Overcoming Resistance to mTOR Inhibition in Pancreatic Neuroendocrine Tumors
Researcher: Eric Nakakura, MD, PhD Location: University of California - San Francisco State: California Year: 2012 Status: Finished
This grant was issued in partnership with American Association for Cancer Research
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To identify therapeutic strategies to overcome resistance to currently available mTOR inhibiting treatments using a mouse model.
In 2011, an mTOR inhibitor was approved by the US FDA to treat patients with pancreatic neuroendocrine tumors. This was an important advance however; therapeutic resistance frequently emerges over time. Models to study resistance to mTOR inhibition and strategies to overcome resistance are needed.
Dr. Nakakura’s lab has developed a new mouse model of pancreatic neuroendocrine tumors that they will use to identify therapeutic strategies to overcome resistance to currently available mTOR inhibiting treatments.
To identify mechanisms of resistance to everolimus in pancreatic neuroendocrine tumors and determine whether the novel mTOR inhibitor, INK128 can overcome them.
Evaluate the utility of (68)GA-DOTATOC PET-CT to monitor tumor response to mTOR inhibition.
For most patients with pancreatic neuroendocrine tumors, surgery, the only potentially curative treatment, is not possible because of extensive metastatic disease. Systemictherapy options for tumor control remain limited. Dysfunction of the mTOR pathway is a critical event in pancreatic neuroendocrine tumors. A partial inhibitor of mTOR, demonstrated anti-tumor activity in a phase III study leading to its approval for the treatment of pancreatic neuroendocrine tumors. However, therapeutic resistance frequently emerges. Our goal is to use a novel in vivo model of pancreatic neuroendocrine tumors to identify therapeutic strategies to overcome resistance to mTOR inhibition.
We propose to test the hypothesis that the novel drug INK128, a complete mTOR inhibitor can overcome resistance to everolimus in pancreatic neuroendocrine tumors. Our approach is transformative because 1) We have the unprecedented ability to study how to overcome resistance to everolimus in pancreatic neuroendocrine tumors using our unique animal model and a powerful new drug, and 2) We will use the radiolabeled somatostatin analog (68)Ga-DOTATOC to perform PET-CT of treated pancreatic neuroendocrine tumors in vivo. We hypothesize that this new imaging modality will permit us to follow the response to therapy in real-time.
Research Progress and Results:
The mTOR inhibitor was recently approved for patients with pancreatic neuroendocrine tumors. Over time, however, many patients develop resistance to treatment with this therapy. Dr. Nakakura’s project sought to understand how resistance develops in patients with neuroendocrine tumors and discover novel methods to overcome this resistance.
In particular, Dr. Nakakura sought to identify mechanisms of resistance to the mTOR inhibitor in pancreatic neuroendocrine tumors and to determine whether the addition of another mTOR inhibitor, INK128 can overcome it. Using a mouse model of pancreatic neuroendocrine tumors developed by his team, Dr. Nakakura studied treatment of pancreatic neuroendocrine tumors. They found that as in patients, treatment of mice resulted in the development of resistance.
Strikingly, they found that most of the time, treating resistant tumors with INK128 either halted tumor growth or shrunk tumors (11/12 cases). They also found that Ga-68-DOTATOC PET-CT accurately detects pancreatic neuroendocrine tumor growth in their mouse model.
Together, these findings from the mouse model could provide preclinical rationale to study INK128 in patients with advanced pancreatic neuroendocrine tumors who progress on standard therapy. Findings also support the use of Ga-68-DOTATOC PET-CT to follow pancreatic neuroendocrine tumor growth in patients.
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