Grants and Contracts Details
Lung cancer is not only the leading cause of cancer-related deaths in United States but also a disease that disproportionally affects military members and veterans due to high smoking rates and exposure to environmental carcinogens. The high mortality rate is not only due to lack of effective early detection but also to poor tumor response to currently available therapies, especially at the late stage of this disease. The emergence of targeted therapeutics against oncogenic alternation has fundamentally changed the treatment paradigm in lung cancer. A new subset of lung cancer in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was recently identified in which Rapamycin-insensitive companion of mTOR (Rictor) gene is amplified. Treatment of Rictor up-regulated lung cancer cells showed that these cells are more sensitive to mTORC1/C2 dual inhibitors than mTORC1-specific inhibitors. However, mTORC1 inhibition induces feedback activations of cell survival and metastasis and mTOCR1-specific inhibitors show very limited response in lung cancer patients. By contrast, mTORC2-specific inhibition has the advantage of not perturbing the mTORC1-dependent feedback loop, offering the intriguing potential for a novel therapeutic. Unfortunately, this idea has not been rigorously examined yet. This proposal builds on exciting preliminary data that a novel RBD peptide specifically inhibits mTORC2 but not mTORC1 activity. The RBD peptide, thus, provides a unique tool to study the effects of specific inhibition of mTORC2 activity on lung cancer cell invasion and metastasis. The central hypothesis is that RBD peptide preferentially suppresses invasion and metastasis in Rictor-amplified lung cancer. To test this hypothesis, two specific aims are proposed: i) establish that Rictor-amplified lung cancer cells are sensitive to migration and invasion suppression by RBD peptide via mTORC2-specific inhibition; ii) validate that mTORC2-specific inhibition by TAT-RBD peptide preferentially suppresses metastasis of Rictor-amplified lung cancer in mice. The accomplishment of the proposed study will not only demonstrate the importance of mTORC2-specific inhibition on the invasion and metastasis in Rictor-amplified lung cancer but also guide us to develop therapeutic mTORC2-specific inhibitor either by modification of RBD peptide or screening small molecule compounds.
|Effective start/end date||7/1/21 → 6/30/23|
- Army Medical Research and Materiel Command: $153,000.00
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