Identifying Mechanisms of Resistance to mTOR Inhibitors in Cancer

Study Overview
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Brief Summary
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mTOR kinase is part of the mTORC1 complex that promotes cap-dependent protein translation, and part of the mTORC2 complex that activates AKT. Everolimus (Afinitor) is an allosteric inhibitor of mTOR that suppresses mTORC1 activity. Everolimus is FDA-approved for the treatment of ER+/HER2- breast cancer (in combination with exemestane), renal cell carcinoma, subependymal giant cell astrocytoma (SEGA), and neuroendocrine tumors of pancreatic origin (PNET), and is currently being tested in ongoing clinical studies in other indications. While everolimus-based therapies elicit anti-cancer effects, most cancers ultimately progress and exhibit everolimus resistance. This study will evaluate genetic mechanisms of resistance to everolimus.

Official Title
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Identifying Mechanisms of Resistance to mTOR Inhibitors in Cancer

Conditions
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Cancer

Intervention / Treatment
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* Other: n/a- this is an observational study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Treatment with everolimus (as a single-agent or in combination) for any malignancy for ≥3 months. A- Patients who are scheduled to undergo a clinically indicated tumor biopsy (as standard of care, or as part of another study) within 5 years following cancer progression on everolimus are eligible. B- Patients who already had such a biopsy procedure performed are eligible. Tumors biopsied shortly after progression on everolimus are strongly preferred. Excess tumor tissue from biopsy must be available for molecular analysis. This will include tumor tissue sufficient to make ≥5 five-micron sections; more tumor tissue is preferred. Patients currently seen at Dartmouth-Hitchcock Medical Center must be capable and willing to provide informed written consent for study participation. Patients who are no longer seen at DHMC will not be consented for use of archived tissues and data. For patients currently seen at Dartmouth-Hitchcock Medical Center, patients must be willing to provide an extra 10-20 mL of blood during a routine, clinically indicated blood draw procedure. Exclusion Criteria: none

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Other: n/a- this is an observational study|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mutations in genes encoding components of the mTOR pathway that are detected in post-everolimus tumors but not pre-everolimus tumors. |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mutations detected in plasma DNA that are present in the post-everolimus tumor but not the pre-everolimus tumor. |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mTOR, Cancer, Tumor, Everolimus, Temsirolimus, Sirolimus, Rapamycin