3K inhibitors were not designed specifically for mesothelioma patients, they may offer a more effective treatment avenue in the future.

Numerous studies demonstrate the PI3K pathway is overactive, or running too quickly, in mesothelioma cells. This appears to contribute to cancer growth and spread.

The new study supports the importance of new investigations of the combined approach of PI3K inhibitors and keto diet to lower insulin and glucose in cancer patients.

Will This Research Benefit Mesothelioma Patients?

For most people with mesothelioma, treatment begins with standard-of-care or best-practice therapies.

These treatments do not offer a cure for people with the asbestos-related disease.

For this reason, mesothelioma doctors continue searching for additional ways to help patients extend their lives with better treatments.

According to the Nature study, this new approach of PI3K inhibitors and a keto diet may offer this type of option.


Suzanne Dixon is a registered dietitian, epidemiologist and experienced medical writer. She has volunteered with the National Cancer Policy Forum, Oncology Nutrition Dietetic Practice Group, American Institute for Cancer Research, American Society for Clinical Oncology, The National Academies of Sciences, Engineering, and Medicine. The New York Times and Time Magazine also have reviewed her cancer patient resources. Read More

Sources
  1. Hopkins, B. D. et al. (2018). Suppression of insulin feedback enhances the efficacy of PI3K inhibitors.
    Retrieved from: https://www.nature.com/articles/s41586-018-0343-4
  2. Weill Cornell Medicine. (2018, July 4). Low-Carb, High-Fat Diet May Boost Targeted Cancer Therapy.
    Retrieved from: https://news.weill.cornell.edu/news/2018/07/low-carb-high-fat-diet-may-boost-targeted-cancer-therapy
  3. Sementino, E. et al. (2018). Inactivation of Tp53 and Pten drives rapid development of pleural and peritoneal malignant mesotheliomas. DOI: 10.1002/jcp.26830.
  4. Yamaji, M. et al. (2017). Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. DOI: 10.1002/cam4.1179
  5. Kanteti, R. et al. (2016). PI3 Kinase Pathway and MET Inhibition is Efficacious in Malignant Pleural Mesothelioma. DOI: 10.1038/srep32992
  6. Shukuya, T. et al. (2014). Identification of actionable mutations in malignant pleural mesothelioma. DOI: 10.1016/j.lungcan.2014.08.004
  7. Banerji, U. et al. (2017, October 24). A Phase 1 open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-mutated breast and gynecologic cancers. DOI: 10.1158/1078-0432.CCR-17-2260

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