Enhancing mTOR-targeted lung cancer therapy
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Lung cancer is the leading cause of cancer-related death worldwide in both man and women. Smoking leads to most cases of lung cancer, and treatment outcomes are disappointing as the five-year survival rate for lung cancer patients has remained low and unchanged (at about 15%) over the last twenty years. In addition, conventional treatment of lung cancer has limited effectiveness. As such, new therapeutic approaches are urgently needed. Recently, targeted cancer therapies have been successful in managing patients with specific cancers. Targeted cancer therapies may possibly be more effective than other types of generalized treatment, such as chemotherapy and radiotherapy, as targeted cancer therapies focus on molecular or cellular alterations specific to cancer. In human lung cancer, the mammalian target of rapamycin (mTOR) signaling protein is commonly dysregulated as an effect of genetic aberrations of its upstream regulators. Rapamycin (from which mTOR derived its name) effectively inhibits the oncogenic mTOR pathway in cancer cells. Thus, rapamycin and its derivatives (for simplicity, we will refer to all analogs as rapamycin from here on) are being actively tested in clinical cancer patients. Unfortunately, recent clinical updates have indicated that rapamycin is not as effective as originally thought for cancer patients. One of the major reasons for this less than desirable result is that rapamycin treatment of tumor cells (including lung cancer cells) unintentionally activates other cellular oncogenic molecules, such as Akt and elF4E, through an unknown mechanism. To identify the key signaling molecule involved in this rapamycin-induced oncogenic response, we made a technological breakthrough (accompanying publications #2 &amp; #3) to simultaneously profile 6,179 regulatory sites in cellular proteins affected by rapamycin treatment (accompanying publication #1). We identified 161 cellular proteins modulated by rapamycin that were previously unknown to be regulated by rapamycin (accompanying publication #1). Among these 161 proteins, there are a number of key signaling molecules present. We screened these signaling molecules and found that one of them, CDC25B, is critical for oncogenic protein Akt activation by rapamycin in lung cancer cells (accompanying publication #1). Since blocking CDC25B can inhibit rapamycin-induced undesirable oncogenic signaling, we hypothesized that CDC25B is a drug target whose activity, when blocked, can significantly enhance rapamycin-dependent lung cancer treatment. To prove this concept, we propose to investigate whether blocking the activity of CDC25B can substantially enhance the anti-cancer effect of rapamycin in inhibiting malignant properties of lung cancer cells and blocking the development of lung tumors in animal. In addition, we will investigate the underlying molecular mechanisms involved in these mTOR inhibition-induced oncogenic events. This proposal aims to identify and study drug targets for significantly enhancing mTOR-targeted lung cancer treatment. The success of this proposal will provide proof-of-principle for a considerably more effective mTOR-targeted lung cancer treatment which will offer immediate clinical benefit to lung cancer patients.