The importance of tumor angiogenesis in tumor progression and metastasis has been well established. The development and maturation of blood vessels in tumor are regulated by a complex interplay between pro- angiogenic and anti-angiogenic factors. A major signaling event downstream of multiple angiogenic factors in tumor vasculature is the activation of Akt, which is regulated by PDK1 and mammalian target of rapamycin (mTOR) complex 2. mTOR is a serine/threonine kinase that functions through at least two distinct classes of multi-protein complex, mTORC1 and mTORC2, regulating a diverse array of cellular processes including cell growth, survival, metabolism, and cytoskeleton dynamics. mTORC1 is extensively studied in cancer; however, relatively little is known about mTORC2, especially in tumor endothelium. We discovered that loss of mTORC2 inhibited endothelial cell proliferation and assembly in vitro and angiogenesis in vivo, using mice with endothelial cell-specific targeted deletion of Rictor, a key component of mTORC2. Our overall objectives are to determine (i) if inactivation of mTORC2 without directly targeting mTORC1 could provide substantial therapeutic benefit, and (ii) if inactivation of this pathway in blood vessels of established tumors could inhibit tumor metastasis and overcome tumor resistance to therapy.
In Specific Aim 1, we will investigate tumor progression, angiogenesis, and metastasis in both spontaneous (MMTV-Neu) and allograft (4T1) mammary tumor models. We will verify our studies in human breast cancer cells and patient-derived tumor xenografts.
In Specific Aim 2, we will elucidate mTORC2-dependent and -independent role of Rictor in endothelial cell function.
In Specific Aim 3, we will analyze therapeutic potential of inhibition of mTORC2 in breast cancer by modeling pharmacologic inhibition using Cre-ERT2 mice to assess effects of global inhibition of mTORC2 on established tumors and determine if endothelial-specific or tumor-specific mTORC2 inhibition sensitizes breast cancer cells to therapeutic agents. Together, these studies will elucidate how mTORC2 signaling affects vascular biology, tumor angiogenesis, and metastasis. Despite the promise of mTOR kinase inhibitors and mTOR-Akt dual inhibitors, these agents affect a broad signaling network and energy metabolism in the body, which may have long-term as-yet-unknown effects to human health. Targeting the mTORC2 branch of mTOR signaling pathway may offer an independent therapeutic approach with potentially lower inherent toxicities and a more acceptable therapeutic window.
Tumor blood vessels supply oxygen and nutrients to support tumor growth and facilitate tumor metastasis. A common signaling molecule that controls blood vessel formation is called mTOR, which functions through two different classes of multi-protein complex, mTORC1 and mTORC2. The aim of this project is to dissect the role of mTORC2 versus mTORC1 in tumor blood vessel, with the goal of developing mTORC2 as an alternative therapeutic target in cancer.
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