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Targeted Treatments for a Type of Pancreatic Cancer: Rapamycin and Other mTOR Inhibitors

Key Points

  • Treatments targeting mTOR (or the mechanistic target of rapamycin)—a protein that frequently mutates in cancer cells—revolutionized how a specific type of pancreatic cancer, known as pNET, is treated.
  • The National Cancer Institute (NCI) supported the basic research that demonstrated the remarkable anticancer effects of mTOR inhibitors.
  • Rapamycin and its next-generation drugs like everolimus represent the true strength of basic research to foster innovation that leads to life-saving advances in cancer.
  • NCI continues to be at the forefront in the fight against cancer by supporting basic research and clinical trials investigating mTOR inhibitors.

Pathway to Discovery

A growing cancer cell divides in two: mTOR inhibitors such as everolimus help regulate cellular processes in cancer.

The target of rapamycin (known as mTOR or the mechanistic target of rapamycin) is a protein that tells cells when to grow, divide, and survive. mTOR often mutates in cancer cells, leading to uncontrolled tumor cell growth. Although originally developed as an antifungal agent, rapamycin was found to substantially suppress the immune system, which led to its use for preventing the rejection of organ transplants. 

In 1972, Suren Sehgal, Ph.D., a scientist at Wyeth-Ayerst pharmaceutical company, had a hunch that rapamycin might also affect cancer cells and sent a sample to NCI for testing. The results were nothing short of astounding. As Dr. Sehgal explained in a 2001 interview in the Journal of the National Cancer Institute, "[NCI] found absolutely fantastic activity of the drug against almost all solid tumors…[in combination with chemotherapy], the anticancer effect was absolutely astonishing."

NCI quickly made rapamycin a priority drug and researchers started developing and testing similar drugs. One of them, known as RAD001, or everolimus (Afinitor), showed great promise against a variety of different cancers with a specific mutation in the mTOR signaling pathway, which regulates cellular processes.


Progressive neuroendocrine tumors of the pancreas, or pNET, is a specific type of pancreatic cancer. New ways of diagnosing pNET have contributed to twice as many patients being diagnosed with this cancer.  Although the disease is being diagnosed earlier and more often, nearly two thirds of patients with pNET are still diagnosed when the disease has already spread to other body organs or tissues. The median survival is only 27 months.

Treatment options were mostly limited to the surgical removal of abnormal tissue, until scientists discovered that the growth of pNET correlates with mTOR sending messages to cells to grow, divide, and survive. With this link established, researchers began to test everolimus.

Enhancing Cancer Care

In 2011, researchers in the Novartis Oncology Group reported the results from an international clinical trial called RAD-001 in Advanced Neuroendocrine Tumors (RADIANT-3). The study tested everolimus in patients with locally advanced pNET or metastatic low-grade or intermediate-grade pNET that had continued to progress despite previous treatment.

The study results showed that progression-free survival—the length of time during and after treatment that a patient's cancer does not get worse— was significantly longer in the group treated with everolimus as compared with the placebo-treated group. Specifically, there was a 65 percent lower risk of the disease getting worse in the everolimus group. These results were so remarkable that researchers recommended the use of everolimus as a standard of care for patients with advanced pNET.

Because of the silent nature of the disease, 65 percent of patients with pNET are diagnosed as "advanced stage" with a poor prognosis (the likely course or outcome of a disease). Everolimus represents the first effective treatment in prolonging the lives of patients with this disease.

Everolimus represents the power of basic science and research to spur innovation and lead to life-saving advances. It originated as rapamycin, an antifungal agent, and emerged as a standard of care for a deadly disease.

Turning Discovery into Health

(From left to right) Victor Velculescu, M.D., Ph.D., Bert Vogelstein, M.D., and Nickolas Papadopoulos, Ph.D., study mTOR pathway genes in pancreatic neuroendocrine tumors at Johns Hopkins University, an NCI-designated comprehensive cancer center.

Mutations in proteins that control mTOR have been associated with aggressive tumors and overall poorer outcomes in multiple cancers besides pNET. So researchers continue to investigate the molecular mechanisms involved in the deregulation of mTOR.

One recent study supported by NCI has shown that pNET tumors have mutations in other proteins involved in regulating mTOR. A better understanding of what causes pancreatic cancer and how it progresses will aid in developing more effective targeted treatments.

Other studies are looking to build on this progress by combining everolimus with other treatments, such as bevacizumab, that work in different ways to target tumors. The FDA has also approved sunitinib, another targeted treatment for pNET. Future studies investigating everolimus in combination with sunitinib could lead to more options for managing and treating pancreatic cancer.

In addition to treating pNET, mTOR inhibitors may play a role in a variety of other cancers. In fact, the FDA has approved everolimus for the treatment of some patients with renal (kidney) cell carcinoma and breast cancer. Recent groundbreaking research in mice also suggests that these inhibitors may be able to slow aging, and further studies are being performed to see the effect of mTOR inhibitors in Alzheimer's disease.

Research to Practice: NCI's Role

NCI played a key role in the discovery of the anticancer properties of rapamycin and its mechanism of action. This discovery led to research detailing the role of the mTOR protein in promoting cancer development and progression. The findings from these studies led to the development of other similar drugs and established the utility of using the option of targeted treatment.

NCI continues to be at the forefront of cancer research by funding numerous basic research studies and clinical trials investigating mTOR inhibitors.

Key Takeaway

Treatments targeting mTOR (or the mechanistic target of rapamycin) for a specific type of pancreatic cancer have given clinicians a powerful treatment tool in the fight against this cancer and has transformed treatment approaches for other cancers.

Selected Resources

Garber K. Rapamycin's resurrection: A new way to target the cancer cell cycle. J Natl Cancer Inst. 2001;93(20):1517-1519.

Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331(6021):1199-1203. [PUBMED Abstract]

Moreno A, Akcakanat A, Munsell MF, Soni A, Yao JC, Meric-Bernstam F. Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors. Endocr Relat Cancer. 2008;15(1):257-266. [PUBMED Abstract]

Thompson LA, Kim M, Wenger SD, O'Bryant CL. Everolimus: A new treatment option for advanced pancreatic neuroendocrine tumors. Ann Pharmacother. 2012;46:1212-1219. [PUBMED Abstract]

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