Project 1: Identifying new therapeutic avenues to selectively target tumors with uncontrolled mTORC1 activation

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Project 1 – Abstract While mTORC1 is activated in a growth factor-independent manner in most human cancers and is believed to contribute to the uncontrolled anabolic growth of tumors, mTOR inhibitors such as rapamycin and its analogs (rapalogs) have had limited clinical success as anti-tumor agents. Furthermore, even in settings in which tumors respond favorably to rapalogs, such as with the genetic tumor syndrome tuberous sclerosis complex (TSC), the effects are reversible, with rapid tumor regrowth upon halting treatment. This limited response is due, at least in part, to the strictly cytostatic nature of rapalogs. In order to identify therapeutic strategies to improve on mTOR inhibitors in both tumor syndromes and sporadic cancers, we must systematically define the molecular response to mTOR inhibitors inherent to cells and tumors. Thus, in this project, we use both hypothesis-driven and unbiased omics approaches to reveal the nature and consequences of network-wide changes in transcription (Aim 1), tumor metabolism (Aim 2), and protein kinase signaling (Aim 3) upon mTORC1 activation and inhibition. Our approaches combine reductionist cell and tissue models in Drosophila, where the mTOR signaling network is very well conserved, with syngeneic mouse tumor models driven in part by uncontrolled mTORC1 signaling. Within the broader context of this P01, this project is discovery-based and foundational to the overarching goal of the program to define and target the signaling network that connects the hamartoma syndrome tumor suppressors and mTORC1, impacting both genetic tumor syndromes and the majority of sporadic cancers. The novel candidate targets and mechanisms revealed through our project serve as a key point of integration for all 3 projects.