Targeting the unique metabolic vulnerabilities of lung cancer
Abstracts
Initial Award Abstract |
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Cancer cells must adapt and change in order to survive the challenging environment of a tumor. Ultimately, the most aggressive and metastatic tumors are those that are able to switch back and forth to evade the effects of therapy. One aspect of this involves cancer cell metabolism, which is how cells can convert nutrients into energy that fuel their growth and spread. Cancer cells can use two main types of metabolism depending on the presence or absence of oxygen. In the absence of oxygen, glycolysis can break down the sugar glucose into energy that the cell can use. In contrast, oxidative phosphorylation or OXPHOS uses oxygen to generate energy.
Unlike normal healthy cells in the body, cancer cells are thought to utilize glycolysis, which has led many to the assumption that OXPHOS is downregulated in all cancers. However, recent studies have shown that OXPHOS can be also upregulated in certain cancers, including leukemias, lymphomas, pancreatic cancers, melanoma, and endometrial carcinoma. OXPHOS inhibitors could therefore be used to target certain cancer subtypes in which OXPHOS is upregulated.
There is already some evidence that tobacco-related cancers may show a unique metabolic profile. Cigarette smoking is known to change how lung cells generate energy, making them more reliant on the OXPHOS pathway. Cigarette smoking also promotes a process known as epithelial to mesenchymal transition (EMT), which itself has been implicated as a trigger for lung cancer cells to shift to an OXPHOS-dependent state. Therefore, I will test the hypothesis that attacking the OXPHOS pathway may be particularly effective against lung cancer cells that have been stressed by cigarette smoking and/or cancer therapy.
The overall objectives of my postdoctoral fellowship proposal are to define how lung cancers can become addicted to OXPHOS and to determine whether this enhances their sensitivity to agents that interfere with the OXPHOS pathway. This fellowship will strengthen my understanding of fundamental cancer cell biology and take advantage of Dr. Cheresh lab's expertise and tools required to study lung cancer progression and response to therapy. Combining this with my own background in cancer cell metabolism will provide me with a path toward an independent research career. |
